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11099196
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Well-ionization chamber response relative to NIST air-kerma strength standard for prostate brachytherapy seeds.
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The response of well-ionization chambers to the emissions of 103Pd and 125I radioactive seed sources used in prostate cancer brachytherapy has been measured. Calibration factors relating chamber response (current or dial setting) to measured air-kerma strength have been determined for seeds from nine manufacturers, each with different designs. Variations in well-ionization chamber response relative to measured air-kerma strength have been observed because of differences in the emitted energy spectrum due to both the radionuclide support material (125I seeds) and the mass ratio of 103Pd to 102Pd (103Pd seeds). Obtaining accurate results from quality assurance measurements using well-ionization chambers at a therapy clinic requires knowledge of such differences in chamber response as a function of seed design.
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11099195
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A dose-volume histogram based optimization algorithm for ultrasound guided prostate implants.
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The task of treatment planning for prostate implants is to find an optimal seed prising the target coverage and dosimetric consideration of critical structures such as the rectum and urethra. An efficient method to plish this is to use an inverse planning technique that derives the optimized solution from a prescribed treatment goal. The goal can be specified in the voxel domain as the desired doses to the voxels of the target and critical structures, or in the dose volume representation as the desired dose volume histograms (DVHs) of the target and critical structures. The DVH based optimization has been successfully used in plan optimization for intensity-modulated radiation therapy (IMRT) but little attention has been paid to its application in prostate implants. Clinically, it has long been known that some normal structure tolerances are more accurately assessed by volumetric information. Dose-volume histograms are also widely used for plan evaluation. When working in the DVH domain for optimization one has more control over the final DVHs. We have constructed an objective function sensitive to the DVHs of the target and critical structures. The objective function is minimized using an iterative algorithm, starting from a randomly selected initial seed configuration. At each iteration step, a trial position is given to a randomly selected source and the trial position is accepted if the objective function is decreased. To avoid being trapped in a less optimal local minimum, the optimization process is repeated. The final plan is selected from a pool of optimized plans obtained from a series of randomized initial seed configurations.
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11099197
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In vivo urethral dose measurements: a method to verify high dose rate prostate treatments.
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Radiation doses delivered in high dose rate (HDR) brachytherapy are susceptible to many inaccuracies and errors, including imaging, planning and delivery. Consequently, the dose delivered to the patient may deviate substantially from the treatment plan. We investigated the feasibility of using TLD measurements in the urethra to estimate the discrepancy in treatments for prostate cancer. The dose response of the 1 mm diam, 6 mm long LiF rods that we used for the in vivo measurements was calibrated with the 192Ir HDR source, as well as a 60Co teletherapy unit. A train of 20 rods contained in a sterile plastic tube was inserted into the urethral (Foley) catheter for the duration of a treatment fraction, and the measured doses pared to the treatment plan. Initial results from a total of seven treatments in four patients show good agreement between theory and experiment. Analysis of any one treatment showed agreement within 11.7% +/- 6.2% for the highest dose encountered in the central prostatic urethra, and within 10.4% +/- 4.4% for the mean dose. Taking the average over all seven treatments shows agreement within 1.7% for the maximum urethral dose, and within 1.5% for the mean urethral dose. Based on these initial findings it seems that planned prostate doses can be accurately reproduced in the clinic.
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11099198
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Fitting and benchmarking of dosimetry data for new brachytherapy sources.
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New source designs of encapsulated low-energy gamma emitting nuclides for permanent implants require dosimetric analysis and calibration standardization. The dosimetry measurements can be incorporated into a treatment planning system by fitting the data. The use of a fitting function whose behavior at range limits mimics the physical phenomena, using as few parameters as possible, eliminates noisy outliers and lends credence to calculations beyond the measured range. Clinical implementation of the new sources also requires benchmarking against existing sources, where the current clinical experience lies. We present an analysis of measured dosimetry data for three brachytherapy sources recently available from North American Scientific, Inc. (North Hollywood, CA): 103Pd source model MED3633 ("PdGold"), 125I source models MED3631-A/M ("IoGold-AM") and MED3631-A/S ("IoGold-AS"). Using the formalism of the Interstitial Collaborative Working Group (ICWG) the radial dose function, g(r), the anisotropy function, F(r, theta), and the anisotropy factor, phi an(r), were previously evaluated from measurements of each source design. In this report we use fitting functions whose forms are chosen to approach reasonable values at data limits. These forms are quite similar to those used in a previous analysis of TG43 Iodine and pendium data. Fitting parameter results for each function are provided for each brachytherapy source model. Fit-data discrepancies are smaller than measurement uncertainties, meaning that incorporation into treatment planning systems will not introduce significant errors in clinical use. Current clinical experience is based on the Theragenics (Norcross, GA) 103Pd seed ("PdThera"), and the ed-Amersham (Arlington Heights, IL) 125I seed models 6711 ("6711") and 6702 ("6702"). The new sources are benchmarked against these seeds.
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11099199
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Dosimetric modeling of the microselectron high-dose rate 192Ir source by the multigroup discrete ordinates method.
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The DANTSYS multigroup discrete puter code is applied to quantitatively estimate the absorbed dose rate distributions in the vicinity of a microSelectron 192Ir high-dose-rate (HDR) source in two-dimensional cylindrical R-Z geometry. The source is modeled in a cylindrical water phantom of diameter 20 cm and height 20 cm. The results are also used for evaluation of the Task Group 43 (TG-43) dosimetric quantities. The DANTSYS accuracy is estimated by parisons with corresponding Monte Carlo results. Our 210-group photon cross section library developed previously, together with angular quadratures consisting of 36 (S16) to 210 (S40) directions and associated weights per octant, are used in the DANTSYS simulations. Strong ray effects are observed but are significantly mitigated through the use of DANTSYS's stochastic ray-tracing first collision source algorithm. The DANTSYS simulations closely approximate Monte Carlo estimates of both direct dose calculations and TG-43 dosimetric quantities. The discrepancies with S20 angular quadrature (55 directions and weights per octant) or higher are shown to be less than +/- 5% (about 2.5 standard deviations of Monte Carlo calculations) everywhere except for limited regions along the Z axis of rotational symmetry, where technical limitations in the DANTSYS first collision source implementation makes adequate suppression of ray effects difficult to achieve. The efficiency of DANTSYS simulations pared with that of the EGS4 Monte Carlo code. It is demonstrated that even with the 210-group cross section library, DANTSYS achieves two-fold efficiency gains using the the S20 quadrature set. The potential of discrete ordinates method for further efficiency improvements is also discussed.
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11099200
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The collapsed cone superposition algorithm applied to scatter dose calculations in brachytherapy.
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Methods for scatter dose calculations in brachytherapy have been developed based on the collapsed cone superposition algorithm. The methods account for effects on the scatter dose caused by the three-dimensional distribution of heterogeneities in the irradiated volume and are considerably faster than methods based on straightforward superposition of kernels or direct Monte Carlo simulations. Use of a successive-scattering approach, in which the dose contribution from once- and multiply scattered photons are calculated separately, was found superior to conventional superposition using a single point kernel for all scatter generations. Use of the successive-scattering approach significantly reduces artifacts stemming from steep fluence gradients, typical of the brachytherapy geometry and critical for the collapsed cone approximation. The algorithm is tested versus Monte Carlo simulations for point sources of energies 28.4, 100, 350, and 662 keV. Results agree well for both a homogeneous water phantom and an air-water half-phantom.
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11099201
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Optimized bounding boxes for three-dimensional treatment planning in brachytherapy.
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It is sometimes necessary to determine the optimal value for a direction dependent quantity. Using a search technique based on Powell's quadratic convergent method such an optimal direction can be approximated. The necessary geometric transformations in n-dimensional space are introduced. As an example we consider the approximation of the minimum bounding box of a set of three-dimensional points. Minimum bounding boxes can significantly improve accuracy and efficiency of the calculations in modern brachytherapy treatment planning of the volumes of objects or the dose distribution inside an object. A covariance matrix based approximation method for the minimum bounding box pared with the results of the search method. The benefits of the use of optimal oriented bounding boxes in brachytherapy treatment planning systems are demonstrated and discussed.
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11099202
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Dose-volume histograms computation comparisons using conventional methods and optimized fast Fourier transforms algorithms for brachytherapy.
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In anatomy based optimization procedures for large volume implants the calculation of dose-volume histograms (DVH) accounts for the major part of the time involved and can be as long as a few hours. This time is proportional to the number of seeds or source dwell positions required for the implant. A procedure for the calculation of brachytherapy seed dose distribution calculation employing fast Fourier transforms (FFT) and the convolution theorem has been described by others and was supposed to significantly improve the speed of the dose putation. Using new significantly improved FFT algorithms and various other optimization techniques we pared the calculated differential and integral DVHs in high dose rate (HDR) brachytherapy with a single stepping source using actual clinical implants. This is so that we could assess the efficiency and accuracy of the FFT method with that of conventional methods. Our results showed that the FFT based method of calculating DVHs in brachytherapy parable in speed with conventional dose calculation methods, but only for implants with more than 287 sources. It is therefore of limited practical use even for large implants. This result is in direct opposition to the claim by other authors.
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11099203
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Measurement of the dose components of fast and thermal neutrons and photons from a 0.1 mg 252Cf source in water for brachytherapy treatment planning.
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The use of 252Cf in brachytherapy is expected to be more effective with the therapy of bulky tumors than the conventional therapy with photons. For treatment planning a code developed for calculation of gamma dose was used to generate the dose distributions of fast and 10B enhanced thermal neutrons and photons. Dose distributions of ponents measured with ionization chambers and a GM counter were fitted to analytical functions as required by the modified treatment planning program. parison of these experimental results and the treatment planning output indicate good agreement. Therefore, the program may be used to optimize the brachytherapy procedure considering all three ponents. A realistic case of a patient being treated with conventional brachytherapy has been used to calculate the dose distribution that would be obtained by use of the 252Cf source.
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11099204
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Determination of the air w-value in proton beams using ionization chambers with gas flow capability.
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The purpose of this work was to determine the w-value of air for protons using the paired gas method. Several plastic- and magnesium-walled chambers were used with air, synthetic air, nitrogen, and argon flowing gases. Using argon as a reference gas, the w-value of air was measured and ranged from 32.7 to 34.5 J/C for protons with energies encountered in radiotherapy. Using nitrogen as a reference gas, the w-value of air ranged from 35.2 to 35.4 J/C over the same range of proton energies. The w-value was found, at a given energy, to be independent of the ion chamber used. The uncertainty in these measurements was estimated at 5.2% at the 2sigma level. This uncertainty was dominated by the 4.4% uncertainty in the w-value of the reference gas.
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11099205
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Confining proton beams with longitudinal magnetic fields: Monte Carlo calculations.
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The problem of the lateral containment of a 160 MeV proton beam interacting with a medium simulating biological material was studied. The confining action of a longitudinal magnetic field was calculated by means of Monte Carlo simulation, where scattering and motion in the magnetic field were treated simultaneously. pression of the beam could only be achieved using fields of the order at least 50 T, much beyond the realm of practical feasibility.
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11099207
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A mathematical study of the area over perimeter rule using the sector-integration equation.
