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PubMed2006

A knowledge-guided active model method of cortical structure segmentation on pediatric MR images.

PURPOSE: To develop an automated method for quantification of cortical structures on pediatric MR images. MATERIALS AND METHODS: A knowledge-guided active model (KAM) approach was proposed with a novel object function similar to the Gibbs free energy function. Triangular mesh models were transformed to images of a given subject by maximizing entropy, and then actively slithered to boundaries of structures by minimizing enthalpy. Volumetric results and image similarities of 10 different cortical structures segmented by KAM were compared with those traced manually. Furthermore, the segmentation performances of KAM and SPM2, (statistical parametric mapping, a MATLAB software package) were compared. RESULTS: The averaged volumetric agreements between KAM- and manually-defined structures (both 0.95 for structures in healthy children and children with medulloblastoma) were higher than the volumetric agreement for SPM2 (0.90 and 0.80, respectively). The similarity measurements (kappa) between KAM- and manually-defined structures (0.95 and 0.93, respectively) were higher than those for SPM2 (both 0.86). CONCLUSION: We have developed a novel automatic algorithm, KAM, for segmentation of cortical structures on MR images of pediatric patients. Our preliminary results indicated that when segmenting cortical structures, KAM was in better agreement with manually-delineated structures than SPM2. KAM can potentially be used to segment cortical structures for conformal radiation therapy planning and for quantitative evaluation of changes in disease or abnormality.

Algorithms↗
PubMed1980

Pharmacokinetics of morphine and its surrogates IV: Pharmacokinetics of heroin and its derived metabolites in dogs.

The pharmacokinetics of intravenously administered heroin and its derived metabolites, 6-O-monoacetylmorphine, morphine, and the glucuronidated conjugates of morphine, were studied in dogs at doses of 0.1-0.5 mg/kg. The spontaneous hydrolysis of the sampled biological fluids was inhibited by tetraethyl pyrophosphate so that the heroin concentration at the times of sampling could be analyzed for the first time. Heroin is concomitantly rapidly metabolized and distributed among body tissues. Metabolic clearance of 2916 +/- 321 ml/min are largely extrahepatic and are sixfold greater than hepatic blood flow. Nevertheless, the terminal half-life of 60-90 min resembles that of morphine and is maintained by the rate-determining return of distributed heroin from esterase-free tissues. Normal renal clearances of 43 +/- 6 ml/min result in 1.6 +/- 0.2% of the dose being renally excreted unchanged. The large overall volume of distribution, 344 +/- 60 liters, is indicative of heroin's wide distribution and lipophilicity, which rapidly equilibrates heroin in the plasma with the cerebrospinal fluid. Heroin is concomitantly metabolized almost equally to 6-O-monoacetylmorphine and morphine. The monoacetylmorphine is metabolized concomitantly to morphine and glucuronide conjugates in a 4:3 ratio and exercises its own activity. Its time course is close to that of heroin, although the total clearance (2200 ml/min) and overall volumes of distribution (90-170 liters) were less. The integrated model of transformations and eliminations was constructed with concomitant metabolism of the heroin metabolite, 6-O-monoacetylmorphine, to morphine and glucuronide conjugates. The assumption that the glucuronide conjugates partition into the bile and systemic circulation in the same ratio as does the conjugate of the derived morphine metabolite gave pharmacokinetic parameters consistent with the morphine pharmacokinetics studied previously and provided excellent fits of the plasma level-time curves of all of the derived metabolites of heroin.

Animals↗
PubMed2026

Epigenetic Reprogramming and Zygotic Genome Activation in Human Preimplantation Development: Mechanisms, Models, and Translational Prospects.

