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Biomedical subjects

C M Dayan

Publications and source records attributed to C M Dayan.

At least 19 recordsLinked to original sources
PubMed2002

Reproducibility of individualized coronary heart disease risk calculations in patients with diabetes mellitus.

AIMS: To determine prospectively, the reproducibility of individualized coronary heart disease (CHD) risk estimations in a high-risk (diabetic) population. METHODS: One hundred and three patients attending a hospital diabetes clinic who were in the primary prevention category for CHD had measurements of cholesterol, HDL-cholesterol and systolic blood pressure (SBP) performed in one of 13 general practices and then 2 weeks later in the hospital clinic. The data were combined with age, sex, smoking history and diabetic status data to produce a 10-year CHD risk estimate for each occasion using the Framingham algorithm. RESULTS: The coefficients of variation for cholesterol, HDL and SBP were 6.0%, 9.4% and 7.0%, respectively. When classified by treatment thresholds of 15% and 30% 10-year CHD risk, 88% of patients were classified in the same category on both occasions. Kappa values for the 15% and 30% risk thresholds were 0.71 and 0.82. This indicates good interobserver agreement for the estimation of CHD risk. The use of a single BP rather than the mean of two, resulted in seven of 206 estimations of CHD risk performed in 103 patients crossing a risk threshold, with 6/7 being placed in a higher risk category. CONCLUSIONS: Estimation of CHD risk on a single occasion is sufficient to make robust treatment decisions based on risk thresholds. Use of a single BP measurement rather than the mean of two overestimates the risk category in around 3% of cases.

Adult↗
PubMed2001

T cell activation by coxsackievirus B4 antigens in type 1 diabetes mellitus: evidence for selective TCR Vbeta usage without superantigenic activity.

Numerous clinical and epidemiological studies link enteroviruses such as the Coxsackie virus group with the autoimmune disease type 1 diabetes mellitus (DM). In addition, there are reports that patients with type 1 DM are characterized by skewing of TCR Vbeta chain selection among peripheral blood and intraislet T lymphocytes. To examine these issues, we analyzed TCR Vbeta chain-specific up-regulation of the early T cell activation marker, CD69, on CD4 T cells after incubation with Coxsackievirus B4 (CVB4) Ags. CD4 T cells bearing the Vbeta chains 2, 7, and 8 were the most frequently activated by CVB4. Up-regulation of CD69 by different TCR families was significantly more frequent in new onset type 1 DM patients (p = 0.04), 100% of whom (n = 8) showed activation of CD4 T cells bearing Vbeta8, compared with 50% of control subjects (n = 8; p = 0.04). T cell proliferation after incubation with CVB4 Ags required live, nonfixed APCs, suggesting that the selective expansion of CD4 T cells with particular Vbeta chains resulted from conventional antigen processing and presentation rather than superantigen activity. Heteroduplex analysis of TCR Vbeta chain usage after CVB4 stimulation indicated a relatively polyclonal, rather than oligo- or monoclonal response to viral Ags. These results provide evidence that new-onset patients with type 1 DM and healthy controls are primed against CVB4, and that CD4 T cell responses to the virus have a selective TCR Vbeta chain usage which is driven by viral Ags rather than a superantigen.

Adult↗
PubMed2001

Interpretation of thyroid function tests.

The introduction of sensitive thyrotropin assays and free thyroid hormone measurements has simplified the interpretation of thyroid function tests. However, important pitfalls and difficult cases still exist. In this review, thyroid function test results are grouped into six different patterns. We propose that if assays for thyrotropin, free T3, and free T4 are all done, knowledge of these patterns coupled with clinical details and simple additional tests allow a diagnosis to be made in almost all cases.

Diagnostic Errors↗
PubMed2001

Thyroid autoantibodies.

Although assays to detect thyroid autoantibodies have been available for more than 40 years, their place in the clinical management of thyroid disease has remained controversial; however, novel automated detection techniques using recombinant antigens are increasing the sensitivity and specificity of the assays, particularly for antibodies to the TSH receptor. In addition, new antigenic targets have been defined including the sodium-iodide symporter and four eye muscle proteins targeted in Graves' ophthalmopathy. This article summarizes the immunobiology, assay methodology and prevalence in thyroid diseases of each of the major thyroid autoantibodies before discussing the clinical indications for their use in thyroid diseases.

Autoantibodies↗
PubMed2000

Effective formation of major histocompatibility complex class II-peptide complexes from endogenous antigen by thyroid epithelial cells.

