Biomedical subjects

S Ruan

Publications and source records attributed to S Ruan.

At least 19 recordsLinked to original sources

PubMed2003

A stereotactic method for the three-dimensional registration of multi-modality biologic images in animals: NMR, PET, histology, and autoradiography.

The objective of this work was to develop and then validate a stereotactic fiduciary marker system for tumor xenografts in rodents which could be used to co-register magnetic resonance imaging (MRI), PET, tissue histology, autoradiography, and measurements from physiologic probes. A Teflon fiduciary template has been designed which allows the precise insertion of small hollow Teflon rods (0.71 mm diameter) into a tumor. These rods can be visualized by MRI and PET as well as by histology and autoradiography on tissue sections. The methodology has been applied and tested on a rigid phantom, on tissue phantom material, and finally on tumor bearing mice. Image registration has been performed between the MRI and PET images for the rigid Teflon phantom and among MRI, digitized microscopy images of tissue histology, and autoradiograms for both tissue phantom and tumor-bearing mice. A registration accuracy, expressed as the average Euclidean distance between the centers of three fiduciary markers among the registered image sets, of 0.2 +/- 0.06 mm was achieved between MRI and microPET image sets of a rigid Teflon phantom. The fiduciary template allows digitized tissue sections to be co-registered with three-dimensional MRI images with an average accuracy of 0.21 and 0.25 mm for the tissue phantoms and tumor xenografts, respectively. Between histology and autoradiograms, it was 0.19 and 0.21 mm for tissue phantoms and tumor xenografts, respectively. The fiduciary marker system provides a coordinate system with which to correlate information from multiple image types, on a voxel-by-voxel basis, with sub-millimeter accuracy--even among imaging modalities with widely disparate spatial resolution and in the absence of identifiable anatomic landmarks.

Algorithms↗

PubMed2001

Oscillations in plankton models with nutrient recycling.

Plankton--nutrient interaction models with both instantaneous and delayed nutrient recycling are considered. The system consists of three components: autotrophic phytoplankton, herbivorous zooplankton and dissolved limiting nutrient. Local stability of the equilibria is analysed. It is shown that the positive equilibrium loses its stability when the nutrient input concentration passes through a critical value and the Hopf bifurcation occurs that induces oscillations of the populations. Numerical simulations are carried out to illustrate the obtained results.

Animals↗

PubMed2001

1,2,5-Thiadiazolidin-3-one 1,1 dioxide: a powerful scaffold for probing the S' subsites of (chymo)trypsin-like serine proteases.

The 1,2,5-thiadiazolidin-3-one 1,1 dioxide scaffold (I) embodies a motif that allows it to dock to the active site of (chymo)trypsin-like proteases in a predictable and substrate-like fashion. Consequently, inhibitors derived from this heterocyclic scaffold interact with both the S and S' subsites of an enzyme. Exploitation of binding interactions with both the S and S' subsites of a target enzyme may lead to compounds with greatly enhanced enzyme selectivity and inhibitory potency. This preliminary report describes the use of a series of compounds having the heterocyclic scaffold linked to various amino acids to probe the S' subsites of human leukocyte elastase (HLE), proteinase 3 (PR 3), and cathepsin G (Cat G). For comparative purposes, a series of compounds derived from a related scaffold, isothiazolidin-3-one 1,1 dioxide (II), was also generated. Several of the compounds were found to be highly potent and selective time-dependent inhibitors of HLE, PR 3, and Cat G.

Cathepsin G↗

PubMed2001

Predator-prey models with delay and prey harvesting.

It is known that predator-prey systems with constant rate harvesting exhibit very rich dynamics. On the other hand, incorporating time delays into predator-prey models could induce instability and bifurcation. In this paper we are interested in studying the combined effects of the harvesting rate and the time delay on the dynamics of the generalized Gause-type predator-prey models and the Wangersky-Cunningham model. It is shown that in these models the time delay can cause a stable equilibrium to become unstable and even a switching of stabilities, while the harvesting rate has a stabilizing effect on the equilibrium if it is under the critical harvesting level. In particular, one of these models loses stability when the delay varies and then regains its stability when the harvesting rate is increased. Computer simulations are carried to explain the mathematical conclusions.

Animals↗

PubMed2001

Global dynamics of a ratio-dependent predator-prey system.

