The influence of propofol or desflurane on postoperative cognitive dysfunction in patients undergoing coronary artery bypass surgery.

We investigated the influence of either propofol or desflurane on the incidence of postoperative cognitive dysfunction in a randomised trial of 180 patients undergoing coronary artery bypass surgery. The primary outcome was incidence of postoperative cognitive dysfunction at 3 months, defined as ≥1 SD deterioration in two or more of 12 neurocognitive tests. Secondary outcomes included early postoperative cognitive dysfunction (between days three and seven), delirium on day one, morbidity and length of hospital stay. Early postoperative cognitive dysfunction was significantly higher with propofol compared with desflurane (56/84 (67.5%) vs 41/83 (49.4%), respectively, p=0.018), but this effect was not seen at 3 months (10/87 (11.2%) vs 9/90 (10.0%), respectively. There was no difference in delirium (7/89 (7.9%) vs 12/91 (13.2%), respectively, length of hospital stay (median (IQR [range]) 7 (6-9 [4-15]) vs 6 (5-7 [5-16) days, respectively or other morbidities. Desflurane was associated with reduced early cognitive dysfunction.

Functional comparison of anaesthetic agents during myocardial ischaemia-reperfusion using pressure-volume loops.

BACKGROUND: Left ventricular (LV) pressure-volume (PV) loops were used to compare the functional effects that accompany the cardioprotection seen with desflurane, sevoflurane, and propofol in a rabbit preparation of coronary ischaemia-reperfusion (IR). METHODS: Male New Zealand White rabbits (n=48) were anaesthetized with propofol (70 mg kg(-1) h(-1)), desflurane (8.9%), or sevoflurane (3.8%) and randomized to receive IR or non-ischaemic time-matched (TC) perfusion protocol. IR groups (desIR, propIR, and sevIR) underwent 30 min of left anterior descending coronary artery occlusion and then 120 min of reperfusion. TC groups (desTC, propTC, and sevTC) were anaesthetized for 150 min without ischaemia. Haemodynamic endpoints included mean arterial pressure, heart rate, cardiac index, systemic vascular resistance index, preload-recruitable stroke-work, time constant of relaxation (tau), and end-diastolic PV relationship (EDPVR). Ventricles in the IR groups were excised and stained with 2,3,5-triphenyl-tetrazolium chloride in order to measure infarct size. RESULTS: Myocardial infarction size was greater in the propIR group [35.74 (sd 11.32)%] compared with the desIR [13.44 (3.09)%] and sevIR [17.96 (6.63)%] groups (P<0.001). EDPVR deteriorated in the sevIR and propIR groups compared with their TC groups, sevTC (P=0.03) and propTC (P=0.044), respectively. There was no difference in any haemodynamic endpoints for the desIR group compared with its TC control (desTC). CONCLUSIONS: During ischaemia, all anaesthetics provide haemodynamic stability and preservation of LV contractility, whereas propofol and sevoflurane, but not desflurane, caused increased LV diastolic stiffness. Desflurane and sevoflurane provide superior cardioprotection compared with propofol.

Randomised comparison of the Classic Laryngeal Mask Airway with the Cobra Perilaryngeal Airway during anaesthesia in spontaneously breathing adult patients.

We tested the hypothesis that the Cobra Perilaryngeal Airway (PLA) with its high volume low-pressure cuff would provide superior airway leakage pressure compared with the Classic Laryngeal Mask Airway (LMA) in spontaneously breathing adult patients. Ninety consecutive adult patients were randomly allocated to receive one of these two supralaryngeal devices. The airway leakage pressure was higher for the PLA compared with the LMA (22 +/- 9 cmH2O vs. 18 +/- 6 cmH2O; P < 0.05). The mean airway device intracuff pressure was lower for the PLA compared to the LMA (36.1 +/- 15.2 mmHg vs. 86.3 +/- 25.3 mmHg P < 0.0001). The time required to achieve successful insertion was greater for the PLA compared with the LMA (39 +/- 21 seconds vs. 27 +/- 10 seconds; P < 0.005). The number of attempts required to achieve successful insertion and the incidence of postoperative complications were similar in both groups. The findings suggest that the PLA provides a superior airway seal at a lower intracuff pressure compared to the LMA. However the time for successful insertion may be increased.

The DNA sequence and analysis of human chromosome 13.

Chromosome 13 is the largest acrocentric human chromosome. It carries genes involved in cancer including the breast cancer type 2 (BRCA2) and retinoblastoma (RB1) genes, is frequently rearranged in B-cell chronic lymphocytic leukaemia, and contains the DAOA locus associated with bipolar disorder and schizophrenia. We describe completion and analysis of 95.5 megabases (Mb) of sequence from chromosome 13, which contains 633 genes and 296 pseudogenes. We estimate that more than 95.4% of the protein-coding genes of this chromosome have been identified, on the basis of comparison with other vertebrate genome sequences. Additionally, 105 putative non-coding RNA genes were found. Chromosome 13 has one of the lowest gene densities (6.5 genes per Mb) among human chromosomes, and contains a central region of 38 Mb where the gene density drops to only 3.1 genes per Mb.

