Probability-driven 3D pharmacophore mapping of antimycobacterial potential of hybrid molecules combining phenylcarbamoyloxy and N-arylpiperazine fragments.

The current study examines in silico characterization of the structure-inhibitory potency for a set of phenylcarbamic acid derivatives containing an N-arylpiperazine scaffold, considering the electronic, steric and lipophilic properties. The main objective of the ligand-based modelling was the systematic study of classical comparative molecular field analysis (CoMFA)/comparative molecular surface analysis (CoMSA) performance for the modelling of in vitro efficiency observed for these phenylcarbamates, revealing their inhibitory activities against a virulent Mycobacterium tuberculosis H37Rv strain. We compared the findings of efficiency modelling produced by a standard 3D methodology (CoMFA) and its neural counterparts (CoMSA) regarding multiple training/test subsets and variables used. Moreover, systematic space inspection, splitting values into the analysed training/test subsets, was performed to monitor statistical estimator performance while mapping the probability-driven pharmacophore pattern. Consequently, a 'pseudo-consensus' 3D-quantitative structure-activity relationship (3D-QSAR) approach was applied to retrieve an 'average' pharmacophore hypothesis by the investigation of the most densely populated training/test subpopulations to specify the potentially important factors contributing to the inhibitory activity of phenylcarbamic acid analogues. In addition, examination of descriptor-based similarity with a principal component analysis (PCA) procedure was employed to visualize noticeable variations in the performance of these molecules with respect to their structure and activity profiles.

In silico estimation of basic activity-relevant parameters for a set of drug absorption promoters.

Finding a balance between a desired drug's potency and its physicochemical properties that are important for its molecule pharmacokinetic or pharmacodynamics profile is still a challenging issue in rational drug discovery. Quantitative assessment of the lipophilic characteristics of potential drug molecules is indispensable for efficient development of Absorption, Distribution, Metabolism, Excretion, Toxicity-tailored structure-activity models; therefore reliable procedures for deriving log P from molecular structure are desirable. In the current work a range of various software log P predictors for estimation of the numerical lipophilic values for a set of cholic acid derivatives were employed and subsequently cross-compared with the experimental parameters. Thus, the empirical lipophilicity (RM) was compared with the corresponding log P characteristics calculated using alternative methods for deducing the lipophilic features. The mean values of the selected molecular descriptors that were averaged over the chosen calculation methods (consensus clog P) were subsequently correlated with the RM parameter. As an additional experiment, the iterative variable elimination partial least squares (IVE-PLS) methodology for an ensemble of descriptors retrieved from Dragon 6.0 software was applied for a set of drug transporters. To investigate the variations within the ensemble of cholic acid derivatives principal component analysis (PCA) and self-organizing neural network (SOM) procedures were used to visualize the major differences in the performance of drug promoters with respect to their lipophilic profile.

Exploratory analysis of data sets with missing elements and outliers.

The main goal of the presented paper was to develop a general strategy allowing exploration of contaminated data sets with missing elements, based on application of robust PLS for initial estimation of missing elements. Using robust distance, the outlying elements were identified. After their identification and replacing by missing elements, the expectation-maximization algorithm (which can be built in into different computational procedures, such as principal component analysis and its generalisation to the N-way data-the TUCKER3 model) was used for construction of the final model.

Dobutamine echocardiography in patients with aortic stenosis and left ventricular dysfunction: predicting outcome as a function of management strategy.

STUDY OBJECTIVE: To prospectively address the question whether the assessment of valvular hemodynamics and myocardial function during low-dose dobutamine infusion can guide decision making in patients with aortic stenosis and left ventricular (LV) dysfunction. PATIENTS AND MEASUREMENTS: Twenty-four patients with aortic stenosis and LV dysfunction (mean ejection fraction, 28%; New York Heart Association class, II to IV) were studied by dobutamine echocardiography assessing mean pressure gradient, aortic valve area, and aortic valve resistance. Patients were prospectively divided into severe and nonsevere aortic stenosis groups according to the response of the valve area to the augmentation of systolic flow. The clinical decision was considered to be concordant with the results of dobutamine echocardiography, when patients with severe aortic stenosis and preserved contractile function were referred by a specialist for aortic valve replacement and when patients with nonsevere aortic stenosis were not. Patients were observed for up to 3 years. RESULTS: All eight patients with severe aortic stenosis who were referred for surgery survived and had good cardiovascular outcomes, and six of eight patients who were not initially referred for surgery had poor outcomes, including heart failure and sudden cardiac death. The eight patients with nonsevere aortic stenosis did comparatively well without valve replacement. Cardiac death or pulmonary edema occurred in 4 of 16 patients (25%) when the clinical decision was concordant with the results of the dobutamine echocardiogram and occurred in 6 of 8 patients (75%) when the clinical decision was discordant (p = 0.019 [chi(2) test]). CONCLUSION: Patients with aortic stenosis, LV dysfunction, and relatively low gradients have better outcomes when management decisions are based on the results of dobutamine echocardiograms. Those patients identified as having severe aortic stenosis and preserved contractile reserve by dobutamine echocardiography should undergo surgery, while patients identified as having nonsevere aortic stenosis can be managed conservatively.