Recently, ratio-dependent predator-prey systems have been regarded by some researchers to be more appropriate for predator-prey interactions where predation involves serious searching processes. However, such models have set up a challenging issue regarding their dynamics near the origin since these models are not well-defined there. In this paper, the qualitative behavior of a class of ratio-dependent predator-prey system at the origin in the interior of the first quadrant is studied. It is shown that the origin is indeed a critical point of higher order. There can exist numerous kinds of topological structures in a neighborhood of the origin including the parabolic orbits, the elliptic orbits, the hyperbolic orbits, and any combination of them. These structures have important implications for the global behavior of the model. Global qualitative analysis of the model depending on all parameters is carried out, and conditions of existence and non-existence of limit cycles for the model are given. Computer simulations are presented to illustrate the conclusions.

Animals↗

PubMed2001

Inhibition of serine proteases by functionalized sulfonamides coupled to the 1,2,5-thiadiazolidin-3-one 1,1 dioxide scaffold.

A challenge associated with drug design is the development of selective inhibitors of proteases (serine or cysteine) that exhibit the same primary substrate specificity, that is, show a preference for the same P(1) residue. While these proteases have similar active sites, nevertheless there are subtle differences in their S and S' subsites which can be exploited. We describe herein for the first time the use of functionalized sulfonamides as a design and diversity element which, when coupled to the 1,2,5-thiadiazolidin-3-one 1,1 dioxide scaffold yields potent, time-dependent inhibitors of the serine proteases human leukocyte elastase (HLE), proteinase 3 (PR 3) and cathepsin G(Cat G). Our preliminary findings suggest that (a) appending to the 1,2,5-thiadiazolidin-3-one 1,1 dioxide scaffold recognition and diversity elements that interact with both the S and S' subsites of a target protease may result in optimal enzyme selectivity and potency and, (b) functionalized sulfonamides constitute a powerful design and diversity element with low intrinsic chemical reactivity and potentially wide applicability.

Cathepsin G↗

PubMed2001

On the number of clusters and the fuzziness index for unsupervised FCA application to BOLD fMRI time series.

The aim of this paper is to present an exploratory data-driven strategy based on Unsupervised Fuzzy Clustering Analysis (UFCA) and its potential for fMRI data analysis in the temporal domain. The a priori definition of the number of clusters is addressed and solved using heuristics. An original validity criterion is proposed taking into account data geometry and the partition Membership Functions (MFs). From our simulations, this criterion is shown to outperform other indices used in the literature. The influence of the fuzziness index was studied using simulated activation combined with real life noise data acquired from subjects under a resting state. Receiver Operating Characteristics (ROC) methodology is implemented to assess the performance of the proposed UFCA with respect to the fuzziness index. An interval of choice around 2, a value widely used in FCA, is shown to yield the best performance.

Algorithms↗

PubMed2001

On the zeros of a third degree exponential polynomial with applications to a delayed model for the control of testosterone secretion.

In this paper, we first study the distribution of the zeros of a third degree exponential polynomial. Then we apply the obtained results to a delay model for the control of testosterone secretion. It is shown that under certain assumptions on the coefficients the steady state of the delay model is asymptotically stable for all delay values. Under another set of conditions, there is a critical delay value, the steady state is stable when the delay is less than the critical value and unstable when the delay is greater than the critical value. Thus, oscillations via Hopf bifurcation occur at the steady state when the delay passes through the critical value. Numerical simulations are presented to illustrate the results.

Animals↗

PubMed2001

Effect of alcohol consumption on host release of interleukin-17 during pulmonary infection with Klebsiella pneumoniae.

BACKGROUND: A link between alcohol abuse and bacterial pneumonia has been recognized for centuries, but mechanisms to explain this relationship are unclarified. Interleukin-17 (IL-17) is a lymphocyte-derived cytokine that is part of the inflammatory cytokine cascade. Previous studies from our laboratory indicated that IL-17 is released in lung tissue in a murine model of bacterial pneumonia caused by Klebsiella pneumoniae. The effects of alcohol consumption on pulmonary release of IL-17 are unknown. METHODS: Mice were maintained on 20% ethanol in drinking water or on a control diet without alcohol. After 2 weeks, alcohol and control mice were challenged with intratracheal K. pneumoniae. Mice were followed for survival after bacterial challenge, neutrophil recruitment was assayed as myeloperoxidase, and IL-17 was measured in lung lavage fluid by enzyme-linked immunosorbent assay. In additional experiments, splenocytes from control mice were incubated with ethanol in vitro, and release of IL-17 was measured in culture supernatants. Finally, control and alcohol mice received intrapulmonary gene transfer of E-1-deleted adenovirus containing the murine IL-17 gene. These mice were then challenged with K. pneumoniae and followed for survival and neutrophil recruitment. RESULTS: In these studies, we demonstrate that a 2-week history of ethanol consumption in mice suppresses release of IL-17 into lung tissue, decreases neutrophil recruitment, and increases mortality from experimental K. pneumonia. In vitro experiments confirm a direct suppressive effect of ethanol on the release of IL-17 from splenocytes. In vivo administration of the IL-17 gene in an adenoviral vector to alcohol-consuming mice results in release of IL-17 into lavage fluid and normalizes neutrophil recruitment and mortality after bacterial challenge. CONCLUSIONS: The results of these experiments strongly implicate IL-17 as an important pathway for the immunosuppression associated with alcohol abuse and support gene therapeutic approaches to augment immune function in the alcoholic host or to treat infections associated with alcoholism.

