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A Mellor

Publications and source records attributed to A Mellor.

At least 19 recordsLinked to original sources
PubMed2005

Isotopic composition and concentration of Pb in suspended particulate matter of the Irish Sea reveals distribution and sources.

The isotopic composition and concentration of Pb was measured in suspended particulate matter of the Irish Sea. Aerosol, surficial and pre-industrial sediment was also analysed to provide information on sources terms. Concentrations of Pb in suspended sediments were lower than previously reported which presumably reflects the international effort to reduce Pb inputs to the environment. Lead concentrations were highest in Liverpool Bay and lowest in the western Irish Sea. A significant negative relationship between Pb and salinity suggests that present inputs and the resuspension of relict lead associated with particles in areas significantly affected by freshwater discharges are the predominant sources of Pb to the Irish Sea. The isotopic composition of Pb in the stratified region of the western Irish Sea demonstrates that atmospheric sources are also significant to this region, which is consistent with current knowledge on the hydrography. Pb isotopic ratios show that water entering the Irish Sea through St George's Channel is significantly influenced by anthropogenic inputs prior to additional contamination by direct inputs to the Irish Sea.

Aerosols↗
PubMed2001

Lead and zinc in the Wallsend Burn, an urban catchment in Tyneside, UK.

This paper examines lead and zinc concentrations in topsoils and stream sediments of public access areas in an urban catchment in Tyneside, UK. It examines the extent and severity of metal contamination, explores spatial patterns in relation to urban and industrial development, and makes inferences about potential metal mobility. Total and acetic-acid extractable lead and zinc concentrations, organic content and pH were determined on 121 topsoil and 22 stream sediment samples using standard laboratory procedures. Using the lowest trigger thresholds for total lead and zinc, almost 75% and 91%, respectively, of topsoil samples were classified as contaminated; proportions were rather lower for acetic acid extractable metals. Similarly, approximately 45% and 95% of stream sediment samples were contaminated with lead and zinc, respectively. The spatial distribution of metal concentrations was characterized by a hotspot pattern, with highest values in central and southern parts of the catchment where there is a long urban and industrial history. The potential mobility of zinc is considerably greater than that of lead in both topsoils and stream sediments, and for both metals is slightly higher in the stream sediments than in the topsoils; both of these differences are statistically significant (P < 0.05). The implications of the findings in this paper for assessment and monitoring of metal contaminated areas are explored.

England↗
PubMed2001

Fat embolism.

Fat embolism syndrome is a collection of respiratory, haematological, neurological and cutaneous symptoms and signs associated with trauma and other disparate surgical and medical conditions. The incidence of the clinical syndrome is low (< 1% in retrospective reviews) whilst the embolisation of marrow fat appears to be an almost inevitable consequence of long bone fractures. There is debate over the pathogenesis of fat embolism syndrome and it seems a variety of factors interact to produce a spectrum of end organ damage. Many therapeutic interventions and prophylactic strategies have been tried with varying success. Current treatments are supportive and the condition is usually associated with a good outcome. The literature on fat embolism syndrome is extensive and this review aims to discuss the incidence, aetiology, pathophysiology, diagnosis and treatment of fat embolism.

Anemia, Sickle Cell↗
PubMed1999

Alternative splicing and hypermutation of a nonproductively rearranged TCR alpha-chain in a T cell hybridoma.

Like Ig genes, TCR genes are formed by somatic rearrangements of noncontiguous genomic V, J, and C regions. Unlike Ig genes, somatic hypermutation of TCR V regions is an infrequent event. We describe the occurrence of spontaneous hypermutation in a nonproductively rearranged TCR alpha-chain gene in a clonal T cell hybridoma that had lost its productively rearranged alpha-chain. The mutating hybridoma was eventually supplanted in culture by a nonmutating variant that had restored an open reading frame in the nonproductively rearranged TCR alpha-chain through the use of cryptic splice sites in the V alpha region. Evidence is presented for the presence of cDNA reverse transcripts of the TCR alpha-chain within the hybridoma, suggesting a role for reverse transcriptase in the generation of mutations.

Alternative Splicing↗
PubMed1999

HLA-G transgenic mice.

We have generated a number of transgenic mice using DNA segments derived from the HLA-G gene. Using these mice we have examined the pattern of expression dictated by HLA-G promoter elements in mice and shown that HLA-G functions both as a restriction element and a transplantation antigen recognized by murine T cells. In addition, we have shown that trophoblast cells expressing H-2Kb under the control of HLA-G promoter elements affect maternal T cell phenotype and responsiveness during pregnancy. Using these same HLA-G/H-2Kb transgenic mice we have shown that trophoblast cells, expressing an inducible enzyme that degrades tryptophan, protects allogeneic conceptus expressing paternally-inherited transgenes from attack by maternal T cells that leads to fetal rejection.

