Unraveling toxicological mechanisms and predicting toxicity classes with gene dysregulation networks

The use of genes for distinguishing classes of toxicity has become well established. In this paper we combine the reconstruction of a gene dysregulation network (GDN) with a classifier to assign unseen compounds to their appropriate class. Gene pairs in the GDN are dysregulated in the sense that they are linked by a common expression pattern in one class and differ in this pattern in another class. The classifier gives a quantitative measure on this difference by its prediction accuracy. As an in‐depth example, gene pairs were selected that were dysregulated between skin cells treated with either sensitizers or irritants. Pairs with known and novel markers were found such as HMOX1 and ZFAND2A, ATF3 and PPP1R15A, OXSR1 and HSPA1B, ZFP36 and MAFF. The resulting GDN proved biologically valid as it was well‐connected and enriched in known interactions, processes and common regulatory motifs for pairs. Classification accuracy was improved when compared with conventional classifiers. As the dysregulated patterns for heat shock responding genes proved to be distinct from those of other stress genes, we were able to formulate the hypothesis that heat shock genes play a specific role in sensitization, apart from other stress genes. In conclusion, our combined approach creates added value for classification‐based toxicogenomics by obtaining novel, well‐distinguishing and biologically interesting measures, suitable for the formulation of hypotheses on functional relationships between genes and their relevance for toxicity class differences. Copyright © 2012 John Wiley & Sons, Ltd.     

A prospective,double-blind,randomized, placebo-controlled study on the efficacy and safety of influenza vaccination in myasthenia gravis

Objective

To investigate the efficacy and safety of an influenza vaccination in patients with myasthenia gravis with acetylcholine receptor antibodies (AChR MG).

An Unusual Complication 4 years After Laparoscopic Adjustable Banding: Jejunal Obstruction Due to the Connecting Tube

Laparoscopic adjustable gastric banding (LAGB) is an often performed bariatric procedure for morbid obesity. Several complications are known, including surgery and port-side-associated complications. As rare but serious late complication of LAGB, we describe a 50-year-old patient with periodic incomplete intestinal constriction due to the silicone connecting tube, 4 years after laparoscopic adjustable gastric banding was performed. Abdominal CT scan showed an obstructive ileus due to a loop in the connecting tube. After surgical removal of the connecting tube, the patient recovered without sequelae.     

Feasibility of assessment of coronary stent patency using 16-slice computed tomography

Intracoronary stent implantation is a frequently performed procedure in the treatment of stenoses in coronary arteries, but in-stent restenosis occurs in approximately 10% to 15% of patients. A noninvasive diagnostic procedure to evaluate in-stent restenosis would therefore be of great benefit. We investigated the feasibility of assessing stent patency with 16-slice computed tomography. Multislice computed tomography (MSCT) was performed in 22 patients with previously implanted stents. For each stent, assessability was determined and related to stent type and diameter. Subsequently, the presence of significant restenosis was determined in the evaluable stents. In addition, peristent lumina (5 mm proximal and distal to the stent) were evaluated. Conventional angiography in combination with quantitative coronary angiography served as the standard of reference. MSCT was performed successfully in all but 1 patient. Of 65 stents, 50 (77%) were determined assessable. Uninterpretable stents tended to have a thicker strut and/or a smaller diameter. In the evaluable stents, 7 of 9 stenoses were detected and the absence of restenosis was correctly identified in all 41 patent stents, resulting in a sensitivity and specificity of 78% and 100%, respectively. Sensitivity and specificity for the detection of peristent stenosis were 75% and 96%, respectively. In conclusion, MSCT may be useful in the assessment of stent patency and may function as a gatekeeper before invasive diagnostic procedures.     

Benefit of combined resynchronization and defibrillator therapy in heart failure patients with and without ventricular arrhythmias.

OBJECTIVES: We attempted to assess the efficacy of combined cardiac resynchronization therapy-implantable cardioverter-defibrillator (CRT-ICD) in heart failure patients with and without ventricular arrhythmias. BACKGROUND: Because CRT and ICDs both lower all-cause mortality in patients with advanced heart failure, combination of both therapies in a single device is challenging. METHODS: A total of 191 consecutive patients with advanced heart failure, left ventricular ejection fraction <35%, and a QRS duration >120 ms received CRT-ICD. Seventy-one patients had a history of ventricular arrhythmias (secondary prevention); 120 patients did not have prior ventricular arrhythmias (primary prevention). During follow-up, ICD therapy rate, clinical improvement after 6 months, and mortality rate were evaluated. RESULTS: During follow-up (18 +/- 4 months), primary prevention patients experienced less appropriate ICD therapies than secondary prevention patients (21% vs. 35%, p < 0.05). Multivariate analysis revealed, however, no predictors of ICD therapy. Furthermore, a similar, significant, improvement in clinical parameters was observed at 6 months in both groups. Also, the mortality rate in the primary prevention group was lower than in the secondary prevention group (3% vs. 18%, p < 0.05). CONCLUSIONS: As 21% of the primary prevention patients and 35% of the secondary prevention patients experienced appropriate ICD therapy within 2 years after implant, and no predictors of ICD therapy could be identified, implantation of a CRT-ICD device should be considered in all patients eligible for CRT.