Animals↗

PubMed2001

PET imaging of (86)Y-labeled anti-Lewis Y monoclonal antibodies in a nude mouse model: comparison between (86)Y and (111)In radiolabels.

UNLABELLED: Absorbed doses in (90)Y radioimmunotherapy are usually estimated by extrapolating from (111)In imaging data. PET using (86)Y (beta(+) 33%; half-life, 14.7 h) as a surrogate radiolabel could be a more accurate alternative. The aim of this study was to evaluate an (86)Y-labeled monoclonal antibody (mAb) as a PET imaging agent and to compare the biodistribution of (86)Y- and (111)In-labeled mAb. METHODS: The humanized anti-Lewis Y mAb hu3S193 was labeled with (111)In or (86)Y through CHX-A"-diethylenetriaminepentaacetic acid chelation. In vitro cell binding and cellular retention of radiolabeled hu3S193 were evaluated using HCT-15 colon carcinoma cells, a cell line expressing Lewis Y. Nude mice bearing HCT-15 xenografts were injected with (86)Y-hu3S193 or (111)In-hu3S193. The biodistribution was studied by measurements of dissected tissues as well as by PET and planar imaging. RESULTS: The overall radiochemical yield in hu3S193 labeling and purification was 42% +/- 2% (n = 2) and 76% +/- 3% (n = 6) for (86)Y and (111)In, respectively. Both radioimmunoconjugates specifically bound to HCT-15 cells. When cellular retention of hu3S193 was studied using (111)In-hu3S193, 80% of initially cell-bound (111)In activity was released into the medium as high-molecular-weight compounds within 8 h. When coadministered, in vivo tumor uptake of (86)Y-hu3S193 and (111)In-hu3S193 reached maximum values of 30 +/- 6 and 29 +/- 6 percentage injected dose per gram and tumor sites were easily identifiable by PET and planar imaging, respectively. CONCLUSION: At 2 d after injection of (111)In-hu3S193 and (86)Y-hu3S193 radioimmunoconjugates, the uptake of (111)In and (86)Y activity was generally similar in most tissues. After 4 d, however, the concentration of (86)Y activity was significantly higher in several tissues, including tumor and bone tissue. Accordingly, the quantitative information offered by PET, combined with the presumably identical biodistribution of (86)Y and (90)Y radiolabels, should enable more accurate absorbed dose estimates in (90)Y radioimmunotherapy.

Animals↗

PubMed2000

Murine CD4+ T lymphocyte subsets and host defense against Pneumocystis carinii.

The recruitment of specific subsets of CD4(+) T lymphocytes to the lungs in response to Pneumocystis carinii was investigated. For mice inoculated with P. carinii, an ELISPOT assay was used to calculate the numbers of lymph node and lung tissue CD4(+) cells that secreted interferon (IFN)-gamma (Th1 cytokine) and interleukin (IL)-4 (Th2 cytokine) after concanavalin A stimulation. An ELISA was used to assay culture supernatants for cytokine concentrations. Precursor frequency of both IFN-gamma- and IL-4-secreting cells was increased in lymph nodes at 1 week, whereas increases in Th1 and Th2 cells in lung tissue were delayed 3 weeks before declining. The frequency of IL-4-secreting cells always was greater than the frequency of IFN-gamma secreting cells. These results demonstrate an early T lymphocyte response in draining lymph nodes, followed by later recruitment of Th1 and Th2 lymphocytes into lung tissue. The overall CD4(+) T cell response to P. carinii involves both Th1 and Th2 subsets, but the response is Th2 dominant in both lymph node and lung tissue.

Animals↗

PubMed2000

A multistep unsupervised fuzzy clustering analysis of fMRI time series.

