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Biomedical subjects

A E Walters

Publications and source records attributed to A E Walters.

8 recordsLinked to original sources
PubMed2000

Anti-silicone antibodies and silicone containing breast implants.

The detection of anti-silicone antibodies in patients with silicone breast implants (SBI) has been undertaken principally in the USA. We undertook a study of 20 women with SBI from different manufacturers from 6 weeks to 20 years after surgery, including those with ruptured implants. They were compared with three control groups: 20 women without implants, 20 women with auto-immune disease and 20 anonymous blood donors. Potential anti-silicone antibodies (IgG) were tested against a variety of silicone polymer antigens using an enzyme linked immunosorbent assay (ELISA) technique which had previously detected positive results in an uncontrolled series. Silicone-free collecting tubes were used. No differences were found between the patients with SBI and controls. However, samples that had been stored for the longest time, or frozen and thawed several times, had the highest levels. These false positives appear to be due to an unknown but human specific IgG binding phenomenon. We conclude that there is no demonstrable anti-silicone antibody formation in these patients with SBI and we would caution that the effect of storage may have been an important factor in previously published assay methods. This study supports the safety of silicone containing breast implants.

Adolescent↗
PubMed1999

The Rho-family GTP exchange factor Vav is a critical transducer of T cell receptor signals to the calcium, ERK, and NF-kappaB pathways.

Vav is a GTP/GDP exchange factor (GEF) for members of the Rho-family of GTPases that is rapidly tyrosine-phosphorylated after engagement of the T cell receptor (TCR), suggesting that it may transduce signals from the receptor. T cells from mice made Vav-deficient by gene targeting (Vav-/-) fail to proliferate in response to TCR stimulation because they fail to secrete IL-2. We now show that this is due at least in part to the failure to initiate IL-2 gene transcription. Furthermore, we analyze TCR-proximal signaling pathways in Vav-/- T cells and show that despite normal activation of the Lck and ZAP-70 tyrosine kinases, the mutant cells have specific defects in TCR-induced intracellular calcium fluxes, in the activation of extracellular signal-regulated mitogen-activated protein kinases and in the activation of the NF-kappaB transcription factor. Finally, we show that the greatly reduced TCR-induced calcium flux of Vav-deficient T cells is an important cause of their proliferative defect, because restoration of the calcium flux with a calcium ionophore reverses the phenotype.

Animals↗
PubMed1999

Defective immunoglobulin class switching in Vav-deficient mice is attributable to compromised T cell help.

Vav, a guanine nucleotide exchange factor for members of the Rho family of small GTPases, is activated through engagement of B and T lymphocyte antigen receptors. It is important for establishing the signaling threshold of the TCR, as mice lacking Vav display defective thymocyte selection. Here, conventional B cells are shown to develop normally in Vav-deficient mice but these mice have few B-1 B cells. The threshold for inducing B cell proliferation through BCR engagement in vitro is greater in Vav-deficient B cells. Nevertheless, in vivo the mutant mice have normal antibody responses to haptenated Ficoll. In contrast, Vav-/- mice show defective class switching to IgG and germinal center formation when immunized with haptenated protein. Interestingly, this defect is reversed in chimeras where normal T cells are present. Antigen-specific proliferation of T cells in the T zone was found to be similar in wild-type and Vav-/- mice but the induction of IL-4 mRNA and switch transcripts was specifically impaired. These results suggest that defective immunoglobulin class switching in Vav-deficient mice is attributable to compromised T cell help.

Animals↗
PubMed1997

Syk tyrosine kinase is required for the positive selection of immature B cells into the recirculating B cell pool.

The tyrosine kinase Syk has been implicated as a key signal transducer from the B cell antigen receptor (BCR). We show here that mutation of the Syk gene completely blocks the maturation of immature B cells into recirculating cells and stops their entry into B cell follicles. Furthermore, using radiation chimeras we demonstrate that this developmental block is due to the absence of Syk in the B cells themselves. Syk-deficient B cells are shown to have the life span of normal immature B cells. If this is extended by over-expression of Bcl-2, they accumulate in the T zone and red pulp of the spleen in increased numbers, but still fail to mature to become recirculating follicular B cells. Despite this defect in maturation, Syk-deficient B cells were seen to give rise to switched as well as nonswitched splenic plasma cells. Normally only a proportion of immature B cells is recruited into the recirculating pool. Our results suggest that Syk transduces a BCR signal that is absolutely required for the positive selection of immature B cells into the recirculating B cell pool.

Animals↗
PubMed1997

Determination of melanotan II in rabbit urine using solid-phase extraction sample preparation followed by reversed-phase high-performance liquid chromatography.

A solid-phase extraction (SPE) method has been developed for the isolation of melanotan II from rabbit urine. The proposed extraction method makes it possible to selectively isolate melanotan II without significant loss of the peptide. Standard curves obtained from high-performance liquid chromatographic (HPLC) analysis of spiked urine extracts are linear from 0.1 to 4.0 micrograms/ml. The analytical method is shown to be highly reproducible, giving a relative standard deviation of less than 5% for both between-day and same-day analyses. The accuracy of the method obtained from standard plots ranges from -3.3 to 3.1%.

Animals↗
PubMed1997

A requirement for the Rho-family GTP exchange factor Vav in positive and negative selection of thymocytes.

The T cell repertoire is shaped by positive and negative selection of thymocytes that express low levels of T cell receptor (TCR) and both CD4 and CD8. TCR-mediated signals that determine these selection processes are only partly understood. Vav, a GDP-GTP exchange factor for Rho-family proteins, is tyrosine phosphorylated following TCR stimulation, suggesting that it may transduce TCR signals. We now demonstrate that mice lacking Vav are viable and display a profound defect in the positive selection of both class I- and class II-restricted T cells. In contrast, Vav is not essential for negative selection, though in its absence negative selection is much less effective. Vav may influence the efficiency of TCR-induced selection events by regulating the intracellular calcium flux of thymocytes.

Animals↗
PubMed1996

Critical role for the tyrosine kinase Syk in signalling through the high affinity IgE receptor of mast cells.

Activation of the high affinity IgE receptor (Fc epsilon RI) of mast cells, a member of the antigen receptor family, leads to the release of allergic mediators, a critical event in the onset of immediate hypersensitivity. Stimulation of Fc epsilon RI results in the rapid association and activation of the Syk tyrosine kinase. Using Syk-deficient mast cells we show that they fail to degranulate, synthesize leukotrienes and secrete cytokines when stimulated through Fc epsilon RI, conclusively demonstrating an essential role for Syk in Fc epsilon RI signalling. Furthermore, our data strongly supports a model of Fc epsilon RI engagement leading to the sequential activation of the tyrosine kinases Lyn and then Syk. A similar mechanism is likely to apply to signal transduction through all members of the antigen receptor family.

Animals↗