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The equivalence between rectangular photon fields and square fields is currently used to simplify tabulation and handling of data as well as to reduce measurement time. Widely used for routine calculation in the case of rectangular fields of moderate elongation, the so-called "area over perimeter rule" (A/P rule) has a remarkable accuracy. Several approaches have been developed to determine the physical and mathematical grounds of this rule, yet the statement that it is independent of depth and energy was not fully clarified. By means of the Clarkson sector-integration equation and Taylor expansion, this work demonstrates that the A/P rule is a first-order approximation on the elongation variable for all cases, i.e., for moderate rectangular field elongation presents a quadratic deviation. To appreciate the degree of approximation of this rule, a model scatter air ratio for Co60 y-rays at 10.0 cm depth was used pute rectangular radiation fields and the results pared to those given by the A/P rule. The model scatter air ratio was the proposed by Day and Aird [Br. J. Radiol. 25, 138-151 (1996)].
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11099206
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Determination of effective electron source size using multislit and pinhole cameras.
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Two independent methods have been utilized for determination of effective source sizes for 6, 12, and 20 MeV electron beams generated by a Varian 2100C linear accelerator. First, a multislit camera has been constructed using parallel aluminum plates and plastic strip spacers, similar to the beam-spot camera for the photon source imaging. Second, pinhole imaging was performed using a lead plate with a small hole on the central axis of the beam. The plate thickness and the hole diameter varied with electron energy. The cameras were positioned directly at the opening of the movable photon collimator. The size of the source distribution from each camera was characterized by its full width at half-maximum (FWHM) value. The measured values of FWHM are different for each camera because of their different imaging principles. For the multislit camera, the measured FWHM values were (6.3 +/- 0.4) cm for the 6 MeV beam, (3.6 +/- 0.4) cm for 12 MeV, and (2.7 +/- 0.4) cm for 20 MeV. For the pinhole camera the measured values of FWHM were (7.9 +/- 0.6) cm for 6 MeV, (4.5 +/- 0.4) cm for 12 MeV, and (3.0 +/- 0.4) cm for the 20 MeV beam. Additionally, the effective source position was derived from output measurements at different values of the SSD, which were fitted to the inverse square law.
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11099208
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Shielding considerations for tomotherapy.
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Tomotherapy presents an evolutionary modality that holds forth the promise of better dose conformation to tumor volumes with a itant reduction in radiation-induced damage to surrounding normal structures. This delivery technique also presents a new set of radiation protection challenges that impact upon the design of the shielding vault required to house such a unit. A formalism is presented to determine the requisite amounts of shielding for both the primary beam and leakage radiation associated with a generic tomotherapy unit. parison is made with the shielding requirements for a conventional linear accelerator operated in a standard manner. Substantial differences in the amount of both primary and secondary shielding are indicated. A tomotherapy primary beam shield is both reduced in width by a factor of almost 10 and increased in thickness by more than a tenth value layer parison to a conventional accelerator. Furthermore, the secondary shielding requirements are enhanced by more than two tenth value layers with respect to conventional shielding demands.
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11099209
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Predictions of a stochastic model of bone marrow cell survival in high dose rate radiation fields with arbitrary neutron to gamma-ray absorbed dose rate ratios.
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In this paper, a stochastic model of cell survival, which was developed by Cotlet and Blue, based on the work of Jones, is extended to describe bone marrow cell survival in high dose rate radiation fields with arbitrary neutron to gamma-ray absorbed dose rate ratios. Mathematical formulas are obtained that describe the interaction of the neutron and ponents of the absorbed dose, for radiation fields with arbitrary neutron to gamma-ray dose rate ratios, for exposures of cells to various absorbed doses, at various high dose rates.
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11099210
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Monte Carlo assessment of computed tomography dose to tissue adjacent to the scanned volume.
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The assessment of the radiation dose to internal organs or to an embryo or fetus is required on occasion for risk assessment or paring imaging studies. Limited resources hinder the ability to accurately assess the radiation dose received to locations outside the tissue volume actually scanned puted tomography (CT). The purpose of this study was to assess peripheral doses and provide tabular data for dose evaluation. Validated Monte Carlo simulation techniques were used pute the dose distribution along the length of water-equivalent cylindrical phantoms, 16 and 32 cm in diameter. For further parisons between physically measured and Monte Carlo-derived air kerma profiles were performed and showed excellent (1% to 2%) agreement. Polyenergetic x-ray spectra at 80, 100, 120, and 140 kVp with beam shaping filters were studied. Using 10(8) simulated photons input to the cylinders perpendicular to their long axis, line spread functions (LSF) of the dose distribution were determined at three depths in the cylinders (center, mid-depth, and surface). The LSF data were then used with appropriate mathematics pute dose distributions along the long axis of the cylinder. The dose distributions resulting from helical (pitch = 1.0) scans and axial scans were approximately equivalent. Beyond about 3 cm from the edge of the CT scanned tissue volume, the fall-off of radiation dose was exponential. A series of tables normalized at 100 milliampere seconds (mAs) were produced which allow the straight-forward assessment of dose within and peripheral to the CT scanned volume. The tables should be useful for medical physicists and radiologists in the estimation of dose to sites beyond the edge of the CT scanned volume.
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11099211
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Scatter/primary in mammography: comprehensive results.
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Monte Carlo procedures using the SIERRA code (validated in panion article) were used to investigate the scatter properties in mammography. The scatter to primary ratio (SPR) was used for quantifying scatter levels as a function of beam spectrum, position in the field, air gap, breast thickness, position, and the area of the field of view (FOV). The geometry of slot scan mammography was also simulated, and SPR values were calculated as a function of slot width. The influence of large air gaps (to 30 cm) was also studied in the context of magnification mammography. X-ray energy and position from 100% adipose to 100% glandular demonstrated little effect on the SPR. Air gaps over a range from 0 to 30 mm showed only slight effects. The SPR increased with increased breast thickness and with larger fields of view. Measurements from 82 mammograms provided estimates of the range pressed breast thickness (median: 5.2 cm, 95% range: 2.4 cm to 7.9 cm) and projected breast area onto the film (left craniocaudal view, median: 146 cm2, 95% range: 58 cm2 to 298 cm2). SPR values for semicircular breast shapes, Mo/Mo spectra, and a 15 mm air gap were parametrized as a function of breast thickness and (semicircular) breast diameter. With the coefficients a = - 2.35452817439093, b = 22.3960980055927, and c = 8.85064260299289, the equation SPR= [a + b x (diameter in cm)--(-1.5) + c x (thickness in cm) --(-0.5)]-- -1 produces SPR data from 2 to 8 cm and from 3 to 30 cm breast diameters with an average error of about 1%.
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11099212
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Linear response theory for detectors consisting of discrete arrays.
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The optical transfer function (OTF) and the noise power or Wiener spectrum are defined for detectors consisting of a lattice of discrete elements with the assumptions of linear response, Gaussian statistics, and stationarity under the discrete group of translations which leave the lattice fixed. For the idealized classification task of determining the presence or absence of a signal under signal known exactly/background known exactly (SKE/BKE) conditions, the Wiener spectrum, the OTF, along with an analog of the gray-scale transfer characteristic, determine the signal-to-noise ratio (SNR), which quantifies the ability of an ideal observer to perform this task. While this result is similar to the established result for continuous detectors, such as screen-film systems, the theory of discrete lattices of detectors must take into account the fact that the lattice only supports a bounded but (in the limit of a detector of arbitrarily great extent) continuous range of frequencies. Incident signals with higher spatial frequencies appear in the data at lower aliased frequencies, and there are pairs of signals which are not distinguishable by the detector (the SNR vanishes for the task of distinguishing such signals). Further, the SNR will in general change if the signal is spatially displaced by a fraction of the lattice spacing, although this change will be small for objects larger than a single pixel. Some of the trade-offs involved in detectors of this sort, particularly in dealing with signal frequencies above those supported by the lattice, are studied in a simple model.
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11099213
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Design of a dual CCD configuration to improve the signal-to-noise ratio.
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The noise of a digital charge coupled device (CCD) detector increases with the readout speed, causing problems in a number of important applications, such as x-ray fluoroscopy and micro-CT. In this paper, we present an approach for the design of a dual-CCD configuration to improve the average signal-to-noise ratio, and hence provide an inexpensive solution within the constraint of the current technology.
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11099214
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Simulating coronary arteries in x-ray angiograms.
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Clinical validation of quantitative coronary angiography (QCA) algorithms is difficult due to the lack of a simple alternative method for accurately measuring in vivo vessel dimensions. We address this problem by embedding simulated coronary artery segments with known geometry in clinical angiograms. Our vessel model accounts for the profile of the vessel, x-ray attenuation in the original background, and noise in the imaging system. We pared diameter measurements of puter simulated arteries with measurements of an x-ray Telescopic-Shaped Phantom (XTSP) with the same diameters. The results show that for both uniform and anthropomorphic backgrounds there is good agreement in the measured diameters of pared to the simulated arteries (Pearson's correlation coefficient 0.99). In addition, the difference in accuracy and precision of the true diameter pared to the XTSP and simulated artery diameters was small (mean absolute error across all diameters was < or = 0.11 mm +/- 0.09 mm).
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11099215
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Automatic segmentation of lung fields in chest radiographs.
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The delineation of important structures in chest radiographs is an essential preprocessing step in order to automatically analyze these images, e.g., for tuberculosis screening support or puter assisted diagnosis. We present algorithms for the automatic segmentation of lung fields in chest radiographs. pare several segmentation techniques: a matching approach; pixel classifiers based on binations of features; a new rule-based scheme that detects lung contours using a general framework for the detection of oriented edges and ridges in images; and a hybrid scheme. Each approach is discussed and the performance of nine systems pared with interobserver variability and results available from the literature. The best performance is obtained by the hybrid scheme bines the rule-based segmentation algorithm with a pixel classification approach. binations of plementary techniques leads to robust performance; the accuracy is above 94% for all 115 images in the test set. The average accuracy of the scheme is 0.969 +/- 0.0080, which is close to the interobserver variability of 0.984 +/- 0.0048. The methods are fast, and implemented on a standard PC platform.
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11099216
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Comparison of rigid and elastic matching of dynamic magnetic resonance mammographic images by mutual information.
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The present study aims at (i) the evaluation of the performance of a rigid and of an elastic matching algorithm for the coregistration of dynamic magnetic resonance (MR) images visualizing the female breast, and (ii) the evaluation of the mutual information (MI) as a matching criterion. To this end, ten patient data sets were analyzed. parison was performed with respect to the achieved increase in the MI and by visual inspection of the dynamic image series in a continuous film sequence ((cine mode). In most cases, the achieved increase in MI by elastic image registration is much higher than that achieved by rigid registration. Only for three of the ten data sets could the MI be increased by rigid image registration to a similar or even larger degree than by elastic image registration. Taking into account the results of the visual inspection of the rigid and elastic matched data sets, however, the elastic match leads to equal or better results for all data sets. Therefore, elastic matching is the gold standard for the registration of dynamic MR mammographic images of the female breast. parison of the increase in MI and the visual inspection further shows that the visual impression agrees in most cases with the result of the calculation of the MI. Therefore, the MI proves to be a suitable matching criterion for the type of data sets studied.
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11099217
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Validation of a precision radiochromic film dosimetry system for quantitative two-dimensional imaging of acute exposure dose distributions.