A paradigm independent multistage strategy based on the Unsupervised Fuzzy Clustering Analysis (UFCA) and its potential for fMRI data analysis are presented. The influence of the fuzziness index is studied using Receiver Operating Characteristics (ROC) methodology and an interval of choice, around the widely used value 2, is shown to yield the best performance. The ill-balanced data problem is also overcome using a pre-processing step to reduce the number of voxels presented to the method. Statistical and anatomical criteria are proposed to exclude some voxels and enhance the UFCA sensitivity. An original postprocessing step aiming at statistically characterizing the obtained clusters is also developed. Two similarity criteria are used: the correlation coefficient on temporal profiles and a novel fuzzy overlap coefficient on membership degree maps. This final step provides a useful analysis tool to study intra-individual reproducibility of the classes across series (stimulation vs. stimulation, noise vs. noise or stimulation vs. noise). Finally, a comparison between this technique and some existing or locally developed postprocessing algorithms is presented using ROC methods. Its sensitivity and robustness is compared to the classical FCA or other techniques as a function of several parameters such as Contrast-to-Noise Ratio (CNR) and noise amplitude. Even without knowledge about the paradigm, the hemodynamic response function and the number of clusters, the performances of the proposed strategy are comparable to those of the classical approaches where extensive prior knowledge has to be added.

Algorithms↗

PubMed2000

A delay-differential equation model of HIV infection of CD4(+) T-cells.

A.S. Perelson, D.E. Kirschner and R. De Boer (Math. Biosci. 114 (1993) 81) proposed an ODE model of cell-free viral spread of human immunodeficiency virus (HIV) in a well-mixed compartment such as the bloodstream. Their model consists of four components: uninfected healthy CD4(+) T-cells, latently infected CD4(+) T-cells, actively infected CD4(+) T-cells, and free virus. This model has been important in the field of mathematical modeling of HIV infection and many other models have been proposed which take the model of Perelson, Kirschner and De Boer as their inspiration, so to speak (see a recent survey paper by A.S. Perelson and P.W. Nelson (SIAM Rev. 41 (1999) 3-44)). We first simplify their model into one consisting of only three components: the healthy CD4(+) T-cells, infected CD4(+) T-cells, and free virus and discuss the existence and stability of the infected steady state. Then, we introduce a discrete time delay to the model to describe the time between infection of a CD4(+) T-cell and the emission of viral particles on a cellular level (see A.V.M. Herz, S. Bonhoeffer, R.M. Anderson, R.M. May, M.A. Nowak [Proc. Nat. Acad. Sci. USA 93 (1996) 7247]). We study the effect of the time delay on the stability of the endemically infected equilibrium, criteria are given to ensure that the infected equilibrium is asymptotically stable for all delay. Numerical simulations are presented to illustrate the results.

CD4 Lymphocyte Count↗

PubMed2000

Utilization of the 1,2,5-thiadiazolidin-3-one 1,1 dioxide scaffold in the design of potent inhibitors of serine proteases: SAR studies using carboxylates.

A series of carboxylate derivatives based on the 1,2,5-thiadiazolidin-3-one 1,1 dioxide and isothiazolidin-3-one 1,1 dioxide scaffolds has been synthesized and the inhibitory profile of these compounds toward human leukocyte elastase (HLE), cathepsin G (Cat G) and proteinase 3 (PR 3) was then determined. Most of the compounds were found to be potent, time-dependent inhibitors of elastase, with some of the compounds exhibiting k(inact)/K1 values as high as 4,928,300 M(-1) s(-1). The inhibitory potency of carboxylate derivatives based on the 1,2,5-thiadiazolidin-3-one 1,1 dioxide platform was found to be influenced by both the pKa and the inherent structure of the leaving group. Proper selection of the primary specificity group (R(I)) was found to lead to selective inhibition of HLE over Cat G, however, those compounds that inhibited HLE also inhibited PR 3, albeit less efficiently. The predictable mode of binding of these compounds suggests that, among closely-related serine proteases, highly selective inhibitors of a particular serine protease can be fashioned by exploiting subtle differences in their S' subsites. This study has also demonstrated that the degradative action of elastase on elastin can be abrogated in the presence of inhibitor 17.

Cyclic S-Oxides↗

PubMed2000

Phantom-based performance evaluation: application to brain segmentation from magnetic resonance images.