Animals↗
PubMed1998

Rejection of H-Y disparate skin grafts by monospecific CD4+ Th1 and Th2 cells: no requirement for CD8+ T cells or B cells.

We wished to determine whether CD4+ T cells could reject a skin graft that was discordant for a single minor transplantation Ag in the absence of CD8+ T cells or Ab. Transgenic A1(M) mice were constructed that express the rearranged V beta 8.2 and V alpha 10 TCR genes from a T cell clone that is specific for the male Ag (H-Y) in the context of H2-Ek. In addition, the RAG-1(-/-) background was bred onto these mice to eliminate any endogenous TCR rearrangements. As expected, clonal deletion was found to be complete in the thymus of male A1(M) x RAG-1(-/-) mice, while only CD4+ T cells were positively selected and found in the periphery of females. Female A1(M) x RAG-1(-/-) mice were able to rapidly reject (in <14 days) male (but not female) skin grafts in a CD4-dependent fashion. After multiple grafts, it was confirmed that no CD8+ T cells or surface Ig+ B cells were present. An immunofluorescent analysis of spleen cells after grafting showed that the majority of T cells expressed activation markers (CD44, CD25, and intracytoplasmic IL-2) and a significant proportion were making IFN-gamma and IL-4. Surprisingly, the transfer of either Th1 or Th2 CD4+ T cell lines from these mice into T cell-depleted recipients was sufficient to cause a specific rejection of male skin.

Animals↗
PubMed1998

Cushing's disease treated by trans-sphenoidal selective adenomectomy in mid-pregnancy.

The clinical course and diagnosis of a patient with Cushing's disease complicated by pregnancy is described, and the anaesthetic management of trans-sphenoidal selective adenomectomy performed during the second trimester outlined. Problems included obesity, diabetes, hypertension and a suboptimal airway. Fibreoptic awake intubation and intravenous anaesthesia were used. Insulin requirements decreased substantially after surgery. Early administration of hydrocortisone after surgery avoided the risk of an addisonian crisis but delayed biochemical confirmation of a metabolic cure.

Adenoma↗
PubMed1998

Increased resistance to Taenia crassiceps murine cysticercosis in Qa-2 transgenic mice.

We previously reported important differences in resistance to Taenia crassiceps murine cysticercosis between BALB/c substrains. It was suggested that resistance might correlate with expression of the nonclassic class I major histocompatibility complex (MHC) Qa-2 antigen; BALB/cAnN is Qa-2 negative and highly susceptible to T. crassiceps, whereas BALB/cJ expresses Qa-2 and is highly resistant. In this study, we investigated the role of Qa-2 in mediating resistance to cysticercosis by linkage analysis and infection of Qa-2 transgenic mice. In BALB/cAnN x (C57BL/6J x BALB/cAnN)F1 and BALB/cAnN x (BALB/cJ x BALB/cAnN)F1 backcrosses, the expression of Qa-2 antigen correlated with resistance to cysticercosis. Significantly fewer parasites were recovered from infected Qa-2 transgenic male and female mice than from nontransgenic mice of similar genetic background. These results clearly demonstrate that the Qa-2 MHC antigen is involved in resistance to T. crassiceps cysticercosis.

Animals↗
PubMed1996

Expression of a second receptor rescues self-specific T cells from thymic deletion and allows activation of autoreactive effector function.

Allelic exclusion at the T-cell receptor alpha chain locus is incomplete resulting in the generation of T cells that express two T-cell receptors. The potential involvement of such T cells in autoimmunity has been suggested [Padovan, E., Casorati, G., Dellabona, P., Meyer, S., Brockhaus, M. & Lanzavecchia, A. (1993) Science 262, 422-424; Heath, W. R. & Miller, J. F. A. P. (1993) J. Exp. Med. 178, 1807-1811]. Here we show that expression of a second T-cell receptor can rescue T cells with autospecific receptors from thymic deletion and allow their exit into the periphery. Dual receptor T cells, created by constitutive expression of two transgenic T-cell receptors on a Rag1-/- background, are tolerant to self by maintaining low levels of autospecific receptor, but selfreactive effector function (killing) can be induced through activation via the second receptor. This opens the possibility that T cells carrying two receptors in the periphery of normal individuals contain putatively autoreactive cells that could engage in autoimmune effector functions after recognition of an unrelated environmental antigen.

