A comparison of antibodies to tissue transglutaminase with conventional serological tests in the diagnosis of coeliac disease

BACKGROUND: Tissue transglutaminase is now recognized as the autoantigen for antiendomysial antibodies. Antibodies to tissue transglutaminase have been proposed as a valuable test for coeliac disease. OBJECTIVE: To determine the value of antibodies to tissue transglutaminase in the diagnosis of coeliac disease in our outpatient population. METHODS: Patients who underwent serological tests for coeliac disease during the first 18 months of the tissue transglutaminase antibody assay were retrospectively identified from the regional serology laboratory database. Patients' symptoms were noted, along with serological results and duodenal histology in those patients who underwent duodenal biopsy.RESULTS In total, 586 patients were identified as having been serologically tested for coeliac disease, of whom 92 patients (33 men; mean age 51.7 years) had been followed up with duodenal biopsies. Of these 92 patients, 29 (31%; 14 men; mean age 52.5 years) had histological features of coeliac disease. The 63 patients with normal histology (19 men; mean age 51.8 years) acted as controls. Weight loss was more frequent in coeliac disease patients compared to controls (7 vs 5; P = 0.04) whereas the frequency of anaemia (P = 0.85) and diarrhoea (P = 0.74) did not differ significantly between the two groups. The sensitivity and specificity of tissue transglutaminase antibodies (86%; 84%) were compared to those for antiendomysial antibodies (90%; 98%) and antigliadin antibodies (76%; 79%). CONCLUSIONS: The diagnostic value of tissue transglutaminase antibodies was intermediate between that of antiendomysial antibodies and antigliadin antibodies. However, duodenal biopsy remains the gold standard diagnostic test for coeliac disease.     

Protease‐activated receptor‐2 signalling by tissue factor on dendritic cells suppresses antigen‐specific CD4+ T‐cell priming

The precise function of tissue factor (TF) expressed by dendritic cells (DC) is uncertain. As well as initiating thrombin generation it can signal through protease‐activated receptor 2 (PAR‐2) when complexed with factor VIIa. We investigated the expression and function of TF on mouse bone marrow (BM) ‐derived DC; 20% of BM‐derived DC expressed TF, which did not vary after incubation with lipopolysaccharide (LPS) or dexamethasone (DEX). However, the pro‐coagulant activity of DEX‐treated DC in recalcified plasma was 30‐fold less than LPS‐treated DC. In antigen‐specific and allogeneic T‐cell culture experiments, the TF on DEX‐treated DC provided a signal through PAR‐2, which contributed to the reduced ability of these cells to stimulate CD4⁺ T‐cell proliferation and cytokine production. In vivo, an inhibitory anti‐TF antibody and a PAR‐2 antagonist enhanced antigen‐specific priming in two models where antigen was given without adjuvant, with an effect approximately 50% that seen with LPS, suggesting that a similar mechanism was operational physiologically. These data suggest a novel TF and PAR‐2‐dependent mechanism on DEX‐DC in vitro and unprimed DC in vivo that contributes to the low immunogenicity of these cells. Targeting this pathway has the potential to influence antigen‐specific CD4⁺ T‐cell activation.     

Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy in Asian Patients: 100 Consecutive Patients in a Single Institution

Background

Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) have been shown to improve survival in selected patients with peritoneal carcinomatosis. We review our institutional experience with the procedure and evaluate the overall survival (OS) and disease-free survival (DFS) rates in 100 consecutive patients.

Methods

Data were prospectively collected from 100 consecutive patients with peritoneal carcinomatosis treated by CRS and HIPEC at the National Cancer Centre Singapore between April 2001 and May 2012. Our primary end points were OS and DFS.

Results

Of the 100 patients, 84 were of Chinese ethnicity, 3 were Malay, 6 were Indian, and 7 were of other ethnicities. Primary tumors were ovarian cancer (n = 39), colorectal cancer (n = 28), primary peritoneal (n = 6), appendiceal cancer (n = 20), and mesothelioma (n = 7). Median follow-up duration was 21 months. At 5 years, the DFS was 26.3 % and OS was 50.9 %. Factors influencing OS and DFS were cytoreductive score, primary cancer, and disease-free interval of more than 12 months on univariate analysis. The only factors that remained significant for prognosis after multivariate analysis were primary cancer and cytoreductive score. Thirty-day morbidity was 56 %, and there were no 30-day mortalities.

