Conor McCarthy

Identification of Naf1/ABIN-1 among TNF-α-induced expressed genes in human synoviocytes using oligonucleotide microarrays

The cytokine tumor necrosis factor alpha (TNF‐α) is a critical effector of the pathogenesis of rheumatoid arthritis (RA). We used oligonucleotide microarray (OM) analysis to assess TNF‐α‐modulated gene expression in cultured primary human synoviocytes in vitro. Genes identified include cytokines and inflammatory mediators, extracellular matrix and adhesion molecules, cell cycle and proliferation related proteins, transcription related proteins, and apoptotic mediators. OM identified 1185 differentially expressed genes in TNF‐α‐treated synoviocytes. The regulation of Nef‐associated factor‐1 (Naf1), an A20‐binding, nuclear factor kappa B (NFκB) inhibitory protein was probed further given its putative role as an endogenous brake for the expression of some TNF‐α‐driven genes. Naf1 mRNA levels were higher in synovial biopsies from patients with active RA and seronegative arthropathy than in those from patients with osteoarthritis. These findings underscore the value of transcriptome analysis in cytokine‐activated synoviocyte cultures in vitro as a means of identifying disease‐associated genes in human arthritis, and implicate Naf1 as a potential modulator of TNF‐α bioactivity in RA.

Evaluation of patients with diabetes mellitus for coronary artery disease using dobutamine stress echocardiography.

BACKGROUND There is a high prevalence of coronary artery disease (CAD) in patients with diabetes mellitus. Detection of inducible ischaemia using treadmill exercise testing may be limited by the relatively poor inherent predictive accuracy of the test. The purpose of this study was to determine the value of dobutamine stress echocardiography (DSE) for the detection of CAD in patients with diabetes mellitus. METHODS Patients with diabetes mellitus referred for cardiac assessment were considered eligible for study. DSE was performed in a standard fashion. Significant CAD was defined as a > 50% luminal diameter stenosis on coronary angiography. RESULTS A total of 52 patients (mean age 59 years) with diabetes mellitus were studied prospectively using DSE. Risk factors for CAD included hypertension in 19, family history in 21, hypercholesterolaemia in 14, history of smoking in 38. The sensitivity, specificity, positive and negative predictive values of DSE for detection of CAD were 82, 54, 84 and 50% respectively. CONCLUSION The specificity of DSE for CAD in patients with diabetes mellitus is low. Whether this reflects an underdetection of small vessel disease by contrast coronary angiography or whether it relates to test performance is unclear.

Safety of dobutamine stress echocardiography in 474 consecutive studies.

BACKGROUND With expanding applications and increasingly aggressive stress protocols, concerns about the safety of dobutamine stress echocardiography (DSE) have arisen. The purpose of this study was to analyse prospectively the safety, adverse event profile and complication rate of DSE. METHODS Prospective data were recorded in a consecutive series of 474 patients undergoing DSE. Dobutamine was administered intravenously in graded infusion, each stage over 3 min, at 10, 20, 40 and, if required, 50 micrograms/kg/min. Atropine (1 mg) was administered thereafter if the response remained suboptimal. RESULTS The mean dose of dobutamine was 42 micrograms/kg/min, with 111 patients (23%) receiving 50 micrograms/kg/min. Atropine was required for 27 patients (6%). No patient died or suffered a myocardial infarction. Sustained ventricular tachycardia occurred in one patient, angina pectoris in 127 (27%), non-sustained ventricular tachycardia in eight (2%) and supraventricular tachycardia in 19 (4%). Profound bradycardia requiring cessation of the test occurred in one patient. Pulmonary oedema developed in one patient. A hypotensive response requiring cessation of the test was seen in one patient. Test termination because the patient complained of nausea, tremor or headache was not required. CONCLUSION DSE is safe. Side effects are rare and when they occur, are usually minor. Ischaemic pain is effectively treated by termination of the test and sublingual administration of nitrates.

