Despite the great morphological diversity of early embryos, the underlying mechanisms of gastrulation are known to be broadly conserved in vertebrates. However, a number of genes characterized as fulfilling an essenti...
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Despite the great morphological diversity of early embryos, the underlying mechanisms of gastrulation are known to be broadly conserved in vertebrates. However, a number of genes characterized as fulfilling an essential function in this process in several model organisms display no clear ortholog in mammalian genomes. We have devised an in silico phylogenomic approach, based on exhaustive similarity searches in vertebrate genomes and subsequent bayesian phylogenetic analyses, to identify such missing genes, presumed to be highly divergent. This approach has been used to identify mammalian orthologs of Not, an homeodomain containing gene previously characterized in Xenopus, chick and zebrafish as playing a critical role in the formation of the notochord. This attempt led to the identification of a highly divergent mammalian Not-related gene in the mouse, human and rat. The results from phylogenetic reconstructions, synteny analyses, expression pattern analyses in wild-type and mutant mouse embryos, and overexpression experiments in Xenopus embryos converge to confirm these genes as representatives of the Not family in mammals. The identification of the mammalian Not gene delivers an important component for the understanding of the genetics underlying notochord formation in mammals and its evolution among vertebrates. The phylogenomic method used to retrieve this gene thus provides a tool, which can complement or validate genome annotations in situations when they are weakly supported. (C) 2004 Elsevier B.V. All rights reserved.
Population pharmacokinetic-dynamic analysis was prospectively integrated in a broad phase II program of lurtotecan (GI147211), a novel camptothecin derived topoisomerase I inhibitor, to determine the population pharma...
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Population pharmacokinetic-dynamic analysis was prospectively integrated in a broad phase II program of lurtotecan (GI147211), a novel camptothecin derived topoisomerase I inhibitor, to determine the population pharmacokinetic profile in a larger population, to estimate individual pharmacokinetic parameters and to investigate relationships with clinical outcome. A sparse sampling method was applied during course one, which involved two sampling time-points. A bayesian algorithm was used to estimate individual pharmacokinetic parameters. in particular total plasma clearance (CL) and volume of distribution. In total, samples were collected of 109 (63%) of 173 patients. Pharmacokinetic-dynamic evaluation could be carried out successfully in 85 (78%) of the sampled patients. CL of lurtotecan showed substantial variability (mean 87 28 L/h) and was of the same magnitude as in the phase I studies where full pharmacokinetic curves were used. Residual variability in the population estimate of CL was 9.9%. No significant relationships were observed between exposure parameters and toxicity nor likelihood of tumor response, however the latter relationship may well have been obscured by the heterogeneity of the studied population. Prospective implementation of large scale population pharmacokinetic-dynamic analysis is feasible and important to establish whether interpatient variability in drug exposure is a major determinant of toxicity or activity.
Carboplatin is associated with significantly less nephrotoxicity and neurotoxicity than is cisplatin. The dose-limiting toxicity of carboplatin is myelotoxicity. A number of dosing methods have been described that all...
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Carboplatin is associated with significantly less nephrotoxicity and neurotoxicity than is cisplatin. The dose-limiting toxicity of carboplatin is myelotoxicity. A number of dosing methods have been described that allow a value for the area under the concentration-time curve to be targeted on the basis of the patient's renal function. Recently a formalised analysis of the pharmacodynamic response to carboplatin revealed a therapeutic window in which the response rate was maximal and toxicity, tolerable. Optimal therapy would result from targeting this window in the individual patient. The aim of this study was to develop a bayesian dose-individualisation method for carboplatin. The method involved (1) development of a highperformance liquid chromatography (HPLC) method to measure serum concentrations of carboplatin;(2) a pharmacokinetic study in 12 women receiving carboplatin for ovarian cancer to estimate the population pharmacokinetic values for this group of patients;(3) development of population models to describe the concentration-time course of carboplatin in serum along with associated errors;and (4) development of an algorithm that uses a sequential bayesian design, which enables estimation of future doses of carboplatin on the basis of feedback from serum concentrations. The results of each of the stages were (1) the coefficient of variation of the assay was 6.3% within day and 8.4% between days (r(2) = 0.9993), and the limit of detection was 0.25 mg/l;(2) Patients' ages ranged from 49 to 68 years, their weights varied from 46 to 85 kg, and their glomerular filtration rate ranged from 3.2 to 7.4 l/h. A geometric mean clearance (Cl) of 6.8 L/h and a steady-state volume of distribution (Vss) of 221 were estimated, which are similar to previously published data;(3) and a two-compartment model best described the data. Two error models were developed, the first describing the error associated with the assay and the second, the error of the two-compartment model,
In this paper, a new color image segmentation method is proposed to extract the region of bladder tumor from a color bladder image. In the past, the diagnosis of bladder tumors mainly relies upon cystoscopic examinati...