This paper presents a new technique for assessing the accuracy of segmentation algorithms, applied to the performance evaluation of brain editing and brain tissue segmentation algorithms for magnetic resonance images. We propose performance evaluation criteria derived from the use of the realistic digital brain phantom Brainweb. This 'ground truth' allows us to build distance-based discrepancy features between the edited brain or the segmented brain tissues (such as cerebro-spinal fluid, grey matter and white matter) and the phantom model, taken as a reference. Furthermore, segmentation errors can be spatially determined, and ranged in terms of their distance to the reference. The brain editing method used is the combination of two segmentation techniques. The first is based on binary mathematical morphology and a region growing approach. It represents the initialization step, the results of which are then refined with the second method, using an active contour model. The brain tissue segmentation used is based on a Markov random field model. Segmentation results are shown on the phantom for each method, and on real magnetic resonance images for the editing step; performance is evaluated by the new distance-based technique and corroborates the effective refinement of the segmentation using active contours. The criteria described here can supersede biased visual inspection in order to compare, evaluate and validate any segmentation algorithm. Moreover, provided a 'ground truth' is given, we are able to determine quantitatively to what extent a segmentation algorithm is sensitive to internal parameters, noise, artefacts or distortions.

Algorithms↗

PubMed2000

Studies of a magnetically focused electrostatic mirror. I. Experimental test of the first order properties

When a uniform magnetic field is superimposed on a uniform electrostatic field, the combination can act as a magnetically focused mirror. This mirror is predicted to have aberrations of opposite sign to those of a magnetic lens and may therefore be useful as a corrector. We have built an electron optical system to test these ideas. The results are presented in two papers. This first paper describes the general design and the results of the measurements of the first order properties. The second paper (Tsai, F., J. Microsc. 197 (2000) 118-135) will describe the measurements of the aberration properties.

Journal Article↗

PubMed2000

Brain tissue classification of magnetic resonance images using partial volume modeling.

This paper presents a fully automatic three-dimensional classification of brain tissues for Magnetic Resonance (MR) images. An MR image volume may be composed of a mixture of several tissue types due to partial volume effects. Therefore, we consider that in a brain dataset there are not only the three main types of brain tissue: gray matter, white matter, and cerebro spinal fluid, called pure classes, but also mixtures, called mixclasses. A statistical model of the mixtures is proposed and studied by means of simulations. It is shown that it can be approximated by a Gaussian function under some conditions. The D'Agostino-Pearson normality test is used to assess the risk alpha of the approximation. In order to classify a brain into three types of brain tissue and deal with the problem of partial volume effects, the proposed algorithm uses two steps: 1) segmentation of the brain into pure and mixclasses using the mixture model; 2) reclassification of the mixclasses into the pure classes using knowledge about the obtained pure classes. Both steps use Markov random field (MRF) models. The multifractal dimension, describing the topology of the brain, is added to the MRFs to improve discrimination of the mixclasses. The algorithm is evaluated using both simulated images and real MR images with different T1-weighted acquisition sequences.

Algorithms↗

PubMed2000

Optimizing the sequence of combination therapy with radiolabeled antibodies and fractionated external beam.

UNLABELLED: The purpose of this study was to determine the optimum sequence for combined modality therapy with radiolabeled antibodies and fractionated external beam radiation. METHODS: The uptake and distribution of a nontherapeutic activity of 125I-labeled tumor-associated A33 monoclonal antibody was determined in SW1222 human colon carcinoma xenografts in nude mice for 4 study groups: group 1, radiolabeled antibody alone; group 2, radiolabeled antibody administered (day 0) immediately before the first of 5 daily fractions of 2-Gy, 320-kilovolt peak x-rays; group 3, radiolabeled antibody administered after the fifth radiation fraction (day 5); and group 4, radiolabeled antibody administered 5 d after irradiation (day 10). Tumors were excised 5 d after antibody administration. Tumors were frozen and sectioned for histology and phosphor plate autoradiography. The percentage of A33 antigen-expressing cells was estimated by immunohistochemical staining. RESULTS: The average tumor uptake values relative to control group 1 were 1.47 (group 2), 0.78 (group 3), and 0.21 (group 4), which illustrates that tumor uptake is increased by almost 50% when the antibody is present in the blood at the start of irradiation. Five days into a fractionated irradiation protocol, antibody uptake was reduced, falling more significantly on day 10. Phosphor plate autoradiographs showed decreased uptake uniformity for groups 3 and 4. Immunohistochemical data showed a reduction in A33 antigen-positive cells from 85%, 64%, 50%, to 41% for groups 1-4, respectively. CONCLUSION: Maximum radiolabeled antibody tumor uptake was achieved when the antibody was administered just before radiation therapy. This might be explained by a transient increase in capillary leakage to macromolecules, followed by a reduction at later times, possibly the result of capillary damage and occlusion.

Animals↗