MS-551 and KCB-328, two class III drugs aggravated adrenaline-induced arrhythmias

1. We investigated the proarrhythmic effects of MS-551 and KCB-328, class III antiarrhythmic drugs using adrenaline-induced arrhythmia models in halothane anaesthetized, closed-chest dogs. In the control period, adrenaline, starting from a low dose of 0.25 to up to 1.0 μg/kg/50 s i.v., was injected to determine the arrhythmia inducing dose and the non-inducing dose. After MS-551 or KCB-328 administration, the adrenaline injection was repeated and the interval between the injection and the occurrence of arrhythmia (latent interval), the changes in arrhythmic ratio (as calculated by dividing the number of ventricular premature contraction by the number of the total heart rate) and the severity of arrhythmia were observed. 2. MS-551 infusion, 1 mg/kg/30 min, decreased the heart rate (HR) by 16% (P<0.01) and prolonged the QTc interval by 20% (P<0.01). During the 30 min of MS-551 infusion, arrhythmias occurred in three out of seven dogs (torsades de pointes (TdP) type VT in one dog). After these arrhythmias disappeared, MS-551 decreased the latent interval of the adrenaline arrhythmias produced by the inducing dose (30±2 s compared with 43±3 s of the control interval, P<0.05), increased the arrhythmic ratio (P<0.05) and induced arrhythmias by non-inducing adrenaline doses (P<0.05). 3. Effect of a new class III drug KCB-328 infusion, 0.3 mg/kg/30 min, was compared witih MS-551 using the same model. KCB-328 decreased the HR by 21% (P<0.01) and prolonged the QTc interval by 25% (P<0.01). During the 30 min of infusion, arrhythmias occurred in five out of seven dogs (TdP in two dogs). KCB-328 also decreased the latent interval of the adrenaline arrhythmias produced by the inducing doses (31±3 s compared with 49±7 s of the control period, P<0.05), but did not significantly alter the arrhythmic ratio. 4. Adrenaline induced TdP only after MS-551 or KCB-328 was administered, i.e. after MS-551, 1 mg/kg/30 min, 3/7 versus 0/7 in the control; KCB, 0.3 mg/kg/30 min, 3/7 versus 0/7 in the control. 5. To examine the direct arrhythmogenic effect of MS-551 and whether an adrenergic mechanism plays some role on this arrhythmogenesis, a bolus injection of MS-551, 3 mg/kg, was injected either without pre-treatment or after pre-treatment with propranolol 0.3 mg/kg. MS-551 induced arrhythmias in five out of seven dogs (TdP in one dog). Also in the propranolol pre-treated dogs, MS-551 induced arrhythmias in five out of seven dogs (TdP in 1 dog). 6. In conclusion, these observations indicate that MS-551 and KCB-328 induced arrhythmias and intensified proarrhythmic effects of adrenaline, MS-551 being stronger than KCB-328 at the same QTc prolonging doses. The direct arrhythmogenic effect of MS-551 was not influenced by β-blocker treatment

Computer-aided diagnosis of pulmonary nodules on CT scans: Improvement of classification performance with nodule surface features

The purpose of this work is to develop a computer-aided diagnosis (CAD) system to differentiate malignant and benign lung nodules on CT scans. A fully automated system was designed to segment the nodule from its surrounding structured background in a local volume of interest (VOI) and to extract image features for classification. Image segmentation was performed with a 3D active contour method. The initial contour was obtained as the boundary of a binary object generated by k-means clustering within the VOI and smoothed by morphological opening. A data set of 256 lung nodules (124 malignant and 132 benign) from 152 patients was used in this study. In addition to morphological and texture features, the authors designed new nodule surface features to characterize the lung nodule surface smoothness and shape irregularity. The effects of two demographic features, age and gender, as adjunct to the image features were also investigated. A linear discriminant analysis (LDA) classifier built with features from stepwise feature selection was trained using simplex optimization to select the most effective features. A two-loop leave-one-out resampling scheme was developed to reduce the optimistic bias in estimating the test performance of the CAD system. The area under the receiver operating characteristic curve, Az, for the test cases improved significantly (p<0.05) from 0.821±0.026 to 0.857±0.023 when the newly developed image features were included with the original morphological and texture features. A similar experiment performed on the data set restricted to primary cancers and benign nodules, excluding the metastatic cancers, also resulted in an improved test Az, though the improvement did not reach statistical significance (p=0.07). The two demographic features did not significantly affect the performance of the CAD system (p>0.05) when they were added to the feature space containing the morphological, texture, and new gradient field and radius features. To investigate if a support vector machine (SVM) classifier can achieve improved performance over the LDA classifier, we compared the performance of the LDA and SVMs with various kernels and parameters. Principal component analysis was used to reduce the dimensionality of the feature space for both the LDA and the SVM classifiers. When the number of selected principal components was varied, the highest test Az among the SVMs of various kernels and parameters was slightly higher than that of the LDA in one-loop leave-one-case-out resampling. However, no SVM with fixed architecture consistently performed better than the LDA in the range of principal components selected. This study demonstrated that the authors’ proposed segmentation and feature extraction techniques are promising for classifying lung nodules on CT images