We tested the ability of the slope (Emax) and the volume intercept (V0) ofthe end-systolic pressure-volume relationship (ESPVR) to indicate contractility changes in conscious dogs instrumented with sonomicrometers measuring left ventricular diameter in three orthogonal axes and a left ventricular pressure microtransducer. ESPVRs were generated by inferior vena caval occlusion under control conditions (C, and C2) and during enhanced (1+) and depressed (I-) inotropic states achieved by infusion of dobutamine and injection of propranolol, respectively. No significant difference between the first control (C,) and I + or between the second control (C2) and I were found for either Emax (C1, 5.31 + 1.68 mmHg/ml, mean + SD;I+, 5.37 + 1.44; C2, 5.20 1.62; I-, 4.18 + 1.32)orVO (C,, 10.3 ± 9.6 ml; 1+, 7.3 ± 9.1; C2, 9.9 ± 9.0; I-, 12.7 ± 12.5), despite significant changes in other indexes of contractility. Comparison of changes in Emax in individual animals in response to I+ and I-revealed that 63% were nonsignificant, 28% were significant and expected, and 9% were significant and paradoxical. Within defined volume limits and irrespective of individual changes in Emax and VO, in all animals I+ shifted the ESPVR above and to the left of C, and I-shifted the ESPVR below and to the right of C2. We thus integrated the changes in Emax and VO by measuring the area beneath each ESPVR between defined limits of end-systolic volume. The values for area were: C,, 612 150 mm Hgml; I+, 745 + 191 (p < .001); C2, 520 + 198; I-, 420 ± 139 (p < .001). We conclude that (1) neither Emax nor VO are individually reliable indexes of changed contractility, and (2) the area beneath the ESPVR between defined end-systolic volume limits is a consistent indicator of variations in inotropic state. Circulation 76, No. 5, 1115-1126

Total dialysis dose (Kt/V) is considered to be a major determinant of morbidity and mortality in hemodialyzed patients. The continuous growth of the blood urea concentration over the 30- to 60-min period following dialysis, a phenomenon known as urea rebound, is a critical factor in determining the true dose of hemodialysis. The misestimation of the equilibrated (true) postdialysis blood urea or equilibrated Kt/V results in an inadequate hemodialysis prescription, with predictably poor clinical outcomes for the patients. The estimation of the equilibrated postdialysis blood urea (eqU) is therefore crucial in order to estimate the equilibrated (true) Kt/V. In this work we propose a supervised neural network to predict the eqU at 60 min after the end of hemodialysis. The use of this model is new in this field and is shown to be better than the currently accepted methods (Smye for eqU and Daugirdas for eqKt/V). With this approach we achieve a mean difference error of 0.22 ± 7.71 mg/ml (mean % error: 1.88 ± 13.46) on the eqU prediction and a mean difference error for eqKt/V of –0.01 ± 0.15 (mean % error: –0.95 ± 14.73). The equilibrated Kt/V estimated with the eqU calculated using the Smye formula is not appropriate because it showed a great dispersion. The Daugirdas double-pool Kt/V estimation formula appeared to be accurate and in agreement with the results of the HEMO study.

Historically, structural elucidation of unknown analytes by mass spectrometry alone has involved tandem mass spectrometry experiments using electron ionization. Most target molecules for bioanalysis in the metabolome are unsuitable for detection by this previous methodology. Recent publications have used high-resolution accurate mass analysis using an LTQ-Orbitrap with the more modern approach of electrospray ionization to identify new metabolites of known metabolic pathways. We have investigated the use of this methodology to build accurate mass fragmentation maps for the structural elucidation of unknown compounds. This has included the development and validation of a novel multi-dimensional LC/MS/MS methodology to identify known uremic analytes in a clinical hemodialysate sample. Good inter- and intra-day reproducibility of both chromatographic stages with a high degree of mass accuracy and precision was achieved with the multi-dimensional liquid chromatography/tandem mass spectrometry (LC/MS/MS) system. Fragmentation maps were generated most successfully using collision-induced dissociation (CID) as, unlike high-energy CID (HCD), ions formed by this technique could be fragmented further. Structural elucidation is more challenging for large analytes >270 Da and distinguishing between isomers where their initial fragmentation pattern is insufficiently different. For small molecules (<200 Da), where fragmentation data may be obtained without loss of signal intensity, complete structures can be proposed from just the accurate mass fragmentation data. This methodology has led to the discovery of a selection of known uremic analytes and two completely novel moieties with chemical structural assignments made.

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