Animals↗
PubMed1996

T cell suppression in transplantation tolerance through linked recognition.

Allogeneic tissues transplanted to mice treated with CD4- and CD8-specific Abs are often accepted indefinitely due to the induction of immunologic tolerance. When transplantation tolerance was induced to grafts mismatched at multiple minor histocompatibility loci, Ag specificity was inferred because third party grafts, mismatched at the MHC, were rejected normally. However, some "third party" grafts were either accepted, or rejected more slowly. Tolerant mice possess CD4+ cells, which suppress rejection by T cells reacting to the same grafts. Therefore, we hypothesized that tolerated third party grafts might share Ags with the original tolerizing graft, and that these Ags are a target for such suppression. To test this idea, we tolerized mice to a set of minor Ags (B10 minors) and challenged them with third party grafts that carried those minors, as well as an additional strong transplantation Ag, the class I MHC molecule, H-2Kb. This class I molecule acts as a good target for rejection in both naive mice and in mice tolerized to B10 minors. However, when this third party class I molecule is provided "linked" to those B10 minors on an F1 graft, rejection was significantly impaired. The data suggest that suppression within tolerant animals operates locally (perhaps on the same APC) via linked recognition. In addition, our preliminary findings suggest that suppression via linked recognition can also lead to tolerance to the third party Ag.

Animals↗
PubMed1996

T cell tolerance and activation to a transgene-encoded tumor antigen.

Much has been learned in recent years concerning the nature of tumor antigens recognized by T cells. To apply this knowledge clinically, the nature of the host response to individual and multiple tumor antigens has to be characterized. This will help to define the efficacy of immune surveillance and the immune status of the host following exposure to tumor antigens expressed on pre-neoplastic tissue. To approach these questions, we have developed a transgenic mouse which expresses the tumor-specific antigen P91A. The single amino acid substitution in P91A results in the expression of a new MHC class I (H-2Ld)-binding peptide. In transgenic tissue, the H-2Ld/P91A complex is expressed in isolation from other tumor-associated antigens, allowing definition of the immune response to a single defined tumor antigen, a situation closely analogous to events during tumorigenesis. We show that CD8+ T cell immune surveillance of P91A is ineffective without the introduction of a helper determinant operating through stimulation of CD4+ T cells. Recognition of the isolated P91A tumor antigen on normal tissue by CD8+ T cells is a tolerogenic process. Induction of T cell tolerance suggests tumor antigen-T cell interactions occurring during tumorigenesis may elicit T cell tolerance and hence confound some immunotherapeutic approaches.

Animals↗
PubMed1996

Genetic control of susceptibility to Taenia crassiceps cysticercosis.

We previously reported that genes within the major histocompatibility complex influence the intensity of Taenia crassiceps murine cysticercosis. This genetic control, readily apparent in mice of BALB background, was further studied in H-2 congenic and recombinant B10 mice as well as in BALB/c substrains differing in expression of Qa-2 antigens. Similarly low parasite numbers were found in all B10-derived strains infected, regardless of H-2 haplotype, indicating that the effect of H-2 genes in controlling susceptibility is overridden in mice of B10 background. BALB/c substrains differed significantly in susceptibility. BALB/cAnN was highly susceptible, whereas BALB/cJ, in contrast, was highly resistant and BALB/cByJ showed intermediate susceptibility. Susceptibility or resistance in BALB/c substrains may be associated to differences known to distinguish them, such as serum testosterone levels and Qa-2 protein expression. In bidirectional F1 hybrids of C57BL/6J and BALB/cAnN resistance to cysticercosis was inherited as a dominant autosomal trait. In F1 hybrids of BALB/cJ with BALB/cAnN, BALB/cByJ and BALB.K resistance was also inherited as a dominant trait. However, in (BALB/cAnN x BALB/cByJ)F1 and (BALB/cAnN x BALB.K)F1 hybrids, dominant susceptibility to cysticercosis was observed.

Animals↗
PubMed1996

Negative selection by endogenous antigen and superantigen occurs at multiple thymic sites.