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We present an evaluation of the precision and accuracy of image-based radiochromic film (RCF) dosimetry performed using mercial RCF product (Gafchromic MD-55-2, Nuclear Associates, Inc.) and mercial high-spatial resolution (100 microm pixel size) He-Ne scanning-laser film-digitizer (Personal Densitometer, Molecular Dynamics, Inc.) as an optical density (OD) imaging system. The precision and accuracy of this dosimetry system are evaluated by performing RCF imaging dosimetry in well characterized conformal external beam and brachytherapy high dose-rate (HDR) radiation fields. Benchmarking of image-based RCF dosimetry is necessary due to many potential errors inherent to RCF dosimetry including: a temperature-dependent time evolution of RCF dose response; nonuniform response of RCF; and optical-polarization artifacts. In addition, laser-densitometer imaging artifacts can produce systematic OD measurement errors as large as 35% in the presence of high OD gradients. We present a RCF exposure and readout protocol that was developed for the accurate dosimetry of high dose rate (HDR) radiation sources. This protocol follows and expands upon the guidelines set forth by the American Association of Physicists in Medicine (AAPM) Task Group 55 report. Particular attention is focused on the OD imaging system, a scanning-laser film digitizer, modified to eliminate OD artifacts that were not addressed in the AAPM Task Group 55 report. RCF precision using this technique was evaluated with films given uniform 6 MV x-ray doses between 1 and 200 Gy. RCF absolute dose accuracy using this technique was evaluated paring RCF measurements to small volume ionization chamber measurements for conformal external-beam sources and an experimentally validated Monte Carlo photon-transport simulation code for a 192Ir brachytherapy source. Pixel-to-pixel standard deviations of uniformly irradiated films were less than 1% for doses between 10 and 150 Gy; between 1% and 5% for lower doses down to 1 Gy and 1% and 1.5% for higher doses up to 200 Gy. Pixel averaging to form 200-800 microm pixels reduces these standard deviations by a factor of 2 to 5. Comparisons of absolute dose show agreement within 1.5%-4% of dose benchmarks, consistent with a highly accurate dosimeter limited by its observed precision and the precision of the dose standards to which it pared. These results provide prehensive benchmarking of RCF, enabling its use in missioning of novel HDR therapy sources.
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11099219
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Novel human topoisomerase I inhibitors, topopyrones A, B, C and D. II. Structure elucidation.
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The structures of novel topoisomerase I inhibitors, topopyrones A, B, C and D were elucidated by spectral analysis of the chemical derivatives. pounds are an anthraquinone type containing a fused 1,4-pyrone moiety. Topopyrones A and B contain a chlorine atom, however C and D do not. It was suggested that topopyrones B and D are converted from topopyrones A and C, respectively by Wessely-Moser type rearrangement.
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11099218
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Novel human topoisomerase I inhibitors, topopyrones A, B, C and D. I. Producing strain, fermentation, isolation, physico-chemical properties and biological activity.
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In the course of a screening program for specific inhibitors of human topoisomerase I using a binant yeast, we have discovered four new pounds. All pounds were isolated from the culture broth of a fungus, Phoma sp. BAUA2861, and two of them were isolated from the culture broth of a fungus, Penicillium sp. BAUA4206. We designated pounds as topopyrones A, B, C and D. Topopyrones A, B, C and D selectively inhibited binant yeast growth dependent on expression of human topoisomerase I with IC50 values of 1.22, 0.15, 4.88 and 19.63 ng/ml, respectively. The activity and selectivity of topopyrone B parable to those of camptothecin. The relaxation of supercoiled pBR322 DNA by human DNA topoisomerase I was inhibited by pounds, however they did not inhibit human DNA topoisomerase II. Topopyrones A, B, C and D were cytotoxic to all tumor cell lines when tested in vitro. Topopyrone B has potent inhibitory activity against herpesvirus, especially varicella zoster virus (VZV). It inhibited VZV growth with EC50 value of 0.038 microg/ml, which is 24-fold stronger than that of acyclovir (0.9 microg/ml). Topopyrones A, B, and C were inhibitory to Gram-positive bacteria.
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11099220
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Tubulysins, new cytostatic peptides from myxobacteria acting on microtubuli. Production, isolation, physico-chemical and biological properties.
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New pounds, tubulysins, were isolated from the culture broth of strains of the myxobacteria Archangium gephyra and Angiococcus disciformis. pounds are peptides partly consisting of unusual amino acids and are distantly related to the dolastatins. The tubulysins were not active against bacteria and only little against fungi, but showed high cytostatic activity against mammalian cell lines with IC50 values in the olar range. An incubation with 50 ng/ml tubulysin A led to plete disappearance of the microtubuli network of the cells within 24 hours. The more active tubulysin D induced multipolar spindles: At 0.5 ng/ml all mitotic cells showed more than four spindle poles.
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11099221
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New triene-ansamycins, thiazinotrienomycins F and G and a diene-ansamycin, benzoxazomycin.
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New triene-ansamycins designated thiazinotrienomycins F (TT-F) and G (TT-G) and a new diene-ansamycin, benzoxazomycin, were isolated from a culture broth of Streptomyces sp. MJ672-m3 and their structures were elucidated by spectroscopic analyses. The Mean Graphs of TT-G suggests that the tumor growth inhibitory activities are almost as strong as TT-B, in respect of GI50 and TGI against several human cancer cell lines.
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11099222
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4'-N-methyl-5'-hydroxystaurosporine and 5'-hydroxystaurosporine, new indolocarbazole alkaloids from a marine Micromonospora sp. strain.
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Two new indolocarbazole alkaloids, 4'-N-methyl-5'-hydroxystaurosporine (2) and 5'-hydroxystaurosporine (3), were isolated together with the known staurosporine (1) from the culture broth of a marine Micromonospora sp. (strain L-31-CLCO-002). The fermentation, structural data and cytotoxic activities of pounds against various tumor cell lines are given.
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11099223
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Phellinsin A, a novel chitin synthases inhibitor produced by Phellinus sp. PL3.
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Phellinsin A, a novel chitin synthases inhibitor was isolated from the cultured broth of fungus PL3, which was identified as Phellinus sp. PL3. Phellinsin A was purified by solvent partition, silica gel, ODS column chromatographies, and preparative HPLC, consecutively. The structure of phellinsin A was assigned as a pound on the basis of various spectroscopic analyses including UV, IR, Mass, and NMR. Its molecular weight and formula were found to be 358 and C18H14O8, respectively. Phellinsin A selectively inhibited chitin synthase I and II of Saccharomyces cerevisiae with an IC50 value of 76 and 28 microg/ml, respectively, in our cell free assay system. pound showed antifungal activity against Colletotrichum lagenarium, Pyricularia oryzae, Rhizoctonia solani, Aspergillus fumigatus, and Trichophyton mentagrophytes.
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11099224
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FR901469, a novel antifungal antibiotic from an unidentified fungus No.11243. I. Taxonomy, fermentation, isolation, physico-chemical properties and biological properties.
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FR901469 is a novel antifungal antibiotic produced by an unidentified fungus No.11243. pound was isolated from the culture broth by solvent extraction, HP-20 and YMC ODS gel column chromatography, and lyophilization. FR901469 is a white powder which melts at 182 approximately 187 degrees C and possesses the molecular formula C71H116N14O23. pound has good water solubility. FR901469 inhibited the activity of 1,3-beta-glucan synthase from Candida albicans with an IC50 value of 0.05 microg/ml, and displayed greater inhibitory activity than other 1,3-beta-glucan synthase inhibitors such as, WF11899A, echinocandin B, aculeacin A, and papulacandin B.
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11099226
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Xanthoepocin, a new antibiotic from Penicillium simplicissimum IFO5762.
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A new antifungal antibiotic xanthoepocin was isolated from the culture broth of Penicillium simplicissimum IFO5762. Xanthoepocin was obtained from the culture fluid by solvent extraction and chromatographic purification. It showed antibiotic activity against Gram-positive bacteria and yeasts.
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11099225
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FR901469, a novel antifungal antibiotic from an unidentified fungus No.11243. II. In vitro and in vivo activities.
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FR901469 is a water-soluble macrocyclic lipopeptidolactone (C71H116N14O23) that has inhibitory activity against 1,3-beta-glucan synthase and exhibits in vitro and in vivo antifungal activity against both Candida albicans and Aspergillus fumigatus. The MICs of FR901469 against Candida albicans FP633 and Aspergillus fumigatus FP1305 in a micro-broth dilution test were 0.63 and 0.16 microg/ml, respectively. FR901469 showed excellent efficacy by subcutaneous injection against both Candida albicans and Aspergillus fumigatus in a murine systemic infection mode, with ED50s of 0.32 and 0.2 mg/kg, respectively. pound also showed potent anti-Pneumocystis activity in the nude mice model with experimental Pneumocystis pneumonia. The hemolytic activity of FR901469 towards mouse red blood cells, is about 30-fold weaker than that of amphotericin B.
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11099228
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New 1-O-acyl alpha-L-rhamnopyranosides and rhamnosylated lactones from Streptomyces sp., inhibitors of 3 alpha-hydroxysteroid-dehydrogenase (3alpha-HSD).
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Chemical screening with extracts of Streptomyces sp. (strain GT 61150) resulted in the detection, isolation, and structure elucidation of two new acyl alpha-L-rhamnopyranosides (1 and 2) and three new rhamnosyllactones A, B1 and B2 (3 approximately 5). Rhamnosyllactones B1 and B2 were obtained as a 5:1 mixture. The structures were confirmed by spectroscopic analysis, especially 2D-NMR techniques. The rhamnosyltransferase of our strain is able to connect the sugar moiety to heteroaromatic carboxylic acids and enols. The metabolites 1 and 4/5 as well as previously reported acylrhamnosides 6 approximately 11 inhibit the enzyme 3alpha-hydroxysteroid-dehydrogenase (3alpha-HSD).
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11099227
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Feigrisolides A, B, C and D, new lactones with antibacterial activities from Streptomyces griseus.
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Four new pounds, named feigrisolides A to D (1 to 4), have been isolated from Streptomyces griseus. The chemical structures were determined by detail analysis of their spectroscopic data and chemical transformations. Structurally, the feigrisolides A (1) and B (2) are hepta-lactones, feigrisolide C (3) and D (4) are 16-membered macrodiolides. Biological studies showed that feigrisolide B (2) exhibited strong antibacterial, as well as medium cyctotoxic, and antiviral activities. Feigrisolides A (1), C (3) and D (4) are medium inhibitors of 3alpha-hydroxysteroid-dehydrogenase (3alpha-HSD) inhibiting activity.
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11099229
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Cyclo(dehydroala-L-Leu), an alpha-glucosidase inhibitor from Penicillium sp. F70614.
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A diketopiperazine (1) has been isolated from the culture broth of Penicillium sp. F70614 and its structure has been determined to be cyclo(dehydroala-L-Leu) by various spectroscopic analyses. pound selectively inhibited yeast alpha-glucosidase and porcine intestinal alpha-glucosidase with IC50 values of 35 and 50 microg/ml, respectively. However, it did not show significant inhibitory effects against almond beta3-glucosidase, Aspergillus alpha-galactosidase, Escherichia coli beta-galactosidase and jack bean alpha-mannosidase.
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11099230
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Structure determination and total synthesis of a novel antibacterial substance, AB0022A, produced by a cellular slime mold.
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A novel antibacterial substance, AB0022A, was isolated from the cellular slime mold Dictyostelium purpureum K1001. It inhibited the growth of Gram-positive bacteria, and its MICs ranged from 0.39 to 50 microg/ml. Because AB0022A was a highly substituted pound, we could not determine its structure based on only its physico-chemical and spectral data. We therefore used a dehalogenated derivative from AB0022A and deduced that its structure was 1,9-dihydroxy-3,7-dimethoxy-2-hexanoyl-4,6,8-trichlorodibenzofuran . To confirm this structure, we synthesized pound having the deduced structure. The pound was identical to naturally occurring AB0022A.