In autoimmune thyroid disease, thyroid epithelial cells (TEC) express major histocompatibility complex (MHC) class II molecules, potentially enabling them to present thyroid self-antigens to CD4-positive T cells. However, despite this, TEC may fail to present endogenous antigen as a result of limited processing or MHC class II loading capacity, or inadequate MHC class II levels. We addressed these issues using the cloned rat TEC line, Fischer rat thyroid cell line (FRTL5), which was transfected using an adenoviral expression vector that expressed ovalbumin (OVA) as an integral membrane protein. OVA-expressing FRTL5 cells very efficiently activated a panel of OVA-specific, class II-restricted T-cell hybridomas. This response was dependent on induction of MHC class II molecules by interferon-gamma (IFN-gamma) and was blocked by anti-MHC class II antibodies. Poor responses were seen to exogenously added OVA or OVA peptides. These results provide the most direct evidence to date that TEC can form MHC class II-peptide complexes derived from self-antigen in sufficient quantities to activate T cells.

Animals↗
PubMed1999

Predicting therapeutic outcome in severe ulcerative colitis by measuring in vitro steroid sensitivity of proliferating peripheral blood lymphocytes.

BACKGROUND: Up to 29% of patients with severe ulcerative colitis (UC) fail to respond to steroid treatment and require surgery. Previous studies have failed to show a clear correlation between failure of steroid treatment in severe UC and measures of disease severity. The reasons for treatment failure therefore remain unknown. AIM: To investigate the hypothesis that patients with severe UC who fail to respond to steroid treatment have steroid resistant T lymphocytes. METHODS: Eighteen patients with severe UC were studied. After seven days' treatment with high dose intravenous steroids they were classified as complete responders (CR), incomplete responders (IR), or treatment failures (TF). Within 48 hours of admission blood was taken and the antiproliferative effect of dexamethasone on phytohaemagglutinin stimulated peripheral blood T lymphocytes was measured. Maximum dexamethasone induced inhibition of proliferation (I(max)) was measured. RESULTS: In vitro T lymphocyte steroid sensitivity of TF and IR patients was significantly less than that of CR patients. Both TF and 3/5 IR patients had an I(max) of less than 60%; all CR patients had an I(max) of greater than 60%. No significant correlation was seen between response to treatment and disease severity on admission. When in vitro T lymphocyte steroid sensitivity was remeasured three months later, there was no difference between the groups. CONCLUSIONS: Results suggest that T lymphocyte steroid resistance is an important factor in determining response to steroid treatment in patients with severe UC and may be more predictive of outcome than disease severity.

Adult↗
PubMed1999

Wide variation in lymphocyte steroid sensitivity among healthy human volunteers.

Steroids are frequently used to treat inflammatory conditions in which lymphocytes play a role. We have recently shown that in severe ulcerative colitis, treatment outcome correlates better with in vitro estimates of lymphocyte steroid sensitivity (LSS) than with disease severity. This lead us to examine the range and variability of LSS in the healthy population. Dexamethasone inhibition of lymphocyte proliferation was measured on 54 occasions in 18 volunteers (mean age, 46 yr; range, 23-60 yr) over an 8-month period. Inter- and intra-assay variation in LSS was low when expressed as maximum inhibition achieved, Imax (2.9% and 3.4%, respectively), allowing us to demonstrate a very wide variation in Imax between healthy individuals (-6.7% to 99.7%). In contrast, within-individual variation of Imax was significantly less than between-individual variation (F test, P < 0.0001), consistent with stability of this parameter over time. No correlation was seen between LSS and glucocorticoid receptor density or affinity, suggesting a postreceptor mechanism. Serum cortisol at the time of sampling and skin sensitivity to glucocorticoids also failed to correlate with LSS. This study suggests Imax is a sufficiently stable parameter to categorize healthy individuals according to LSS. The wide range of LSS demonstrated is striking and suggests that up to 30% of the healthy population would fail to respond to steroid therapy for severe inflammatory conditions.

Adult↗
PubMed1999

In vitro measurement of lymphocyte steroid sensitivity: lack of agreement between whole blood culture and separated lymphocyte culture.

The use of a whole blood culture to measure steroid sensitivity has previously been compared to the use of a separated lymphocyte assay. Good correlation between the two methods was reported. However the number of subjects studied appears to have been small and no patients with steroid resistance were studied. We have studied a large number of subjects and compared steroid sensitivity measured by a whole blood culture with an established separated lymphocyte assay. Proliferation was stimulated with phytohaemagglutinin and inhibited by dexamethasone. A wide range of steroid sensitivity was found between individuals. In steroid sensitive subjects, good agreement was seen between the two assays. However in individuals identified as steroid resistant by the separated lymphocyte assay, steroid resistance was not seen using the whole blood assay. This is important because in vitro lymphocyte steroid resistance, as measured by the separated lymphocyte assay has been shown to predict a poor in vivo response to steroid therapy. Using the whole blood culture this steroid resistance would not be demonstrated. Hence the use of a whole blood assay can not be recommended.