Correlation of myocardial histologic changes in hibernating myocardium with dobutamine stress echocardiographic findings

OBJECTIVE The objective of this study was to correlate histologic changes in hibernating myocardium with dobutamine stress echocardiography (DSE). METHODS Patients (n = 8) with anterior regional wall motion abnormalities in the seven echocardiographic segments representing the territory supplied by a significantly stenosed left anterior descending coronary artery had preoperative DSE performed (yielding 56 segments for analysis). Two transmural biopsy specimens were taken from the anterior wall of the left ventricle during coronary artery bypass grafting. RESULTS Morphometric histologic analysis of biopsy specimens showed significantly less fibrosis in segments demonstrating inotropic reserve (p < 0.05) and significantly less fibrosis in segments demonstrating improvement in wall motion on echocardiography 3 months after revascularization (p < 0.05). DSE had a sensitivity of 100% and a specificity of 62% for detection of hibernating myocardial segments. Percent fibrosis was inversely correlated with percent nucleated cells (r = 0.66, p < 0.01) and directly correlated with cytoplasmic clearance (r = 0.76, p < 0.01). CONCLUSION Inotropic response during DSE correlates with histologic evidence of hibernating myocardium.

Comparison of dobutamine stress echocardiography and treadmill exercise electrocardiography for detection of coronary artery disease

BackgroundCritical analysis of treadmill exercise testing (TMET) for the detection of coronary artery disease has revealed many shortcomings. Excellent diagnostic accuracy has been reported for dobutamine stress echocardiography (DSE). MethodsA prospective comparison of DSE and TMET for the detection of coronary artery disease in routine clinical practice was performed using contrast cineangiography (significant stenosis ± 50%) as a gold standard. ResuttsA total of 116 patients (82 men, 34 women) were studied. Significant stenosis was detected by coronary angiography in 92 patients (79%). Single vessel disease occurred in 28, double-vessel disease in 32. and multivessel disease in 32 patients. Although sensitivity of DSE was better than that of TMET (82 versus 40%). specificity was worse (63 versus 79%). Positive predictive values for both DSE and TMET were good at 89 and 87%, respectively, whereas negative predictive values were poor for both (47% for DSE. 26% for TMET). ConclusionsOverall, DSE performs better than TMET in terms of sensitivity and positive and negative predictive value. Its lower specificity than that of TMET may lead to more patients being referred for diagnostic coronary angiography. The poor negative predictive value of DSE and TMET means that one should not be falsely reassured by normal results.

Predicting Failure in Multi-Bolt Composite Joints Using Finite Element Analysis and Bearing-Bypass Diagrams

A three-dimensional finite element model of a three-bolt, single-lap composite joint is constructed using the non-linear finite element code MSC.Marc. The model is validated against an experiment where the load distribution in the joint is measured using instrumented bolts. Two different joint configurations are examined, one with neat-fit clearances at each bolt-hole and another with a 240 µm clearance at one hole with neat-fits at the others. Bearing and by-pass stresses are extracted from the model and used in conjunction with published bearing/by-pass diagrams to predict the failure load, mode and location for the joints. It is shown that the proposed model accurately predicts the failure behaviour of the joints, as determined from experiments on three-bolt joints loaded to failure. It is also shown that introducing a clearance into one hole significantly changes the failure sequence, but does not affect the ultimate failure load, mode or location. The proposed method demonstrates a simple approach to predicting damage in complex multi-bolt composite joints.

An Investigation into Scalpel Blade Sharpness Using Cutting Experiments and Finite Element Analysis

This paper presents an investigation into the sharpness of a surgical scalpel blade. An experiment was carried out in which a surgical scalpel blade was pushed through an elastomeric substrate at a constant velocity. The force-displacement characteristics were examined by plotting the stiffness as a function of blade displacement and it was found that this curve could clearly identify the point where the material separates to form a cut. A blade sharpness measurement was defined as the energy required to initiate an opening or cut in the substrate. A finite element model was developed to examine the stress state in the substrate at the point where the opening initiates. The development of this model is described. The model was validated against the experiment and close agreement was obtained. The von-Mises stress distribution under the blade tip was plotted and it was shown that the peak stress actually occurs away from the blade tip, suggesting that material separation would initiate away from the substrate surface.