Soluble P-selectin and the postoperative course following cardiopulmonary bypass in children.

BACKGROUND: Cytokine-inducible leucocyte-endothelial adhesion molecules were shown to affect the postoperative inflammatory response following cardiopulmonary bypass (CPB). Soluble P-selectin (sP-selectin) is one of these molecules. We investigated the correlation between plasma sP-selectin levels and the intra- and postoperative course in children undergoing CPB. METHODS: Serial blood samples of 13 patients were collected preoperatively upon initiation of CPB and seven times postoperatively. Plasma was recovered immediately and frozen at - 70 degrees C until use. Circulating soluble selectin molecules were measured with a sandwich enzyme-linked immunoabsorbent assay technique. RESULTS: The significant post-CPB changes in sP-selectins plasma levels were associated with patient characteristics, operative variables and postoperative course. sP-selectin levels correlated significantly with surgery time, aortic cross-clamping time and inotropic support, as well as with the postoperative Pediatric Risk of Mortality score, hypotension and tachycardia. CONCLUSIONS: A relation between CPB-induced mediators and both early and late clinical effects is suggested. The up-regulation and expression of sP-selectin indicate neutrophil activation as a possible mechanism for the increase, and inhibiting it may reduce the inflammatory response associated with CPB.

Ruptured interventricular septum after blunt chest trauma: ultrasonographic diagnosis.

A 6-year-old child was found under a heavy bookcase that compressed her chest. On admission to the emergency room she was found to be dyspneic with a systolic murmur and complete atrioventricular (A-V) block. Her condition deteriorated rapidly, leading to cardiogenic shock and loss of consciousness. Echocardiographic Doppler evaluation demonstrated a large ventricular septal defect and tricuspid insufficiency. A pericardial patch was put over the tear in the septum, and torn chordae tendinae were reimplanted to the papillary muscles. A pacemaker was inserted. Her situation improved, but on the third day cardiogenic shock and right ventricular dysfunction ensued and the patient expired. A review of the previous 13 cases from the pediatric literature is presented.

Alert to users of calcium supplements as antihypertensive agents due to trace metal contaminants.

Although there are controversies in the role of calcium as an antihypertensive agent, the use of "health food" supplements, such as dolomite and bone meal, is on the rise especially among the older population. One brand of commercial dolomite tablets were investigated for metallic contents such as aluminum (Al), arsenic (As), cadmium (Cd), chromium (Cr), copper (Cu), lead (Pb), manganese (Mn), sclemium (Se), and zinc (Zn). Ten randomly selected tablets were weighted, dried, pulverized and low-temperature plasma ashed. An ash aliquot of each tablet was dissolved in 35% Ultrex nitric acid, and after dilution analyzed using a Perkin-Elmer Model 5000 atomic absorption spectrophotometer equipped with an HGA-500 graphite furnace, As-1 autosampler, and PRS-10 printer sequencer. The results (presented as mean wt/g of powder +/- 95% confidence limits) are: Al 900 +/- 300 micrograms/g; As 1.3 +/- 0.3 micrograms/g; Cd 0.16 +/- 0.04 micrograms/g; Cr 5.9 +/- 1.4 micrograms/g; Cu 3.0 +/- 0.6 micrograms/g; Pb 1.9 +/- 0.5 micrograms/g; Mn 66 +/- 7.0 micrograms/g; Se 1.6 +/- 0.4 micrograms/g; and Zn 147 +/- 88 micrograms/g. These trace metals could pose health hazards to the public such as lead poisoning, dementia, and hypertension due to cadmium. Also, zinc can potentiate cadmium-hypertensive effects. The need exists to initiate some regulations to limit maximal content of trace metals in "health food" supplements to protect high-risk groups and that sector of the population who use megadoses of such products.

Chelating properties of alpha-oximinocarboxamides--II syn-alpha-oximinophenylacetamide: copper(II) complexes.

Syn-alpha-oximinophenylacetamide forms two complexes with Cu(II), a CuL complex at pH < 8.4 and CuL(2) at pH > 8.4. log K(1) = 7.82 +/- 0.07 log beta(2) = 14.32 +/- 0.06.