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11099237
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Determination of optimal injection parameters for intraarterial gadolinium-enhanced MR angiography.
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Rapid vascular depiction with use of a minimum of gadolinium (Gd) contrast agent will be required to generate road-map vascular images for magnetic resonance (MR) imaging-guided endovascular interventions. The objective of this study was to optimize intraarterial injections of MR contrast agent during magnetic resonance angiography (MRA), obtained during interventions, by determining the optimal Gd vascular concentration ([Gd]) for vessel depiction.
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11099235
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Chemoembolization of liver tumor in a rabbit model: assessment of tumor cell death with diffusion-weighted MR imaging and histologic analysis.
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To assess the efficacy of chemoembolization of liver tumors by determining the fraction of viable tumor cells remaining after treatment with use of diffusion magnetic resonance (MR) imaging and histologic analysis.
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11099241
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Venous thrombosis associated with the placement of peripherally inserted central catheters.
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Peripherally inserted central catheters (PICCs) have e an ponent of the management of an increasing number of patients, including patients who may require hemodialysis. Reported symptomatic venous thrombosis rates associated with PICC lines are based on clinical signs and symptoms and range from 1% to 4%. The purpose of this study is to evaluate the true rate of thrombosis of upper extremity veins after the placement of PICCs and the potential impact on future access in hemodialysis patients.
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11099239
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Endovascular management of acute extensive iliofemoral deep venous thrombosis caused by May-Thurner syndrome.
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The authors report their experience on the treatment of acute extensive iliofemoral deep venous thrombosis (DVT) due to May-Thurner syndrome using endovascular techniques.
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11099242
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Change in peripherally inserted central catheter tip position with abduction and adduction of the upper extremity.
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This study examines whether the tip of peripherally inserted central catheters (PICCs) moves significantly with changes in arm position from abduction to adduction.
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11099238
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Long-term outcome of embolotherapy and surgery for high-flow extremity arteriovenous malformations.
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To assess the long-term efficacy of embolotherapy bination with surgery for management of symptomatic high-flow arteriovenous malformations (HFAVMs) of the lower and upper extremities.
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11099244
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Small intestinal submucosa covered expandable Z stents for treatment of tracheal injury: an experimental pilot study in swine.
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To evaluate efficacy of small intestinal submucosa (SIS) as a stent covering in healing experimentally created tracheal defects and to explore the trachea's reaction to placement of SIS-covered stents.
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11099243
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Congenital lacrimal system obstruction: treatment with balloon dilation.
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To evaluate the safety and effectiveness of balloon dilation for the treatment of congenital lacrimal system obstruction.
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11099253
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A systematic approach to dynamic programming in bioinformatics.
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Dynamic programming is probably the most popular programming method in bioinformatics. parison, gene recognition, RNA structure prediction and hundreds of other problems are solved by ever new variants of dynamic programming. Currently, the development of a successful dynamic programming algorithm is a matter of experience, talent and luck. The typical matrix recurrence relations that make up a dynamic programming algorithm are intricate to construct, and difficult to implement reliably. No general problem independent guidance is available.
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11099254
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ComboScreen facilitates the multiplex hybridization-based screening of high-density clone arrays.
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The construction of physical maps based on bacterial clones [e.g. bacterial artificial chromosomes (BACs)] is valuable for a number of molecular genetics applications, including the high-resolution mapping of genomic regions of interest and the identification of clones suitable for systematic sequencing. mon approach for large-scale screening of bacterial clone libraries involves the hybridization of high-density arrays of immobilized, lysed colonies with collections of DNA probes. The use of a multiplex hybridization screening strategy, whereby pooled probes are analysed en masse, simplifies the effort by reducing the total number of parallel experiments required. However, this approach generates large amounts of hybridization-based data that must be carefully analysed, assimilated, and disambiguated in a careful but efficient manner.
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11099249
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Plasminogen-enriched pulse-spray thrombolysis with tPA: further developments.
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To further improve methods for pulsed plasminogen-enriched thrombolysis and pare results with the best obtainable with use of tissue plasminogen activator (tPA) alone.
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11099255
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Generation of patterns from gene expression data by assigning confidence to differentially expressed genes.
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A protocol is described to attach expression patterns to genes represented in a collection of hybridization array experiments. Discrete values are used to provide an easily interpretable description of differential expression. Binning cutoffs for each sample type are chosen automatically, depending on the desired false-positive rate for the predictions of differential expression. Confidence levels are derived for the statement that changes in observed levels represent true changes in expression. We have a novel method for calculating this confidence, which gives better results than the standard methods. Our method reflects the broader change of focus in the field from studying a few genes with many replicates to studying many (possibly thousands) of genes simultaneously, but with relatively few replicates. Our approach differs from standard methods in that it exploits the fact that there are many genes on the arrays. These are used to estimate for each sample type an appropriate distribution that is employed to control the false-positive rate of the predictions made. Satisfactory results can be obtained using this method with as few as two replicates.
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11099248
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Elevated plasma levels of matrix metalloproteinase-9 in patients with abdominal aortic aneurysms: a circulating marker of degenerative aneurysm disease.
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Matrix metalloproteinase-9 (MMP-9) is abundantly expressed in abdominal aortic aneurysms (AAAs), where it plays a pivotal role in connective tissue destruction. Elevated plasma concentrations of MMP-9 (MMP-9PL) also have been reported in patients with AAAs, but it is unclear if this can distinguish patients with AAAs from those with atherosclerotic occlusive disease (AOD). The purpose of this study was to further define the utility of elevated MMP-9PL levels in the diagnosis and evaluation of AAAs, and to examine if changes in MMP-9PL can be used as a functional biomarker of degenerative aneurysm disease.
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11099256
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Six-fold speed-up of Smith-Waterman sequence database searches using parallel processing on common microprocessors.
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Sequence database searching is among the most important and challenging tasks in bioinformatics. The ultimate choice of sequence-search algorithm is that of Smith-Waterman. However, because of putationally demanding nature of this method, heuristic programs or special-purpose hardware alternatives have been developed. Increased speed has been obtained at the cost of reduced sensitivity or very expensive hardware.
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11099257
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Genetic network inference: from co-expression clustering to reverse engineering.
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Advances in molecular biological, analytical putational technologies are enabling us to systematically investigate plex molecular processes underlying biological systems. In particular, using high-throughput gene expression assays, we are able to measure the output of the gene regulatory network. We aim here to review datamining and modeling approaches for conceptualizing and unraveling the functional relationships implicit in these datasets. Clustering of co-expression profiles allows us to infer shared regulatory inputs and functional pathways. We discuss various aspects of clustering, ranging from distance measures to clustering algorithms and multiple-cluster memberships. More advanced analysis aims to infer causal connections between genes directly, i.e. who is regulating whom and how. We discuss several approaches to the problem of reverse engineering of genetic networks, from discrete Boolean networks, to continuous linear and non-linear models. We conclude that bination of predictive modeling with systematic experimental verification will be required to gain a deeper insight into living organisms, therapeutic targeting and bioengineering.
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11099258
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Inferring qualitative relations in genetic networks and metabolic pathways.
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Inferring genetic network architecture from time series data of gene expression patterns is an important topic in bioinformatics. Although inference algorithms based on the Boolean network were proposed, the Boolean network was not sufficient as a model of a genetic network.
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11099260
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TRES: comparative promoter sequence analysis.
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Comparative promoter analysis is a promising strategy for elucidation mon regulatory modules conserved in evolutionarily related sequences or in genes mon expression profiles. To facilitate such analysis, we have developed a software tool that detects conserved transcription factor binding sites, cis-elements, palindromes and k-tuples simultaneously in a set of sequences, and thus helps to identify putative motifs for designing further experiments.
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11099261
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A comparison of signal sequence prediction methods using a test set of signal peptides.
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We describe the creation of a test set containing secretory and non-secretory proteins. Five existing prediction programs for signal sequences and their cleavage sites pared on the basis of this test set: SPScan, SigCleave, SignalP V1.1, SignalP V2.0. b2-HMM and SignalP V2.0.b2-NN.
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11099262
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gff2ps: visualizing genomic annotations.
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gff2psis a program for visualizing annotations of genomic sequences. The program takes the annotated features on a genomic sequence in GFF format as input, and produces a visual output in PostScript. While it can be used in a very simple way, it also allows for a great degree of customization through a number of options and/or customization files.
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11099263
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BBID: the biological biochemical image database.
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The Biological Biochemical Image Database is a WWW accessible relational database of archived images from research articles that describe regulatory pathways of higher eukaryotes. Pathway information is annotated and can be queried in the study plex gene expression. In this plex regulatory pathways can be tested empirically in an efficient manner in the context of large-scale gene-expression systems.
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11099264
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PASS: prediction of activity spectra for biologically active substances.
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The concept of the biological activity spectrum was introduced to describe the properties of biologically active substances. The PASS (prediction of activity spectra for substances) software product, which predicts more than 300 pharmacological effects and biochemical mechanisms on the basis of the structural formula of a substance, may be efficiently used to find new targets (mechanisms) for some ligands and, conversely, to reveal new ligands for some biological targets. We have developed a WWW interface for the PASS software. A WWW server for the on-line prediction of the biological activity spectra of substances has been constructed.
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11099281
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Collusion in doctor-patient communication about imminent death: an ethnographic study.
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To discover and explore the factors that result in "false optimism about recovery" observed in patients with small cell lung cancer.
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11099280
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Atypical antipsychotics in the treatment of schizophrenia: systematic overview and meta-regression analysis.
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To develop an evidence base for mendations on the use of atypical antipsychotics for patients with schizophrenia.
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11099284
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Randomised controlled trial of non-directive counselling, cognitive-behaviour therapy, and usual general practitioner care for patients with depression. I: clinical effectiveness.
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pare the clinical effectiveness of general practitioner care and two general practice based psychological therapies for depressed patients.
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11099285
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Randomised controlled trial of non-directive counselling, cognitive-behaviour therapy, and usual general practitioner care for patients with depression. II: cost effectiveness.
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pare the cost effectiveness of general practitioner care and two general practice based psychological therapies for depressed patients.
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11099302
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Apoptosis of thyrocytes and effector cells during induction and resolution of granulomatous experimental autoimmune thyroiditis.
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Experimental autoimmune thyroiditis (EAT) with granulomatous histopathology (G-EAT) can be induced by cells from mouse thyroglobulin (MTg)-immunized donors activated in vitro with MTg and IL-12. G-EAT lesions reach maximum severity 18-21 days after cell transfer and, if some thyroid follicles remain, lesions pletely resolve by day 35. CD8(+) cells are required for G-EAT resolution. To begin to determine the mechanisms involved in G-EAT resolution, apoptosis in thyroids was analyzed by TUNEL staining. Apoptotic thyrocytes and inflammatory cells were present in the thyroids of both CD8(+) and CD8-depleted recipient mice at day 19-21. By day 35, apoptotic cells were rare in thyroids of mice whose lesions had resolved; the few apoptotic inflammatory cells were generally in close proximity to thyroid follicles. Thyroids of CD8-depleted mice had ongoing inflammation at day 35 and most apoptotic cells were thyroid follicular cells. The expression of Fas and Fas ligand (FasL) mRNA in thyroids was also determined by RT-PCR in both CD8(+) and CD8-depleted recipient mice. Fas was expressed in normal thyroids and its expression was relatively constant throughout the course of disease. FasL mRNA was not expressed in normal thyroids. FasL mRNA expression generally correlated with G-EAT severity, being maximal at day 21 and diminishing as lesions resolved. However, FasL mRNA expression in thyroids of CD8-depleted mice in which resolution was delayed was pared to thyroids of CD8(+) mice parable disease severity, suggesting that FasL expressed by CD8(+) cells may play a role in G-EAT resolution.