Mining and visualizing large anticancer drug discovery databases.

In order to find more effective anticancer drugs, the U.S. National Cancer Institute (NCI) screens a large number of compounds in vitro against 60 human cancer cell lines from different organs of origin. About 70,000 compounds have been tested in the program since 1990, and each tested compound can be characterized by a vector (i.e., "fingerprint") of 60 anticancer activity, or -[log(GI50)], values. GI50 is the concentration required to inhibit cell growth by 50% compared with untreated controls. Although cell growth inhibitory activity for a single cell line is not very informative, activity patterns across the 60 cell lines can provide incisive information on the mechanisms of action of screened compounds and also on molecular targets and modulators of activity within the cancer cells. Various statistical and artificial intelligence methods, including principal component analysis, hierarchical cluster analysis, stepwise linear regression, multidimensional scaling, neural network modeling, and genetic function approximation, among others, can be used to analyze this large activity database. Mining the database can provide useful information: (a) for the development of anticancer drugs; (b) for a better understanding of the molecular pharmacology of cancer; and (c) for improvement of the drug discovery process.

A gene expression database for the molecular pharmacology of cancer.

We used cDNA microarrays to assess gene expression profiles in 60 human cancer cell lines used in a drug discovery screen by the National Cancer Institute. Using these data, we linked bioinformatics and chemoinformatics by correlating gene expression and drug activity patterns in the NCI60 lines. Clustering the cell lines on the basis of gene expression yielded relationships very different from those obtained by clustering the cell lines on the basis of their response to drugs. Gene-drug relationships for the clinical agents 5-fluorouracil and L-asparaginase exemplify how variations in the transcript levels of particular genes relate to mechanisms of drug sensitivity and resistance. This is the first study to integrate large databases on gene expression and molecular pharmacology.

The arterial blood propofol concentration preventing movement in 50% of healthy women after skin incision.

To target appropriate drug concentrations and to facilitate comparisons between drugs, the potency of propofol must be firmly established. We therefore determined the arterial blood propofol concentration preventing movement in 50% of patients after skin incision and the ability of arterial blood pressure and heart rate to predict movement after incision. Fifteen healthy women scheduled for breast surgery were randomly assigned to computer-targeted propofol blood concentrations. No other drugs were administered. Fifteen minutes after starting the propofol infusion, a 5-cm skin incision was made. Patients were observed for gross purposeful movement for 1 min. Arterial blood was sampled for propofol to confirm steady-state blood concentrations. Arterial blood pressure and heart rate were measured noninvasively. Logistic regression was used to calculate the propofol blood concentrations and arterial blood pressures at which 50% and 95% of patients did not move after skin incision (CP50 and CP95, MABP50 and MABP95, respectively). The CP50 and CP95 values for propofol were 14.3 +/- 1.6 microg/mL (mean +/- SE) and 20.6 microg/mL, respectively. The MABP50 and MABP95 values were 63 +/- 4 mm Hg and 43 mm Hg, respectively. Heart rate did not differ significantly in patients who moved and who did not move. Propofol blood concentrations required to prevent movement in most patients resulted in significant arterial hypotension.

Maximum likelihood multivariate calibration.

Two new approaches to multivariate calibration are described that, for the first time, allow information on measurement uncertainties to be included in the calibration process in a statistically meaningful way. The new methods, referred to as maximum likelihood principal components regression (MLPCR) and maximum likelihood latent root regression (MLLRR), are based on principles of maximum likelihood parameter estimation. MLPCR and MLLRR are generalizations of principal components regression (PCR), which has been widely used in chemistry, and latent root regression (LRR), which has been virtually ignored in this field. Both of the new methods are based on decomposition of the calibration data matrix by maximum likelihood principal component analysis (MLPCA), which has been recently described (Wentzell, P. D.; et al. J. Chemom., in press). By using estimates of the measurement error variance, MLPCR and MLLRR are able to extract the optimum amount of information from each measurement and, thereby, exhibit superior performance over conventional multivariate calibration methods such as PCR and partial least-squares regression (PLS) when there is a nonuniform error structure. The new techniques reduce to PCR and LRR when assumptions of uniform noise are valid. Comparisons of MLPCR, MLLRR, PCR, and PLS are carried out using simulated and experimental data sets consisting of three-component mixtures. In all cases of nonuniform errors examined, the predictive ability of the maximum likelihood methods is superior to that of PCR and PLS, with PLS performing somewhat better than PCR. MLLRR generally performed better than MLPCR, but in most cases the improvement was marginal. The differences between PCR and MLPCR are elucidated by examining the multivariate sensitivity of the two methods.