The site of negative selection in the thymus has been inferred from a range of different experiments. Analysis of thymic deletion of V beta 5+, V beta 11+ or V beta 17a+ cells in H-2E transgenic mice led to the theory that negative selection occurs predominantly in the medulla (specifically, through presentation by medullary dendritic cells). Other experiments investigated whether transgenic TCR are deleted at the double-positive (DP) or single-positive stage following encounter with peptide ligand: by flow cytometric analysis deletion is generally found to occur at the DP thymocyte stage and as these cells are found predominantly in the cortex, it has been inferred that this is the key site of negative selection. The visualization of apoptotic thymocytes in situ has recently been reported for specific examples of negative selection. Using a panel of TCR transgenic lines in which negative selection occurs at different stages of thymocyte development, we have used TUNEL staining to analyse the anatomical sites of thymocyte apoptosis. For the first time we have been able to compare directly the sites of deletion induced by the endogenous cognate peptides or by endogenous superantigen. We show that generalization from the medullary deletion of V beta 5+, V beta 11+ or V beta 17a+ cells by the endogenous superantigens Mtv 8 and 9 from limited examples of cortical deletion by exogenous peptide administered to TCR transgenic mice is over-simplified. Apoptotic thymocytes in mice lacking Mtv superantigens are indeed localized in the cortex. However, when deletion is induced by cognate self peptide, apoptosis can occur in the cortex, the medulla or at the junction between the two.

Animals↗
PubMed1995

Influence of MHC class I molecules on T-cell proliferation induced by CD3 or Thy-1 stimulation.

We have reported that class I- [and lymphocyte function-associated antigen-1 (LFA-1-)] specific monoclonal antibodies (mAb) inhibit anti-CD3-mediated activation of naive T cells. The present study investigated the mechanism of this inhibition. CD28-specific mAb augmented stimulation induced by soluble CD3 mAb, but this costimulation was also inhibited by anti-class I or anti-LFA-1 mAb. However, stimulation of T cells was not inhibited when activated B cells were present. Neither B7-1- nor B7-2-specific blocking mAb or soluble CTLA-4, CD40 or gp39 restored the inhibition. Thus, other molecules expressed on activated B cells are implicated for T-cell activation, which could compensate blockade of class I or LFA-1 molecules. Inhibition induced by class I-specific mAb could potentially be mediated through extracellular, transmembrane or cytoplasmic domains of the target molecules. These possibilities were evaluated by the use of mice transgenic for the Qa-2 molecule, selected for expression of Qa-2 at levels equivalent to classical class I molecules. Qa-2 is inserted in the membrane through phosphatidylinositol linkages. Antibodies directed to Qa-2 inhibited CD3-induced stimulation, demonstrating that cytoplasmic and transmembrane protein sequences of class I molecules are not necessary for the inhibitory effect. Inhibition thus presumably depends on extracellular domains. Finally, T cells from beta 2-microglobulin knock-out mice responded to CD3-specific mAb as well as their class I-positive littermates. Nevertheless, stimulation of T cells from these mice with mitogenic anti-Thy-1 mAb was markedly reduced. Signalling by Thy-1 and the CD3 complex may normally occur through pathways in which class I molecules are implicated.

Animals↗
PubMed1995

Mannose binding protein is involved in first-line host defence: evidence from transgenic mice.

Mannose binding protein (MBP) is a calcium-dependent C-type lectin secreted by the liver which seems to be an important component of innate or natural immunity. We have investigated the effects of Candida albicans and thioglycolate injection into transgenic mice bearing the human MBP gene. The transgenes contained a 15 kb fragment of the MBP gene which included the complete coding sequence. Northern blot hybridization showed human MBP mRNA transcripts in the liver of two transgenic lines with low and high copy number respectively. Western blot analysis showed the presence in serum of human MBP which associated into the higher multimeric forms which are capable of activating complement. Enzyme-linked immunosorbent assays (ELISA) showed that serum human MBP concentrations in the transgenes (1.90 +/- 0.16 mg/l, mean +/- SEM) were about twice as high as the levels in man. The serum concentration of MBP A, which is the mouse homologue of MBP, (13.9 +/- 0.45 mg/l) was about seven times that of human MBP. Intravenous injection of Candida albicans caused the serum human MBP level to fall by more than 50% in the first hour and then slowly recover, but it did not return the initial value by 72 hr. Candida injection caused a 25% fall in serum mouse MBP A in the first hour which then rose to supranormal levels by 72 hr. Following Candida injection mouse MBP A mRNA concentrations increased over 72 hr in contrast to human MBP mRNA which remained constant in both transgenic lines. These data indicate that the human MBP gene fragment in the transgene did not include the regulatory elements of the gene. Total haemolytic complement activity and C3 concentrations also fell immediately after Candida and thioglycolate injection while the concentrations of mannose specific immunoglobulin G (IgG) and immunoglobulin M (IgM) did not fall. The data indicate that mannose binding protein plays an important role in the initial stages of defence against infection which, in this model, is quantitatively greater than that of mannose-specific IgG and IgM antibodies. Mannose binding protein is probably most important in defense of previously unexposed and non-immune hosts.

Animals↗