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11099303
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Aberrant T cell responses to myelin antigens during clinical exacerbation in patients with multiple sclerosis.
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Multiple sclerosis (MS) is a demyelinating disease of presumed T cell autoimmunity against self myelin. We hypothesized that if myelin-reactive T cells are associated with the disease processes, they may undergo activation and expansion during acute exacerbation. In this study, we examined the precursor frequency, epitope recognition and cytokine profile of myelin-reactive T cells in 14 relapsing/remitting MS patients during exacerbation and remission. The study revealed that T cells recognizing the immunodominant peptides of candidate myelin antigens, including myelin basic protein (MBP), proteolipid protein and myelin oligodendrocyte glycoprotein, occurred at increased precursor frequency during acute exacerbation. The T cell responses to MBP focused on the immunodominant regions (residues 83-99 and 151-170) during exacerbation and shifted toward other epitopes of MBP at the time of remission. Furthermore, there was a marked increase in the production of T(h)1 cytokines among T cell lines obtained during pared to those obtained during remission. The study demonstrated that myelin-reactive T cells underwent selective activation and expansion during acute MS exacerbation. In contrast, myelin-reactive T cells found during remission in the same patients generally resembled those identified in healthy controls with some discrepancies. The findings suggest potential association of aberrant myelin-reactive T cell responses with acute exacerbation in MS, which may reflect transient activation of myelin-reactive T cell populations of pathogenic potential.
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11099304
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Cytokine profile and T cell adhesiveness to endothelial selectins: in vivo induction by a myasthenogenic T cell epitope and immunomodulation by a dual altered peptide ligand.
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Myasthenia gravis (MG) is a T cell-regulated antibody-mediated autoimmune disease. Immunization with two myasthenogenic peptides, p195-212 and p259-271, that are sequences of the human acetylcholine receptor alpha subunit was shown to induce experimental autoimmune MG (EAMG)-associated immune responses. A posed of the two altered peptide ligands (APL) of the myasthenogenic peptides (designated as dual APL) inhibited, in vitro and in vivo, those responses. The objectives of this study were to examine (i) whether in vivo T cell activation by p259-271 affects the cytokine profile and the T cell migration ability, and (ii) whether the latter are immunomodulated by in vivo administration of the dual APL. Our results showed that immunization of mice with p259-271 enriched the population of lymph node and spleen cells with subsets of T cells with strong adhesiveness towards E- and P-selectins. This enrichment was associated with an acquisition of a T(h)1-type cytokine profile. Treatment of the immunized mice with the dual APL interfered with both the migratory potential of the autoreactive T cells, and the production of the T(h)1-type cytokines IL-2 and IFN-gamma (known to play a pathogenic role in MG and EAMG). T cells derived from APL-treated mice acquired a T(h)3-type cytokine profile, characterized by the secretion of the immunosuppresive cytokine transforming growth factor-ss. Thus, our results suggest that T cell selectin ligands and T cell-derived cytokines are involved in the induction and immunomodulation of EAMG- and MG-associated T cell responses.
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11099305
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Lack of correlation between chemokine receptor and T(h)1/T(h)2 cytokine expression by individual memory T cells.
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Chemokine and chemokine receptor interactions may have important roles in leukocyte migration to specific immune reaction sites. Recently, it has been reported that CXC chemokine receptor (CXCR) 3 and CC chemokine receptor (CCR) 5 were preferentially expressed on T(h)1 cells, and CCR3 and CCR4 were preferentially expressed on T(h)2 cells. To investigate chemokine receptor expression by T(h) subsets in vivo, we analyzed cytokine (IL-2, IL-4 and IFN-gamma) and chemokine receptor (CXCR3, CXCR4, CCR3, CCR4 and CCR5) mRNA expression by individual peripheral CD4(+) memory T cells after short-term stimulation, employing a single-cell RT-PCR method. This ex vivo analysis shows that the frequencies of cells expressing chemokine receptor mRNA were not significantly different between T(h)1 and T(h)2 cells in normal peripheral blood. To assess a potential role of in vivo stimulation, we also analyzed unstimulated rheumatoid arthritis synovial CD4(+) memory T cells. CXCR3, CXCR4, CCR3 and CCR5 expression was detected by individual synovial T cells, but the frequencies of chemokine receptor mRNA were not clearly different between T(h)1 and non-T(h)1 cells defined by expression of IFN-gamma or lymphotoxin-alpha mRNA in all RA patients. These data suggest that chemokine receptor expression does not identify individual memory T cells producing T(h)-defining cytokines and therefore chemokine receptor expression cannot be a marker for T(h)1 or T(h)2 cells in vivo.
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11099307
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Unusual cytotoxic activities of thymus-independent, self-antigen-specific CD8(+) T cells.
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pared the cytotoxic activities of thymus-dependent and thymus-independent CD8(+) T cells. Thymus-dependent CD8(+) T cells, which are foreign antigen specific, acquired cytotoxic activity to tumor cells with a basal dose of the antigen peptides and to hybridoma cells expressing anti-TCR mAb only after differentiation into effector cytotoxic T lymphocytes (CTL). In contrast, thymus-independent CD8(+) T cells, which have been shown to be self-antigen specific, never showed cytotoxic activity to the target cells with a basal dose of the self-antigen peptide, while they could lyse hybridoma cells expressing anti-TCR mAb even without prior antigenic stimulation. Furthermore, the ex vivo cytotoxic activity of thymus-independent CD8(+) T cells was also observed against the target cells with high doses of the antigen peptides, which were not lysed by freshly isolated thymus-dependent CD8(+) T cells. Thus it is revealed that thymus-independent, self-antigen-specific CD8(+) T cells already acquire mature CTL functions in situ but have an increased threshold of TCR-mediated signaling for activation. These differences in cytotoxic activities between thymus-dependent and thymus-independent CD8(+) T cells suggest distinct roles of the two subsets of CD8(+) T cells in vivo.
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11099306
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Requirement for IFN-gamma in IL-12 production induced by collaboration between v(alpha)14(+) NKT cells and antigen-presenting cells.
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Two cytokines IL-4 and IL-12 are known to determine the balance between T(h)1 and T(h)2 development. In addition to IL-4 production of V(alpha)14(+) NKT cells, they have recently been demonstrated to have the capacity to stimulate IL-12 production by antigen-presenting cells (APC). This study demonstrates that IFN-gamma is absolutely required for the NKT cell-stimulated IL-12 production. Culture of B cell-depleted spleen cells from C57BL/6 mice with alpha-galactosylceramide (alpha-GalCer) capable of selectively stimulating V(alpha)14/J(alpha)281(+) NKT cells resulted in the production of IL-12 together with IL-4. Whereas IL-4 production occurred in culture of IFN-gamma(-/-) C57BL/6 splenocytes, the same culture failed to generate IL-12 production. While IL-12 production induced during culture of V(alpha)14(+) NKT cells and APC depended on the interaction between CD40 ligand on NKT cells and CD40 on APC, the expression levels of these key molecules parable in cells from wild-type and IFN-gamma(-/-) mice. Addition of rIFN-gamma to alpha-GalCer stimulated IFN-gamma(-/-) splenocyte culture, and administration of rIFN-gamma to alpha-GalCer-injected IFN-gamma(-/-) mice resulted in the restoration of IL-12 production in vitro and in vivo. These results illustrate a mandatory role for IFN-gamma in V(alpha)14(+) NKT cell-stimulated IL-12 production by APC.
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11099308
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HSP70 from Trypanosoma cruzi is endowed with specific cell proliferation potential leading to apoptosis.
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The Trypanosoma cruzi HSP70 binant protein has the capacity to stimulate splenocytes or lymph node cells from naive mice in a non-haplotype-restricted way. The proliferative response is abolished by proteinase K digestion and by specific anti-HSP70 antibodies. The induced stimulation index was maximal after 24 h of incubation with the protein. This stimulation leads to cell death in a Fas-Fas ligand-independent way. The phenotype of the expanded cells was CD3(+) TCRalphass(+) CD4(+). HSP70-responsive cells express a broad range of cytokines including IFN-gamma, IL-2 and tumor necrosis factor-alpha. After 48 h of incubation with HSP70 there was a significant increase in relative intracellular levels of CD3 TCRalphass receptors. The expanded CD4(+) cell population expressed CD25; however, in contrast to concanavalin A-treated culture, delayed CD44 expression was observed.
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11099309
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Involvement of cytokines in the skin-to-lymph node trafficking of cells of the monocyte-macrophage lineage expressing a C-type lectin.
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The mechanism by which dermal cells expressing a macrophage calcium-type lectin (MGL) trafficked to regional lymph nodes was investigated. Conditioned medium prepared from organ cultures of mouse skin sensitized with a mixture of acetone and dibutylphthalate was shown to decrease the number of MGL(+) cells in the dermis in ex vivo organ culture assays. In in vitro culture of sensitized skin, the loss of MGL(+) cells was abrogated by the addition to the culture medium of mAb against IL-1ss, while addition of binant IL-1ss to the medium in which untreated skin was cultured induced loss of MGL(+) cells. Intradermal injection of binant IL-1ss also resulted in a transient increase of MGL(+) cells in the T cell area of draining lymph nodes in vivo, indicating that IL-1ss is central in the entire process of MGL(+) cell trafficking to the lymph nodes. Supporting this is that cells producing IL-1ss were detected in the epidermis of cultured skin even early after sensitization. The possibility that IL-1ss simply down-regulates MGL expression was eliminated by Western blotting experiments with isolated MGL(+) cells treated with or without IL-1ss. IL-1alpha and tumor necrosis factor (TNF)-alpha were also able to induce migration of MGL(+) cells in the ex vivo assay in a manner akin to IL-1ss, and antibodies against them abrogated this. Isolated MGL(+) cells from skin cultured in type I collagen matrix in vitro displayed morphological changes upon exposure to IL-1ss, IL-1alpha or TNF-alpha, indicating that these cytokines exert a direct effect on these cells. Thus, pro-inflammatory cytokines, particularly IL-1ss, are produced at the site of skin sensitization and are involved in at least initiating the trafficking of cells expressing MGL to the lymph nodes.
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11099311
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Nasal application of a naturally processed and presented T cell epitope derived from TCR AV11 protects against adjuvant arthritis.
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Reactivity towards TCR peptides plays an important role in the regulation of several experimental autoimmune diseases. In a previous paper, we showed the TCRAV11 usage by an arthritogenic T cell clone isolated from a rat with adjuvant arthritis (AA). Moreover, we identified three immunogenic peptides in AV11: AV11 24-40, 41-55 and 66-80. In the present study, we show that T cells directed towards all three epitopes are part of the immune repertoire. The strongest delayed-type hypersensitivity (DTH) reaction was observed against the peptide derived from the third framework region, peptide AV11 66-80. DTH reactions to this peptide were detectable in naive rats and increased significantly after AA induction. Interestingly, modulation of the AV11 66-80 T cell response by nasal AV11 66-80 administration resulted in reduced DTH responses and in a strong inhibition of AA. These findings suggest that during the natural course of AA, T cells directed towards the third framework region of AV11 do not have a disease regulatory function, but instead play a role in the deterioration of AA.