PURPOSE: Early human embryogenesis unfolds through a tightly coupled sequence of events-clearance of maternal transcripts, remodeling of parental chromatin, zygotic genome activation (ZGA), lineage segregation, implantation, and post-implantation patterning-accompanied by epigenetic reprogramming, including X-chromosome dosage compensation around the time of implantation. This review aims to synthesize recent advances in understanding this developmental program and to consider their implications for reproductive medicine. METHODS: I review recent literature on human early embryogenesis, with particular emphasis on findings enabled by single-cell genomics and stem-cell-based embryo modeling, and integrate these insights to identify human-specific features of early development. RESULTS: These approaches have made previously inaccessible aspects of human early embryogenesis experimentally tractable, revealing molecular and epigenetic features that distinguish human development from that of model organisms, including species-specific dynamics of ZGA, maternal transcript clearance, chromatin reprogramming, and X-chromosome dosage compensation. CONCLUSIONS: Advances in single-cell genomics and embryo modeling are transforming our understanding of human early embryogenesis. Building on these insights, while recognizing their current limitations, I propose a vision for improving reproductive medicine, including the potential for next-generation embryo selection strategies.

Journal Article↗
PubMed1999

Effects of Carboxylic Acids on Calcite Formation in the Presence of Mg2+ Ions.

The effects of seven carboxylic acids on calcite formation in the presence of Mg2+ ions, whose molar concentration ratio Mg2+/Ca2+ = 0.5 exclusively induced aragonite precipitation in the absence of carboxylic acids, were studied using a double diffusion technique. The presence of carboxylic acids, acrylic acid, maleic acid, tartaric acid, malonic acid, malic acid, succinic acid, and citric acid in the gel medium favored the formation of magnesian calcite relative to the amount of the additives. Induction time and the positions of the first precipitation were measured to analyze the behavior of crystallization based on the equivalency rule. The formation of magnesian calcite was also studied with the help of Avrami's equation (solid-state model for transformation). The results of applying this equation suggested that aragonite transformed into calcite through a solid-to-solid process. The formation of magnesian calcite was interpreted as the following process: aragonite nuclei, formed owing to Mg2+ ions at the initial stage of CaCO3 crystallization, transformed into calcite nuclei through a solid-to-solid process while their growth was inhibited by the adsorption of carboxylic acids. The magnesian calcite crystals grew on crystal seeds of calcite formed from aragonite nuclei. Copyright 1999 Academic Press.

Journal Article↗
PubMed2001

Landmark-based morphometrics of the normal adult brain using MRI.

We describe the application of statistical shape analysis to homologous landmarks on the cortical surface of the adult human brain. Statistical shape analysis has a sound theoretical basis. Landmarks are identified on the surface of a 3-D reconstruction of the segmented cortical surface from magnetic resonance image (MRI) data. Using publicly available software (morphologika) the location and size dependence of the landmarks are removed and the differences in landmark distribution across subjects are analysed using principal component analysis. These differences, representing shape differences between subjects, can be visually assessed using wireframe models and transformation grids. The MRI data of 58 adult brains (27 female and 15 left handed) were examined. Shape differences in the whole brain are described which concern the relative orientation of frontal lobe sulci. Analysis of all 116 hemispheres revealed a statistically significant difference (P < 0.001) between left and right hemispheres. This finding was significant for right- but not left-handed subjects alone. No other significant age, gender, handedness, or brain-size correlations with shape differences were found.

Adolescent↗
PubMed1996

Exposure of organ cultures from human tracheal epithelium to chemical carcinogens and subsequent long-term co-cultivation with autologous isotopic fibroblasts.

As a continuation of previous experiments introducing an extracorporeal model for transformation of human respiratory epithelium that might be able to mimic a spontaneously occurring malignant tumor, we prepared organ cultures from tracheal specimens and exposed them repeatedly to chemical carcinogens, using benzo(a)pyrene and methylnitronitrosoguanine for 6 weeks. We then tried to select possibly initiated cells by subsequent co-cultivation with autologous isotopic fibroblasts for 2 years. Nontreated controls were maintained from the same specimens and cultured in the same manner. By this technique we selected from specimen La24 three long-living cell lines with varying morphology and an antigenic pattern indicating dedifferentiation. The cells expressed simultaneously a panel of cytokeratins, vimentin and neuroectodermal antigens. Transplantation of these cell lines under the subrenal capsule of athymic mice resulted in tumorlike nodules of limited size. Success rate was dependent on time of previous in vitro culture and carcinogen treatment. None of the lines produced invasive or metastasizing tumors.

Animals↗
PubMed1993

Lysosomal glycosphingolipid storage in chloroquine-induced alpha-galactosidase-deficient human endothelial cells with transformation by simian virus 40: in vitro model of Fabry disease.