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In this paper, a new color image segmentation method is proposed to extract the region of bladder tumor from a color bladder image. In the past, the diagnosis of bladder tumors mainly relies upon cystoscopic examination with an in vivo staining technique. This manner heavily depends on the interpreter's experience and often results in errors in diagnosis. Instead of previous method, we use methylene blue in vivo staining combined with color segmentation techniques to improve the accuracy of the diagnosis of bladder tumors. The segmentation task can be decomposed into two stages. First, cluster detection combined with probabilistic relaxation is used to extract the clusters of specified colors from the HLS color space. Then, in order to refine the chromatic properties, the bayesian algorithm is employed to reject the false region from the clusters obtained in the first stage. Experimental results show that the proposed method can segment the bladder tumor successfully. The technique could serve as an auxiliary tool for doctors or researchers in the diagnosis of bladder tumors.
In this review paper, a qualitative comparison of the performance of nine different segmentation algorithms on a data base of infrared images of vehicles is described. The segmentation methods are categorised accordin...
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In this review paper, a qualitative comparison of the performance of nine different segmentation algorithms on a data base of infrared images of vehicles is described. The segmentation methods are categorised according to their mode of operation into three distinct generic classes of algorithm: namely ‘grey level threshold techniques’, ‘three dimensional histogram methods’ and ‘pixel classification techniques’. Each segmentation technique is guided to a subset of the image by a spoke filter detection algorithm which locates regions of the scene that most resemble blob shaped man-made objects. A short list of four segmentation algorithms is compiled, of which two methods from the ‘pixel classification’ class, aK-nearest neighbour (KNN) and a bayesian algorithm, are selected. The final preference is for the bayesian technique, the KNN method being less favoured owing to the higher computational burden.
Phenytoin dosing in paediatric patients is complicated both by alterations in patient requirements due to growth and maturation changes and by the capacity-limited characteristics of phenytoin metabolism. This study e...
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Phenytoin dosing in paediatric patients is complicated both by alterations in patient requirements due to growth and maturation changes and by the capacity-limited characteristics of phenytoin metabolism. This study examines 2 pharmacokinetic methods to adjust phenytoin dosage based on a single dosing-rate/steady-state serum phenytoin concentration pair. A bayesian forecaster and a fixed parameters [rate of metabolism (Vmax)] method were examined with previously published sets of a priori parameter estimates. The fixed Vmax method was utilised with the parameter derived from native Japanese (method 1), US Caucasian (method 2) and European (method 3) patients. The bayesian forecaster used a priori parameter estimates obtained from native Japanese (method 4) and European (method 5) patients. Each method was examined retrospectively in 34 paediatric patients with a total of 48 predictions possible. Measures of absolute predictability, bias (mean error, % dose) and precision (root mean squared error, % dose), were -3.58/12.2, -1.51/12.2, 4.06/9.96, -4.38/13.2, and -3.10/11.5, for methods 1, 2, 3, 4 and 5, respectively. There was no significant difference among the 5 methods. However, the bayesian algorithm tended to be more robust over a broad range of situations, providing predictions in all cases. The fixed Vmax methods could not provide predictions in every case. Finally, all methods had a significant number of overpredictions of dosage. Poorer results were observed when prediction of steady-state serum concentrations were performed, partly due to the retrospective nature of the study. We conclude that close monitoring of patients, regardless of the method chosen to adjust dosage, is recommended.
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