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11099312
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Antigen contacts by Ni-reactive TCR: typical alphass chain cooperation versus alpha chain-dominated specificity.
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VB17(+) TCR dominate in Ni-driven T cell cultures from highly Ni-sensitized patients. Using transfection of TCR from three CD4(+), VB17(+), Ni-specific human T cell clones, we studied their Ni-MHC contacts by site-directed TCR mutation bination of alpha and ss chains between different TCR. All three TCR exhibited N-nucleotide-determined Arg-Asp motifs in their CDR3-ss sequences. Two of them were specifically restricted to HLA-DR13, while the third one accepted a variety of HLA-DR alleles. The highly similar alpha or ss chains of the DR13-restricted TCR were interchangable without loss of specificity, but alpha or ss chains of other TCR were not tolerated. Mutations of their Arg-Asp motif revealed loss of reactivity upon exchanging Asp for Glu or Ala and of Arg for Ala but not of Arg for Lys or the Ni binding His. Reactivity was also destroyed by mutation of alpha chain position 51, proposed as a general contact site for MHC. Hence, in these two TCR the Arg-Asp motif is clearly involved in contacting plexes, and close cooperation between alpha and ss chain is required. In contrast, the third TCR retained Ni reactivity upon mutation of alpha chain position 51 or of its ss chain Arg-Asp motif, which rather affected the pattern of DR cross-restriction. Moreover, its alpha chain paired with various ss chains from other, even mouse TCR, irrespective of their specificity, retaining Ni reactivity as well as promiscuous HLA-DR restriction. This preponderance of an alpha chain in defining specificity indicates fundamental differences in Ni interactions of individual TCR and implies that ss chain similarities may not necessarily result from antigen selection.
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11099313
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Induction of IL-4-dependent, anaphylactic-type and IL-4-independent, non-anaphylactic-type IgG1 antibodies is modulated by adjuvants.
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Adjuvants can modulate the levels of anaphylactic- and non-anaphylactic-type IgG1 antibodies produced in response to a particular antigen. Mice immunized with ovalbumin (OVA) in Al(OH)(3) gel (alum) produced mostly the anaphylactic type, irrespective of the s.c. or i.p. route used, and this antibody was not detectable in IL-4(-/-) mice. In contrast, when OVA was injected plete Freund's adjuvant (CFA), it induced substantial amounts of non-anaphylactic-type IgG1 in both IL-4(+/+) and IL-4(-/-) mice, and some anaphylactic IgG1 antibody in IL-4(+/+) mice only. When IFN-gamma was neutralized by specific mAb in wild-type mice immunized with OVA in CFA, the anaphylactic-type IgG1 antibody increased reaching the same levels as in alum-injected mice. This result indicates that the induction of IFN-gamma by the immunization with CFA down-regulates the production of IL-4-dependent, anaphylactic-type IgG1. Despite their different effects on IgG1 antibody production, both adjuvants dramatically increased the production of IgG2a in IL-4-deprived mice and did not induce any detectable IgE in these mice.
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11099314
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Dendritic cells efficiently cross-prime HLA class I-restricted cytolytic T lymphocytes when pulsed with both apoptotic and necrotic cells but not with soluble cell-derived lysates.
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Dendritic cells (DC) have been shown to efficiently present antigen to CD8(+) cytolytic T cells (CTL) when pulsed with apoptotic cells as a source of cell-derived antigen. Such cross-priming could not be detected by the use of necrotic cells, while conflicting results have been reported for cell-derived soluble lysates. In this study, we reinvestigated this issue by using autologous Epstein-Barr virus-transformed lymphoblastoid cell lines (LCL) as a source of antigen to pulse monocyte-derived DC. Both autologous and HLA-mismatched allogeneic LCL have been used either in the form of apoptotic or of necrotic cells or of soluble cell lysates. At day 7, DC were co-cultured with the autologous CD8(+) lymphocyte fraction for an additional 9 days, in the presence of exogenous IL-2 (added after 48 h). At the end of the culture period, CD8(+) CTL efficiently lysed autologous LCL only when they had been co-cultured with DC pulsed with necrotic or apoptotic cells. That an efficient cross-priming of autologous CD8(+) cells could be induced by DC pulsed with apoptotic or necrotic LCL but not with cell lysates was further demonstrated in assays of IFN-gamma production in response to short-term re-stimulation of CD8(+) cells with LCL. In addition, LCL-specific CD8(+) cells could specifically lyse autologous DC that had been pulsed with LCL-derived antigens, further suggesting that DC presented exogenous antigens on HLA class I molecules.
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11099315
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Potential pathways for regulation of NK and T cell responses: differential X-linked lymphoproliferative syndrome gene product SAP interactions with SLAM and 2B4.
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SAP, the gene that is altered or absent in the X-linked lymphoproliferative syndrome (XLP), encodes a small protein prises a single SH2 domain and binds to the cell-surface protein SLAM which is present on activated or memory T and B cells. Because defective NK cell activity also has been reported in XLP patients, we studied the SAP gene in NK cells. SAP was induced upon viral infection of SCID mice and shown to be expressed in NK cells by in vitro culturing in the presence of IL-2. Moreover, SAP was expressed in the NK cell lines YT and RNK 16. Because SLAM, the cell-surface protein with which SAP interacts, and 2B4, a membrane protein having sequence homologies with SLAM, also were found to be expressed on the surfaces of activated NK and T cell populations, they may access SAP functions in these populations. Whereas we found that 2B4 also binds SAP, 2B4-SAP interactions occurred only upon tyrosine phosphorylation of 2B4. By contrast, SLAM-SAP interactions were independent of phosphorylation of Y281 and Y327 on SLAM. As CD48, the ligand for 2B4, is expressed on the surface of Epstein-Barr virus (EBV)-infected B cells, it is likely that SAP regulates signal transduction through this pair of cell-surface molecules. These data support the hypothesis that XLP is a result of both defective NK and T lymphocyte responses to EBV. The altered responses may be due to aberrant control of the signaling cascades which are initiated by the SLAM-SLAM and 2B4-CD48 interactions.
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11099318
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Immunotherapy of hormone-refractory prostate cancer with antigen-loaded dendritic cells.
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Provenge (Dendreon Corp, Seattle, WA) is an immunotherapy product consisting of autologous dendritic cells loaded ex vivo with a binant fusion protein consisting of prostatic acid phosphatase (PAP) linked to granulocyte-macrophage colony-stimulating factor. Sequential phase I and phase II trials were performed to determine the safety and efficacy of Provenge and to assess its capacity to break immune tolerance to the normal tissue antigen PAP.
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11099319
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Preliminary results of a randomized radiotherapy dose-escalation study comparing 70 Gy with 78 Gy for prostate cancer.
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To determine the effect of radiotherapy dose on prostate cancer patient e and biopsy positivity in a phase III trial.
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11099320
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Phase II study of vinorelbine in patients with malignant pleural mesothelioma.
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To evaluate the response rate and impact on quality of life of vinorelbine given as cycles of 30 mg/m(2) weekly for 6 weeks to patients with malignant pleural mesothelioma.
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11099321
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Autografting followed by nonmyeloablative immunosuppressive chemotherapy and allogeneic peripheral-blood hematopoietic stem-cell transplantation as treatment of resistant Hodgkin's disease and non-Hodgkin's lymphoma.
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To investigate the use of a nonmyeloablative fludarabine-based immunosuppressive regimen to allow engraftment of HLA-sibling donors' mobilized stem cells and induction of a graft-versus-lymphoma effect for patients with advanced resistant Hodgkin's disease and non-Hodgkin's lymphoma.
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11099322
|
Identifying breast cancer patients at high risk for bone metastases.
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To identify patient populations at high risk for bone metastases at any time after diagnosis of operable breast cancer, because these patients are potential beneficiaries of treatment with bisphosphonates.
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11099323
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p53 gene status and response to platinum/paclitaxel-based chemotherapy in advanced ovarian carcinoma.
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The p53 gene plays a critical role in cellular response to DNA damage and has been implicated in the response to pounds in ovarian carcinoma patients. Because taxanes could induce p53-independent apoptosis, we assessed the relevance of p53 gene status to response in ovarian carcinoma patients receiving paclitaxel and platinum-containing chemotherapy.
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11099324
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Gene expression for dihydropyrimidine dehydrogenase and thymidine phosphorylase influences outcome in epithelial ovarian cancer.
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Dihydropyrimidine dehydrogenase (DPD) is a pyrimidine salvage enzyme responsible for degradation of thymine, which is produced from thymidine by thymidine phosphorylase (TP). Our purpose was to determine whether DPD affects prognosis in patients with epithelial ovarian cancer and how the two enzymes may interact in such effects.
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11099325
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Phase I and pharmacokinetic trial of weekly oral fluorouracil given with eniluracil and low-dose leucovorin to patients with solid tumors.
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Fluorouracil (5-FU) given as a weekly, high-dose 24-hour infusion is active and tolerable. We evaluated an oral regimen of eniluracil (which inactivates dihydropyrimidine dehydrogenase [DPD]), 5-FU, and leucovorin to simulate this schedule.
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11099326
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Phase I study in advanced cancer patients of a diversified prime-and-boost vaccination protocol using recombinant vaccinia virus and recombinant nonreplicating avipox virus to elicit anti-carcinoembryonic antigen immune responses.
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This trial sought to determine, for the first time, the validity in human vaccinations of using two different binant vaccines in diversified prime-and-boost regimens to enhance T-cell responses to a tumor antigen.
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11099327
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Phase I and pharmacokinetic study of the differentiating agent vesnarinone in combination with gemcitabine in patients with advanced cancer.
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To evaluate the maximum-tolerated dose, dose-limiting toxicities (DLTs), and pharmacokinetic profile of vesnarinone given once daily bination with gemcitabine.
|
11099328
|
Phase I and pharmacokinetic study of the camptothecin analog DX-8951f administered as a 30-minute infusion every 3 weeks in patients with advanced cancer.
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DX-8951f is a totally synthetic derivative of camptothecin with greater cytotoxicity and more potent topoisomerase I inhibition than SN-38, topotecan, and camptothecin in preclinical studies. This phase I study aimed to describe the toxicity and to determine the maximum-tolerated dose (MTD) and pharmacokinetics of DX-8951f given as a 30-minute intravenous infusion every 3 weeks.
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11099344
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Fraction of the dark current carried by Ca(2+) through cGMP-gated ion channels of intact rod and cone photoreceptors.