Human umbilical venous endothelial cells were transformed with a temperature-sensitive mutant of simian virus 40, tsA640, and a cell line, subcultured for over 20 serial passages, was established at a temperature permissive for the virus. Treatment of transformed endothelium with 3 micrograms/ml chloroquine caused a specific reduction of alpha-galactosidase activity, without cell injury, and revealed several electron-dense materials surrounded by single unit membranes. Crystalline lamellae in lysosomes with a periodicity of 6.5 nm, which are typically seen in various tissues in Fabry disease, were produced in the presence of a glycosphingolipid mixture. These cells should be useful for in vitro pathophysiological studies on Fabry endothelium.

Cell Transformation, Viral↗
PubMed1999

Performance of short-time spectral parametric methods for reducing the variance of the Doppler ultrasound mean instantaneous frequency estimation.

To achieve an accurate estimation of the instantaneous turbulent velocity fluctuations downstream of prosthetic heart valves in vivo, the variability of the spectral method used to measure the mean frequency shift of the Doppler signal (i.e. the Doppler velocity) should be minimised. This paper investigates the performance of various short-time spectral parametric methods such as the short-time Fourier transform, autoregressive modelling based on two different approaches, autoregressive moving average modelling based on the Steiglitz-McBride method, and Prony's spectral method. A simulated Doppler signal was used to evaluate the performance of the above mentioned spectral methods and Gaussian noise was added to obtain a set of signals with various signal-to-noise ratios. Two different parameters were used to evaluate the performance of each method in terms of variability and accurate matching of the theoretical Doppler mean instantaneous frequency variation within the cardiac cycle. Results show that autoregressive modelling outperforms the other investigated spectral techniques for window lengths varying between 1 and 10 ms. Among the autoregressive algorithms implemented, it is shown that the maximum entropy method based on a block data processing technique gives the best results for a signal-to-noise ratio of 20 dB. However, at 10 and 0 dB, the Levinson-Durbin algorithm surpasses the performance of the maximum entropy method. It is expected that the intrinsic variance of the spectral methods can be an important source of error for the estimation of the turbulence intensity. The range of this error varies from 0.38% to 24% depending on the parameters of the spectral method and the signal-to-noise ratio.

Blood Flow Velocity↗
PubMed2003

Visually guided orientation in flies: case studies in computational neuroethology.

To understand the functioning of nervous systems and, in particular, how they control behaviour we must bridge many levels of complexity from molecules, cells and synapses to perception behaviour. Although experimental analysis is a precondition for understanding by nervous systems, it is in no way sufficient. The understanding is aided at all levels of complexity by modelling. Modelling proved to be an inevitable tool to test the experimentally established hypotheses. In this review it will by exemplified by three case studies that the appropriate level of modelling needs to be adjusted to the particular computational problems that are to be solved. (1) Specific features of the highly virtuosic pursuit behaviour of male flies can be understood on the basis of a phenomenological model that relates the visual input to the motor output. (2) The processing of retinal image motion as is experienced by freely moving animals can be understood on the basis of a model consisting of algorithmic components and components which represent a simple equivalent circuit of nerve cells. (3) Behaviourally relevant features of the reliability of encoding of visual motion information can be understood by modelling the transformation of postsynaptic potentials into sequences of spike trains.

Animals↗
PubMed1990

Promoter is an important determinant of developmentally regulated puffing at the Sgs-4 locus of Drosophila melanogaster.

Sgs-4 is one of the eight known genes coding for larval secretion proteins in Drosophila melanogaster. High-level transcription of the endogenous Sgs genes in salivary glands is accompanied by chromosome puffing at the Sgs gene loci. Naturally occurring mutations of the Sgs-4 promoter region diminish both the level of Sgs-4 expression and the puff size; in null-producers no puff is formed. P element-mediated transformation experiments were performed to clarify this apparent causal relation between transcription and puffing. Sgs-4 upstream sequences, unchanged or recombined with sequences from differently expressed alleles, were fused with Sgs-4 coding and downstream sequences or with the coding sequence of the viral oncogene v-mil. Analyses of the expression of these fragments at the RNA and protein levels and of their capacity for puff formation demonstrate uncoupling of transcription and puffing. That is, high-level transcription is independent of chromosome puffing and does not necessarily induce puffing, and developmentally regulated chromosome puffing is independent of significant transcriptional activity within the puff. Our results show that the strength of the Sgs-4 promoter located within the upstream region from -1 to -840 determines the formation of a puff. No specific effects could be detected on either transcription or puffing by decondensed versus compact chromatin adjoining the transposed DNA at the sites of insertion in transformants. A model in which trans-acting factors binding to the promoter region initiate puffing is proposed.