Adult↗
PubMed1997

An antisense oligodeoxynucleotide complementary to corticotropin-releasing hormone mRNA inhibits rat splenocyte proliferation in vitro.

Expression of neuropeptides in immune tissues has been implicated in the paracrine control of immune functions. The effects of the endogenous splenic neuropeptide corticotropin-releasing hormone (CRH) on immune cell proliferation were investigated by incubating splenocytes from adult male Wistar rats in vitro with a specific antisense oligodeoxynucleotide probe complementary to CRH mRNA. Incubation of cells with 1 microgram/ml phosphodiester antisense probe for 24 h prior to stimulation with concanavalin A (Con A) resulted in a 30-65% decrease in 3H-thymidine uptake compared to controls. In spleen cells incubated with a random base sequence (nonsense) probe the uptake of 3H-thymidine was not different to that in control cells. Incubation of cells with either antisense or nonsense phosphorothioate-protected probes resulted in variable uptake of 3H-thymidine, demonstrating that these probes, unlike the phosphodiester probes, have non-specific effects on cells. Addition of synthetic CRH to the cells incubated with the antisense phosphodiester probe partially restored the proliferative response of splenocytes to Con A. Immunoreactive (ir) CRH measured by radioimmunoassay in splenocytes incubated with the antisense probe was significantly less than ir-CRH in splenocytes incubated with the nonsense probe or without probe, indicating that the expression of splenic CRH mRNA was specifically impaired. This attenuation of the cell proliferative response following reduced expression of splenic ir-CRH provides functional evidence for the involvement of endogenously synthesised immune ir-CRH in splenocyte activation.

Animals↗
PubMed1996

Human self-reactive T cell clones expressing identical T cell receptor beta chains differ in their ability to recognize a cryptic self-epitope.

Recognition of self-antigens by T lymphocytes is a central event in autoimmunity. Understanding of the molecular interactions between T cell receptors (TCR) and self-epitopes may explain how T cells escape thymic education and initiate an autoimmune reaction. We have studied five human in vivo activated T cell clones specific for the region 535-551 of human thyroid peroxidase (TPO) established from a Graves' patient. Three clones (37, 72, and 73) expressed identical TCR beta and alpha chains rearranging V beta 1.1 and V alpha 15.1, and were considered sister clones. Clone 43 differed from clone 37 and its sisters in the J alpha region only. Clone NP-7 expressed V beta 6.5 but rearranged two in-frame TCR alpha chain, both using the V alpha 22.1 segment. Fine epitope mapping using nested peptides showed that clones using identical TCR beta chains, identical V alpha, but a different J alpha recognized distinct, nonoverlapping epitopes in the TPO 535-551 region. This finding shows that a different J alpha region alone leads to a heterogeneous pattern of recognition. This indicates that the "restricted" TCR V region usage sometimes found in autoimmune diseases may not always correspond to identical epitope recognition. To confirm that clones 37 (and its sisters) and 43 recognize different epitopes, the T cell clones were stimulated with a TPO-transfected autologous Epstein-Barr virus (EBV) cell line (TPO-EBV) that presents TPO epitopes afer endogenous processing. Only clone 37 and its sisters recognizes the TPO-EBV cell line, suggesting that the epitope recognized by clone 43 is not presented upon endogenous processing. We have shown that thyroid epithelial cells (TEC), the only cells that produce TPO, express HLA class II molecules in Graves' disease and can act as an antigen-presenting cells, presenting TPO after endogenous processing to autoantigen-reactive T cell clones. We tested, therefore, whether autologous TEC induced the same pattern of stimulation as TPO-EBV; T cell clone 37 recognizes the TEC, whereas it is stimulated poorly by the TPO loaded to autologous peripheral blood mononuclear cells (PBMC). Clone 43, which fails to recognize the TPO-EBV, also fails to recognize the TEC, but is activated by exogenous TPO presented by autologous PBMC. These results show that exogenous versus endogenous processing in vivo generates a different TPO epitope repertoire, producing a "cryptic" epitope (epitope not always available for recognition). Our findings define a route by which human self-reactive T cells may escape thymic selection and become activated in vivo, thus possibly leading to autoimmunity.

Amino Acid Sequence↗