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The selectivity for Ca(2+) over Na(+), PCa/PNa, is higher in cGMP-gated (CNG) ion channels of retinal cone photoreceptors than in those of rods. To ascertain the physiological significance of this fact, we determined the fraction of the cyclic nucleotide-gated current specifically carried by Ca(2+) in intact rods and cones. We activated CNG channels by suddenly (<5 ms) increasing free 8Br-cGMP in the cytoplasm of rods or cones loaded with a caged ester of the cyclic nucleotide. Simultaneous with the uncaging flash, we measured the cyclic nucleotide-dependent changes in membrane current and fluorescence of the Ca(2+)-binding dye, Fura-2, also loaded into the cells. The ratio of changes in fura-2 fluorescence and the integral of the membrane current, under a restricted set of experimental conditions, is a direct measure of the fractional Ca(2+) flux. Under normal physiological salt concentrations, the fractional Ca(2+) flux is higher in CNG channels of cones than in those of rods, but it differs little among cones (or rods) of different species. Under normal physiological conditions and for membrane currents </=200 pA, the Ca(2+) fractional flux in single cones of striped bass was 33 +/- 2%, and 34 +/- 6% in catfish cones. parable conditions, the Ca(2+) fractional flux in rod outer segments of tiger salamander was 21 +/- 1%, and 14 +/- 1% in catfish rods. Fractional Ca(2+) flux increases as extracellular Ca(2+) rises, with a dependence well described by the Michaelis-Menten equation. KCa, the concentration at which Ca(2+) fractional flux is 50% was 1.98 mM in bass cones and 4.96 mM in tiger salamander rods. Because Ca(2+) fractional flux is higher in cones than in rods, light flashes that generate equal photocurrents will cause a larger change in cytoplasmic Ca(2+) in cones than in rods.
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11099346
|
Mutation of a single residue in the S2-S3 loop of CNG channels alters the gating properties and sensitivity to inhibitors.
|
We previously found that native cyclic nucleotide-gated (CNG) cation channels from amphibian rod cells are directly and reversibly inhibited by analogues of diacylglycerol (DAG), but little is known about the mechanism of this inhibition. We recently determined that, at saturating cGMP concentrations, pletely inhibits cloned bovine rod (Brod) CNG channels while only partially inhibiting cloned rat olfactory (Rolf) channels (Crary, J.I., D.M. Dean, W. Nguitragool, P.T. Kurshan, and A.L. Zimmerman. 2000. J. Gen. Phys. 116:755-768; in this issue). Here, we report that a point mutation at position 204 in the S2-S3 loop of Rolf and a mouse CNG channel (Molf) found in olfactory epithelium and heart, increased DAG sensitivity to that of the Brod channel. Mutation of this residue from the wild-type glycine to a glutamate (Molf G204E) or aspartate (Molf G204D) gave dramatic increases in DAG sensitivity without changing the apparent cGMP or cAMP affinities or efficacies. However, unlike the wild-type olfactory channels, these mutants demonstrated voltage-dependent gating with obvious activation and deactivation kinetics. Interestingly, the mutants were also more sensitive to inhibition by the local anesthetic, tetracaine. Replacement of the position 204 glycine with a tryptophan residue (Rolf G204W) not only gave voltage-dependent gating and an increased sensitivity to DAG and tetracaine, but also showed reduced apparent agonist affinity and cAMP efficacy. parisons show that the glycine at position 204 in the S2-S3 loop is highly conserved, and our findings indicate that its alteration can have critical consequences for channel gating and inhibition.
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11099345
|
Mechanism of inhibition of cyclic nucleotide-gated ion channels by diacylglycerol.
|
Cyclic nucleotide-gated (CNG) channels are ponents in the visual and olfactory signal transduction pathways, and they primarily gate in response to changes in the cytoplasmic concentration of cyclic nucleotides. We previously found that the ability of the native rod CNG channel to be opened by cGMP was markedly inhibited by analogues of diacylglycerol (DAG) without a phosphorylation reaction (Gordon, S.E., J. Downing-Park, B. Tam, and A.L. Zimmerman. 1995. Biophys. J. 69:409-417). Here, we have studied cloned bovine rod and rat olfactory CNG channels expressed in Xenopus oocytes, and have determined that they are differentially inhibited by DAG. At saturating [cGMP], DAG inhibition of homomultimeric (alpha subunit only) rod channels was similar to that of the native rod CNG channel, but DAG was much less effective at inhibiting the homomultimeric olfactory channel, producing only partial inhibition even at high [DAG]. However, at low open probability (P(o)), both channels were more sensitive to DAG, suggesting that DAG is a closed state inhibitor. The Hill coefficients for DAG inhibition were often greater than one, suggesting that more than one DAG molecule is required for effective inhibition of a channel. In single-channel recordings, DAG decreased the P(o) but not the single-channel conductance. Results with chimeras of rod and olfactory channels suggest that the differences in DAG inhibition correlate more with differences in the transmembrane segments and their attached loops than with differences in the amino and carboxyl termini. Our results are consistent with a model in which multiple DAG molecules stabilize the closed state(s) of a CNG channel by binding directly to the channel and/or by altering bilayer-channel interactions. We speculate that if DAG interacts directly with the channel, it may insert into a putative hydrophobic crevice among the transmembrane domains of each subunit or at the hydrophobic interface between the channel and the bilayer.
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11099347
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Gating induces a conformational change in the outer vestibule of ENaC.
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The epithelial Na(+) channel (ENaC) prised of three homologous subunits (alpha, beta, and gamma). The channel forms the pathway for Na(+) absorption in the kidney, and mutations cause disorders of Na(+) homeostasis. However, little is known about the mechanisms that control the gating of ENaC. We investigated the gating mechanism by introducing bulky side chains at a position adjacent to the extracellular end of the second membrane spanning segment (549, 520, and 529 in alpha, beta, and gammaENaC, respectively). Equivalent "DEG" mutations in related DEG/ENaC channels in Caenorhabditis elegans cause swelling neurodegeneration, presumably by increasing channel activity. We found that the Na(+) current was increased by mutagenesis or chemical modification of this residue and adjacent residues in alpha, beta, and gammaENaC. This resulted from a change in the gating of ENaC; modification of a cysteine at position 520 in betaENaC increased the open state probability from 0. 12 to 0.96. Accessibility to this side chain from the extracellular side was state-dependent; modification occurred only when the channel was in the open conformation. Single-channel conductance decreased when the side chain contained a positive, but not a negative charge. However, alterations in the side chain did not alter the selectivity of ENaC. This is consistent with a location for the DEG residue in the outer vestibule. The results suggest that channel gating involves a conformational change in the outer vestibule of ENaC. Disruption of this mechanism could be important clinically since one of the mutations that increased Na(+) current (gamma(N530K)) was identified in a patient with renal disease.
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11099350
|
Anion permeation in Ca(2+)-activated Cl(-) channels.
|
Ca(2+)-activated Cl channels (Cl(Ca)Cs) are an important class of anion channels that are opened by increases in cytosolic [Ca(2+)]. Here, we examine the mechanisms of anion permeation through Cl(Ca)Cs from Xenopus oocytes in excised inside-out and outside-out patches. Cl(Ca)Cs exhibited moderate selectivity for Cl over Na: P(Na)/P(Cl) = 0.1. The apparent affinity of Cl(Ca)Cs for Cl was low: K(d) = 73 mM. The channel had an estimated pore diameter >0.6 nm. The relative permeabilities measured under bi-ionic conditions by changes in E(rev) were as follows: C(CN)(3) > SCN > N(CN)(2) > ClO(4) > I > N(3) > Br > Cl > formate > HCO(3) > acetate = F > gluconate. The conductance sequence was as follows: N(3) > Br > Cl > N(CN)(2) > I > SCN > COOH > ClO(4) > acetate > HCO(3) = C(CN)(3) > gluconate. Permeant anions block in a voltage-dependent manner with the following affinities: C(CN)(3) > SCN = ClO(4) > N(CN)(2) > I > N(3) > Br > HCO(3) > Cl > gluconate > formate > acetate. Although these data suggest that anionic selectivity is determined by ionic hydration energy, other factors contribute, because the energy barrier for permeation is exponentially related to anion hydration energy. Cl(Ca)Cs exhibit weak anomalous mole fraction behavior, implying that the channel may be a multi-ion pore, but that ions interact weakly in the pore. The affinity of the channel for Ca(2+) depended on the permeant anion at low [Ca(2+)] (100-500 nM). Apparently, occupancy of the pore by a permeant anion increased the affinity of the channel for Ca(2+). The current was strongly dependent on pH. Increasing pH on the cytoplasmic side decreased the inward current, whereas increasing pH on the external side decreased the outward current. In both cases, the apparent pKa was voltage-dependent with apparent pKa at 0 mV = approximately 9.2. The channel may be blocked by OH(-) ions, or protons may titrate a site in the pore necessary for ion permeation. These data demonstrate that the permeation properties of Cl(Ca)Cs are different from those of CFTR or ClC-1, and provide insights into the nature of the Cl(Ca)C pore.
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11099349
|
The role of steady phosphodiesterase activity in the kinetics and sensitivity of the light-adapted salamander rod photoresponse.
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We investigated the kinetics and sensitivity of photocurrent responses of salamander rods, both in darkness and during adaptation to steady backgrounds producing 20-3,000 photoisomerizations per second, using suction pipet recordings. The most intense backgrounds suppressed 80% of the circulating dark current and decreased the flash sensitivity approximately 30-fold. To investigate the underlying transduction mechanism, we expressed the responses as a fraction of the steady level of cGMP-activated current recorded in the background. The fractional responses to flashes of any fixed intensity began rising along mon trajectory, regardless of background intensity. We interpret these invariant initial trajectories to indicate that, at these background intensities, light adaptation does not alter the gain of any of the amplifying steps of phototransduction. For subsaturating flashes of fixed intensity, the fractional responses obtained on backgrounds of different intensity were found to "peel off" from mon initial trajectory in a background-dependent manner: the more intense the background, the earlier the time of peeling off. This behavior is consistent with a background-induced reduction in the effective lifetime of at least one of the three major integrating steps in phototransduction; i.e., an acceleration of one or more of the following: (1) the inactivation of activated rhodopsin (R*); (2) the inactivation of activated phosphodiesterase (E*, representing plex G(alpha)-PDE of phosphodiesterase with the transducin alpha-subunit); or (3) the hydrolysis of cGMP, with rate constant beta. Our measurements show that, over the range of background intensities we used, beta increased on average to approximately 20 times its dark-adapted value; and our theoretical analysis indicates that this increase in beta is the primary mechanism underlying the measured shortening of time-to-peak of the dim-flash response and the decrease in sensitivity of the fractional response.