Animals↗
PubMed1995

The c-erbB transmembrane growth factor receptors as serum biomarkers in human cancer studies.

Over-expression of the transmembrane growth factor receptors encoded by the c-erbB oncogenes contributes to cellular transformation in model systems and is found to be a frequent occurrence in human tumors. Over-expression of these receptors results in accumulation of the extra-cellular domain in the extra-cellular supernatant in vitro and in elevated levels of the extra-cellular domain in serum in vivo in animal models. Similarly, elevated levels of the extra-cellular domain of these receptors have been detected in the serum of individuals with various cancers, including of the breast, ovary, prostate, stomach, pancreas, colon, liver, and lung. In some cases, elevated serum levels have been detectable prior to the time of clinical diagnosis of disease. Thus, the serum levels of the extra-cellular domains of the c-erbB transmembrane growth factor receptors may be useful biomarkers of carcinogenesis in human studies.

Biomarkers, Tumor↗
PubMed1987

Global factors generate the McCollough effect.

It has recently been demonstrated that certain globally orthogonal pattern pairs derived from Hoffman's Lie Transformation Group Model of Neuropsychology (LTG/NP) are sufficient to generate McCollough effects (pattern-contingent colour aftereffects: PCCAES). We now provide evidence that the global factors postulated to generate these particular PCCAEs are also necessary. In Experiment 1 observers made controlled eye movements over the induction patterns and subsequently showed PCCAEs which were as strong as those obtained under central fixation. The induction process therefore did not depend on selectively adapting local oriented and colour-specific edge detectors. The global structure of the inducing patterns appears to be a necessary component of the generation of such aftereffects. In Experiment 2, a number of pattern pairs having various degrees of global organization were used as induction patterns, but in every case there was an equal degree of local orthogonality. Local orthogonality was shown not to be sufficient to induce PCCAEs, but global orthogonality was. These results lend strong support to the notion that McCollough-type PCCAEs are generated in a structure of the visual system somewhat above the level of strictly local operations, whether defined as edge and bar detectors or, equivalently, as units selectively tuned to different spatial frequencies and orientations. The global nature of the effects, and the particular pattern structures involved, lead us to suggest that Hoffman's LTG/NP provides a sound basis for explaining our findings.

Adolescent↗
PubMed1995

Aging of polymer networks as studied by material property NMR imaging.

Relaxation-weighted NMR imaging is a powerful tool for the investigation of aging processes in rubber networks, in particular if it is combined with a theoretical description to relate the NMR data with suitable parameters of the material. Following this concept, spin-spin relaxation decays in rubber samples, consisting of differently aged pieces of natural rubber have been acquired in a spatially resolved experiment. The data were evaluated using a dynamical model and transformed into images of those material properties, which are affected by the aging process. Images representing the crosslink density and the correlation times, which characterize the polymer chain dynamics, have been calculated. The differently aged rubber pieces can be easily discriminated in such material property (MAP) images.

Magnetic Resonance Spectroscopy↗
PubMed2005

Melatonin strongly interacts with zwitterionic model membranes--evidence from Fourier transform infrared spectroscopy and differential scanning calorimetry.