Conclusions

CRS and HIPEC can be safely carried out in Asian patients with peritoneal carcinomatosis from ovarian, colorectal, appendiceal, mesothelioma, and primary peritoneal origins. Overall, the ovarian, appendiceal, mesothelioma, and primary peritoneal cancer patients tended to do better than the colorectal patients, but careful patient selection ensuring that optimal cytoreduction can be achieved is essential for the success of this procedure.     

Activation of factor XI in plasma is dependent on factor XII [see comments]

The activation of factor XI initiates the intrinsic coagulation pathway. Until recently it was believed that the main activator of factor XI is factor XIIa in conjunction with the cofactor high molecular weight kininogen on a negatively charged surface. Two recent reports have presented evidence that in a purified system factor XI is activatable by thrombin together with the soluble polyanion dextran sulfate. To assess the physiological relevance of these findings we studied the activation of factor XI in normal and factor XII-deficient plasma. We used either kaolin/cephalin or dextran sulfate as a surface for the intrinsic coagulation pathway, tissue factor to generate thrombin via the extrinsic pathway, or the addition of alpha-thrombin directly. 125I-factor XI, added to factor XI-deficient plasma at physiologic concentrations (35 nmol/L), is rapidly cleaved on incubation with kaolin. The kinetics appear to be exponential with half the maximum cleavage at 5 minutes. Similar kinetics of factor XI cleavage are seen when 40 nmol/L factor XIIa (equal to 10% of factor XII activation) is added to factor XII-deficient plasma if an activating surface is provided. Tissue factor (1:500) added to plasma did not induce cleavage of factor XI during a 90-minute incubation, although fibrin formation within 30 seconds indicated that thrombin was generated via the extrinsic pathway. Adding 1 mumol/L alpha-thrombin (equivalent to 50% prothrombin activation) directly to factor XII deficient or normal plasma (with or without kaolin/cephalin/Ca2+ or dextran sulfate) led to instantaneous fibrinogen cleavage, but again no cleavage of factor XI was observable. We conclude that in plasma surroundings factor XI is not activated by thrombin, and that proposals of thrombin initiation of the intrinsic coagulation cascade are not supportable.     

Double blind cross-over placebo controlled study of omeprazole in the treatment of patients with reflux symptoms and physiological levels of acid reflux--the "sensitive oesophagus".

BACKGROUND: At least 10-15% of patients with reflux symptoms have a normal endoscopy and physiological levels of acid reflux on pH monitoring. Such patients with 50% or more of symptoms associated with acid reflux episodes have "a positive symptom index" (SI), and it has been proposed that this defines the "sensitive oesophagus". AIM: To test the response to omeprazole 20 mg twice daily for four weeks of patients with normal levels of acid reflux using a randomised, placebo controlled, double blind, cross-over design. PATIENTS: Eighteen patients with normal levels of reflux, 12 of whom had a positive SI. METHODS: Response was measured by symptomatic assessment and the SF-36 quality of life (QOL) questionnaire. RESULTS: Patients with a positive SI showed the following improvements on omeprazole compared with placebo: decrease in symptom frequency (p < 0.01), severity (p < 0.01) and consumption of antacids (p < 0.01). In the group with a negative SI only one patient clearly improved. The QOL parameters for bodily pain (65.6 v 53.4, p = 0.03) and vitality (60.6 v 48.8, p = 0.049) were significantly better on omeprazole than placebo for the group overall. CONCLUSION: Omeprazole improves symptoms in 11 of 18 patients with normal endoscopy and pH monitoring, particularly those with a positive SI. This supports the theory that such patients have an oesophagus which is "sensitive" to acid reflux and are part of the GORD spectrum.