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11099351
|
Dynamics of signaling between Ca(2+) sparks and Ca(2+)- activated K(+) channels studied with a novel image-based method for direct intracellular measurement of ryanodine receptor Ca(2+) current.
|
Ca(2+) sparks are highly localized cytosolic Ca(2+) transients caused by a release of Ca(2+) from the sarcoplasmic reticulum via ryanodine receptors (RyRs); they are the elementary events underlying global changes in Ca(2+) in skeletal and cardiac muscle. In smooth muscle and some neurons, Ca(2+) sparks activate large conductance Ca(2+)-activated K(+) channels (BK channels) in the spark microdomain, causing spontaneous transient outward currents (STOCs) that regulate membrane potential and, hence, voltage-gated channels. Using the fluorescent Ca(2+) indicator fluo-3 and a high speed widefield digital imaging system, it was possible to capture the total increase in fluorescence (i.e., the signal mass) during a spark in smooth muscle cells, which is the first time such a direct approach has been used in any system. The signal mass is proportional to the total quantity of Ca(2+) released into the cytosol, and its rate of rise is proportional to the Ca(2+) current flowing through the RyRs during a spark (I(Ca(spark))). Thus, Ca(2+) currents through RyRs can be monitored inside the cell under physiological conditions. Since the magnitude of I(Ca(spark)) in different sparks varies more than fivefold, Ca(2+) sparks appear to be caused by the concerted opening of a number of RyRs. Sparks with the same underlying Ca(2+) current cause STOCs, whose amplitudes vary more than threefold, a finding that is best explained by variability in coupling ratio (i.e., the ratio of RyRs to BK channels in the spark microdomain). The time course of STOC decay is approximated by a single exponential that is independent of the magnitude of signal mass and has a time constant close to the value of the mean open time of the BK channels, suggesting that STOC decay reflects BK channel kinetics, rather than the time course of [Ca(2+)] decline at the membrane. Computer simulations were carried out to determine the spatiotemporal distribution of the Ca(2+) concentration resulting from the measured range of I(Ca(spark)). At the onset of a spark, the Ca(2+) concentration within 200 nm of the release site reaches a plateau or exceeds the [Ca(2+)](EC50) for the BK channels rapidly parison to the rate of rise of STOCs. These findings suggest a model in which the BK channels lie close to the release site and are exposed to a saturating [Ca(2+)] with the rise and fall of the STOCs determined by BK channel kinetics. The mechanism of signaling between RyRs and BK channels may provide a model for Ca(2+) action on a variety of molecular targets within cellular microdomains.
|
11099355
|
Early repolarization syndrome: clinical characteristics and possible cellular and ionic mechanisms.
|
Early repolarization syndrome (ERS) has traditionally been regarded as benign. In the electrocardiogram (ECG), it is characterized by a diffuse upward ST-segment concavity ending in a positive T wave in leads V2-V4 (5). Clinical interest in this ECG phenomenon has recently been rekindled because of similarities with the electrocardiographic manifestations of the highly arrhythmogenic Brugada syndrome and the potential for misdiagnosis. This article addresses the clinical characteristics and cellular and ionic basis for ERS. In experimental models, the ECG signature of ERS can be converted to that of the Brugada syndrome, raising the possibility that ERS may not be as benign as generally thought, and that under certain conditions known to predispose to ST-segment elevation, patients with ERS may be at greater risk. Further clinical and experimental data are clearly required to test these hypotheses, and the characteristics of ERS need to be more fully delineated within the framework of what has been learned about the Brugada syndrome in recent years.
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11099356
|
Mechanisms in T-wave alternans caused by intraventricular block.
|
It is recognized that 2:1 intraventricular (IV) block can result in T-wave alternans but is usually assumed that it would also affect QRS waveform. Block in a local region is not, however, varied activation sequence of the same muscle mass because the blocked region is not activated and is not part of the mass that is activated in cycles without block. Also, the block region may have electrocardiogram (ECG) effects when its state differs from other regions. In view of those considerations, the ECG effects of IV block were evaluated by using puter model of excitation and recovery. ECGs were calculated from differences between the excited state and various degrees of recovery. Results provided evidence that boundaries associated with regions of block rather than regions having varied activation sequence were the major factors in T-wave alternans caused by IV block. Effects of the boundaries included cancellation of the effects of IV block on plexes. Findings suggest that IV block cannot be excluded as a mechanism of T-wave alternans in the absence of QRS alternans.
|
11099357
|
Effects of cardiovascular autonomic function tests on QT dispersion in the 12-lead electrocardiogram of healthy patients.
|
Changes in autonomic tone modulate QT interval duration. How cardiovascular autonomic reflexes affect QT dispersion, a suggested marker of arrhythmia risk, is not well established. We studied 10 healthy young adult volunteer men during quiet and deep breathing, the Valsalva maneuver, sustained handgrip, hyperventilation, the cold pressor test, and mental stress. An automated method was used for measurement of QT-peak and QT-end intervals, and QT dispersion was defined as maximum-minimum of the measured intervals. QT-peak dispersion was greater on deep expiration than deep inspiration (49 +/- 20 ms vs 37 +/- 14 ms, P < .05). QT-end dispersion decreased in the tachycardia phase of the Valsalva maneuver (45 +/- 23 ms vs 35 +/- 21 ms, P < .05), but QT dispersion did not change during the other interventions. Rapid cardiovascular autonomic reflex adjustment does not change QT dispersion in healthy young adult men. However, large intrathoracic volume and intrathoracic pressure changes during forced respiratory movements might confound QT dispersion measurements.
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11099358
|
The added diagnostic value of automated QT-dispersion measurements and automated ST-segment deviations in the electrocardiographic diagnosis of acute cardiac ischemia.
|
The purpose of this study was to determine the added value of automated QT dispersion and ST-segment measurements to physician interpretation of 12-lead electrocardiograms (ECGs) in patients with chest pain. To date, poor reproducibility of manual measurements and lack of shown added value have limited the clinical use of QT dispersion. Twelve-lead ECGs (n = 1,161) from the Milwaukee Prehospital Chest Pain Database were independently classified by 2 physicians into 3 groups (acute myocardial infarction (AMI), acute cardiac ischemia (ACI), or nonischemic), and their consensus was obtained. QT-end and QT-peak dispersions were measured by puterized system. puter also identified ST-segment deviations. Sensitivity, specificity, and positive predictive values (PPVs) and negative predictive values (NPV) for AMI and ACI were evaluated independently and binations. For AMI, physicians' consensus classification was remarkably good (sensitivity, 48%, specificity, 99%). Independent classification by QT-end and QT-peak dispersions or ST deviations was not superior to the physicians' consensus. Optimal classification occurred bining automated QT-end dispersion and ST deviations with physicians' consensus. bination increased sensitivity for the diagnoses of AMI by 35% (65% vs 48%, P < .001) and ACI by 55% (62% vs 40%, P < pared with physicians' consensus, while parable specificity. This study supports a potential clinical role for automated QT dispersion bined with other diagnostic methods for detecting AMI and ACI.
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11099359
|
The ability of a computer program based on the Marquette Matrix-12 short measurement matrix to replicate coding by the Minnesota ECG coding laboratory.
|
The study was undertaken to determine whether puter program that uses "short measurement matrix" data from the Marquette Matrix-12 system can replicate Minnesota electrocardiogram (ECG) coding laboratory interpretations. An agreement was found between coding of plex ECGs at the Minnesota ECG coding laboratory and coding based on Marquette Matrix-12 short measurement matrix. parison was based on 763 ECGs plus chest pain history and serum enzyme values for a stratified random sample of 141 patients hospitalized in 1990 or 1991 for an event coded as HICDA 410.x (acute myocardial infarction), 411 (other acute and subacute forms of ischemic heart disease), 413 (angina pectoris), or 796.9 (other ill defined and unknown causes of morbidity and mortality). The population was reconstructed from the stratified random sample to enable population-based inferences. Exact agreement between Matrix-12 and Minnesota coding laboratory interpretation on 4 ECG patterns (evolving diagnostic, diagnostic, equivocal, or other ECG pattern) was 74.5% (Kappa = 0.63 +/- 0.05) for the stratified random sample and 78.8% (Kappa = 0.66 +/- 0.05) for the reconstructed population. For coding myocardial infarction based on the ECG, serum enzyme levels, and ischemic chest pain, agreement was 91.5% (Kappa = 0.85 +/- 0.04) for the stratified random sample and 90% (Kappa = 0.83 +/- 0.04) for the reconstructed population. Although ECG interpretation by puter program based on the short measurement matrix of the Matrix 12 system results in better agreement than prior attempts to replicate the Minnesota coding laboratory, interpretation remains unacceptably discordant.
|
11099361
|
Effects of intracellular calcium elevation on action potential and L-type calcium current of normal and chronically infarcted rat ventricles.
|
The present work investigated the effects of raising [Ca+2]i levels on action potential (AP) and L-type calcium current (I(Ca.L)) of normal and chronically infarcted rat ventricles. Experiments were performed by conventional electrophysiology and whole-cell patch-clamp techniques. In the former, APs were recorded in ventricular strips subjected to different pacing rates or elevation of [Ca+2]o levels. In the latter, I(Ca.L) was studied in isolated myocytes in the absence of an intracellular Ca+2 chelator. The acceleration of heart rate (6 to 240 beats/min) reduced AP duration measured at 20%, 50%, and 90% repolarization (APD20, APD50, and APD90) in the infarcted group, and increased APD20 and APD50 in the control group. Rising [Ca+]o (1.25 to 5.0 mmol/L) induced a decrease of APD20 and APD50 in both groups. Voltage clamp revealed a smaller I(Ca.L) density at approximately -17 mV in myocytes from infarcted ventricles (-1.86 +/- 0.37 vs -3.98 +/- 0.65 pA/pF, P < .05), and the appearance of a non-K+ outward current coupled to I(Ca.L). The results suggest the participation of a Ca+2-activated outward current in the repolarization of normal and infarcted rat ventricles.
|
11099362
|
Apparent bradycardia-dependent sinoatrial block associated with respiration.
|
In our previous patients, apparent bradycardia-dependent block has been shown in the atrioventricular (AV) junction and in the accessory pathway. It was suggested that these previous cases were not of true bradycardia-dependent block; namely, that, as a result of periodic increases in vagal tone associated with respiration, conductivity in the AV junction or in the accessory pathway was depressed to a greater degree than automaticity in the sinus node. In the present article, 3 patients with frequent sinoatrial (SA) block were reported. In 1 patient, sinus escape-capture bigeminy caused by SA block was found. In these present patients, when the sinus cycle lengthened, SA block occurred. The purpose of the present article is to show that the patients have apparent bradycardia-dependent SA block, namely, not true bradycardia-dependent SA block. In all patients, the respiration curve was recorded simultaneously with the electrocardiogram. In all patients, during inspiration, the sinus cycle gradually shortened; on the other hand, during expiration, the sinus cycle gradually lengthened, and then a sinus impulse was blocked in the SA junction. These findings suggested that increased vagal tone during expiration depressed conductivity in the SA junction to a greater degree than automaticity in the sinus node.
|
11099360
|
Onset dynamics of reentrant tachycardia and rate-dependent conduction changes in canine ventricular muscle: effects of Na+ and Ca2+ channel blockade.
|
To show that cycle-length (CL) prolongation occurring at the onset of reentrant tachycardias may be associated with an increase in conduction time (CT), and to investigate the involvement of Na+ and Ca2+ channel activity, reentrant activity was induced by programmed stimulation in thin ventricular muscle slices with a central cryothermal lesion, as documented with 7 to 12 bipolar recordings. We studied the course of the CL measured in successive tachycardia beats, as well as the course of conduction times after abrupt transition from a pacing CL of 1,000 to 400 ms (pacing paradigm). The majority of the tachycardias displayed a dynamic behavior in which CL increased progressively, with an exponential rate constant of 37 +/- 35 beats (mean +/- SD), stabilizing at 325 +/- 67 ms after a total increase of 17 +/- 17 ms. In the pacing paradigm, CT was prolonged from 68 +/- 21 ms to 79 +/- 24 ms according to a biphasic course consisting of an abrupt increase in the first response to 400 ms, followed up by an exponential increase, stabilizing with a rate constant of 18 +/- 23 beats. Lidocaine 5 x 10(-5) mol/L induced an increase in steady-state CT, which was not further modified by adding verapamil 10(-5) mol/L. However, verapamil prolonged the rate constant of the exponential course by 60 +/- 40 beats. Thus, the onset dynamics of reentrant tachycardias mon features with the dynamic behavior of CT in the pacing paradigm, in which both Na+ channel activity and Ca2+-modulated cellular coupling appear to be involved.
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