Interactions of melatonin with zwitterionic dipalmitoyl phosphatidylcholine (DPPC) multilamellar liposomes (MLVs) were investigated as a function of temperature and melatonin concentration (1-30 mol%) by using two noninvasive techniques, namely Fourier transform infrared (FTIR) spectroscopy and differential scanning calorimetry (DSC). The investigation of the C-H, CO, and PO2- antisymmetric double stretching modes in FTIR spectra and DSC studies reveal that melatonin changes the physical properties of the DPPC bilayers by decreasing the main phase transition temperature, abolishing the pretransition, ordering the system in the gel phase, and increasing the dynamics of the system both in the gel and liquid crystalline phases. It also causes significant decrease in the wavenumber for the CO stretching and PO2- antisymmetric double bond stretching bands, which indicates strong hydrogen bonding The results imply that melatonin locates in the interfacial region of the membrane. Furthermore, in the DSC curve, more than one signal is observed at high melatonin concentrations (24 and 30 mol%), which indicates melatonin-induced phase separation in DPPC membranes.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed2003

Dosimetric quality endpoints for low-dose-rate prostate brachytherapy using biological effective dose (BED) vs. conventional dose.

The purpose of this study was to compare conventional low-dose-rate prostate brachytherapy dosimetric quality parameters with their biological effective dose (BED) counterparts. To validate a model for transformation from conventional dose to BED, the postimplant plans of 31 prostate brachytherapy patients were evaluated using conventional dose-volume histogram (DVH) quality endpoints and analogous BED-DVH endpoints. Based on CT scans obtained 4 weeks after implantation, DVHs were computed and standard dosimetric endpoints V100 (volume receiving 100% of the prescribed dose), V150, V200, HI (1-[V150/V100]), and D90 (dose that 90% of the target volume received) were obtained for quality analysis. Using known and reported transformations, dose grids were transformed to BED-early (alpha/beta = 10 Gy) and BED-late (alpha/beta = 3 Gy) grids, and the same dosimetric endpoints were analyzed. For conventional, BED-early and BED-late DVHs, no differences in V100 were seen (0.896, 0.893, and 0.894, respectively). However, V150 and V200 were significantly higher for both BED-early (0.582 and 0.316) and BED-late (0.595 and 0.337), compared with the conventional (0.539 and 0.255) DVHs. D90 was significantly lower for the BED-early (103.1 Gy) and BED-late transformations (106.9 Gy) as compared with the conventional (119.5 Gy) DVHs. The conventional prescription parameter V100 is the same for the corresponding BED-early and BED-late transformed DVHs. The toxicity parameters V150 and V200 are slightly higher using the BED transformations, suggesting that the BED doses are somewhat higher than predicted using conventional DVHs. The prescription/quality parameter D90 is slightly lower, implying that target coverage is lower than predicted using conventional DVHs. This methodology can be applied to analyze BED dosimetric endpoints to improve clinical outcome and reduce complications of prostate brachytherapy.

Brachytherapy↗
PubMed2003

A simple model to predict coronary disease in patients undergoing operation for mitral regurgitation.

BACKGROUND: Coexistent coronary disease can be identified in a third of patients with mitral valve disease. This study aims to evaluate candidate selection strategy using risk factor identification and logistic regression and to develop an additive model for the prediction of coexistent coronary disease. METHODS: The sample is a consecutive series of patients who had mitral repair from 1987 to 1999. Sensitivities and specificities were calculated for each risk factor. Variables for prediction of coronary disease were entered into a univariate analysis, and predictors were entered into a forward and backward stepwise multivariate logistic regression model to form a predictive score. An additive model was derived from transformation of the logistic model. Receiver operating characteristic curves were used to compare discrimination and precision quantified by the Hosmer-Lemeshow statistic. RESULTS: The American Heart Association and American College of Cardiology risk factor identification selection criteria for the 359 patients who had screening coronary angiography yielded 100% sensitivity and 1% specificity. Risk prediction with our logistic model produced a receiver operating characteristic curve area of 0.91 and Hosmer-Lemeshow score of 3.4 (p = 0.9). Similar discriminating ability for our patients was achieved by the Cleveland Clinic logistic model (receiver operator characteristic curve area of 0.79; Hosmer-Lemeshow score of 12; p = 0.1). Our five-item additive model produced receiver operating characteristic curve area of 0.91 and Hosmer-Lemeshow score of 3.81 (p = 0.80). CONCLUSIONS: Simple risk factor identification has excellent sensitivity but is limited by specificity. Logistic regression modeling is an accurate risk prediction method but is difficult to apply at the bedside. Simplicity and accuracy may be achieved by the logistic regression-derived simple additive model.

Aged↗