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David Nordlund, 14, at left, and Mitchel Cartwright, 16, confer about their game concept during a game jam Saturday at Descutes County Fair & Expo Center. The event was sponsored by Deschutes 4-H and TechStart to introduce kids to the Oregon Game Project Challenge, a video game design competition held in May.
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Methods for chromogen separation-based image analysis are provided, with such methods being directed to quantitative video-microscopy techniques in cellular biology and pathology applications.
1. A method of obtaining measurements of a sample from an image thereof, comprising:
selecting a region of interest in the sample from an RGB image thereof by:
selecting a positively contrasted region from a surrounding thereof in a marker-only image corresponding to the RGB image, the marker-only image being obtained through chromogen separation of the RGB image of the sample, the positively contrasted region of the marker-only image including at least one of a relatively larger nuclei and a relatively higher cell density than the surrounding;
segmenting the region of interest in the RGB image to identify any objects of interest therein by:
applying a low pass filter to the marker-only image of the sample obtained through chromogen separation of the RGB image of the sample;
determining a marker-only histogram of pixels in the marker-only image; and
binarizing the marker-only image according to a threshold in the marker-only histogram so as to form a mask for discriminating between negative and positive regions of the sample;
implementing feature extraction to determine measurements for the identified objects of interest; and
determining cell scores with respect to marker localization and signal to noise ratio.
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12. A method of segmenting objects of interest in an image of a sample, characterized in that the image is an RGB image and the method comprises:
applying a low pass filter to a marker-of-interest-only image of the sample, the marker-only image resulting from chromogen separation of the RGB image of the sample and including at least one marker-of-interest;
determining a marker-only histogram of pixels for non-background regions of the marker-only image, the non-background regions being determined from a luminance image of the sample; and
binarizing the marker-only image according to a threshold in the marker-only histogram so as to form a mask for discriminating between negative and positive regions of the sample, the negative region being below the threshold and the positive region being above the threshold.
13. The method according to
selecting a region of interest in the sample from the RGB image thereof by:
selecting a positively contrasted region having a positive contrast with respect to a region surrounding the positively contrasted region in the marker-only image, the positively contrasted region at the marker-only image including at least one of a relatively larger nuclei and a relatively higher cell density than the surrounding;
implementing feature extraction to determine measurements for the identified objects of interest; and
determining cell scores with respect to at least one of marker localization and signal to noise ratio.
This application is a divisional of U.S. patent application Ser. No. 11/433,114, filed May 12, 2006, which claims priority to U.S. Provisional Patent Application No. 60/680,991, filed May 13, 2005, both of which are hereby incorporated by reference in their entirety.
1. Field of the Invention
The present invention relates to image analysis and, more particularly, to methods for chromogen separation-based image analysis related to quantitative video-microscopy techniques in cellular biology and pathology applications.
2. Description of Related Art
The assessment and analysis of tissues is the domain of pathology. During the recent past, methodological and technological developments have turned digital image analysis into one of the most efficient tools to assist pathologists in interpreting images with increased accuracy. Though such image analysis techniques contribute substantially to provide cytologists with accurate, reproducible and objective cellular analysis, histological interpretation techniques still tend to depend on the subjective analysis of specimens. Such histological interpretation techniques may also be subject to varying intra- as well as inter-observer agreement, which further tend to provide less accurate, less reproducible, and less objective results. For such reasons, image analysis of tissues was initially restricted to technologies developed for the analysis of cytological specimens.
With the evolution and availability of high performance computers, local and wide area communication, cost-effective database solutions, improved storage technology, and cost-effective high-resolution digital cameras and/or scanners, the situation has now changed. More sophisticated algorithms, formerly ineffective due to lack of CPU power, could not before be applied to tissue sections in a routine environment. However, such algorithms can now be used to assess and quantify tissue-specific features related to marker quantification and sub cellular localization. At the same time, more comprehensive support for a reproducible and more standardized visual assessment of tissue sections has become available based on the initial step in image analysis, namely the creation and management of digital images. This is especially true in the fields of quality control, quality assurance and standardization. Digital images of difficult cases can be exchanged with reference pathologists via telepathology to get a second opinion. Such images can also be effectively used for proficiency testing. Digital images are also the basis of powerful image reference databases, which can be accessed via network, and play an increasingly important role in the documentation of cases and evaluation results, particularly in comprehensive electronic or printed reports.
Once a tissue slide is prepared, a pathologist visually examines the tissue specimen under a microscope. If image analysis should be applied with respect to the slide, the microscope must be at least equipped with a camera or other image capturing device, which is connected to a computer system via an interface. The camera samples the optical microscopic image of the tissue sample via the microscope. As a result, a digital image is collected in the memory of the computer and can be displayed on the monitor thereof. However, the acquisition of these digital images must be performed such that the important details of the optical images are still correctly represented by the stored data.
Generally, the next step for a quantitative assessment of the digitized images is segmentation, which sometimes includes an additional intermediate step of preprocessing. During segmentation, the cells are separated from each other and from the image background. In some instances, algorithmic advances have made it possible to segment cells down to the sub-cellular component level (i.e., nucleus, cytoplasm, and membranes). Although it may appear an easy task, segmentation is often a difficult and error-prone step in image analysis. For slides where the cells are nicely separated and stained in a way that good contrasts occur in the digitized image, segmentation can be done very reliably in many cases. As soon as one of the above conditions is not fulfilled, however, highly sophisticated and time consuming segmentation algorithms, using additional a priori knowledge about the cells and their relationship to each other, or about marker and counter stain sub-cellular localization, have to be applied. This is the case, for example, in instances of tissue sections of infiltrating tumors, where most of the cells are no longer nicely separated on the slide, but tend to be touching and overlapping each other.
Using a marker-based algorithm, it is possible to circumscribe the region of interest automatically, and let the pathologist decide, using his own subjective expertise, if the region presented is adequate or needs to be manually refined. Once the meaningful areas of an image are determined, the feature extraction takes place. For each cell (and its sub-cellular components), a set of densitometric, morphometric, texture, and contextual features can be measured, with a goal of characterizing the individual cells and their interactions as comprehensively as possible.
The last step is the presentation of the raw data and compilation thereof into meaningful results and/or scores. The resulting output of an image analysis system should desirably match the form of visual and/or semi-quantitative grading systems already in use by the pathologist so as to promote consistency, to be easily applicable, or to be capable of being interpreted in routine use.
The platform for the evaluation of tissue samples via image analysis is shifting more and more from the general-purpose image analyzer to specialized and dedicated "pathology workstations" configured for routine work. Such workstations combine tools needed to provide the pathologist with the necessary information to derive the best results possible. Central to such a workstation is the microscope, possibly equipped with robotic parts including a motorized stage, an automatic focus device, an objective changer, and a light intensity adjustment device. Different input devices, such as cameras capable of fast automatic focusing and acquisition of high resolution images, are linked to the workstation. The workstation can be part of a Local Area Network (LAN). The workstation can also support different communication protocols, so that available communication channels can be used to connect the workstation with other places in the world (Wide Area Network or WAN).
When integrated within a LAN and/or WAN, the workstation can be granted access to existing reference databases and Hospital Information Systems (HIS) such that any new cases to be examined can be compared with the pictures and accompanying information of reference cases which have been accumulated over time. In addition, images acquired from the slides under review can be complemented with the patient and case history.
The pathology workstation is preferably suited for a comprehensive tissue evaluation. Starting with information and digital pictures of the initial tissue sample, images of the slides prepared from the tissue can be taken. The patient and case information, the images themselves, and any quantitative information about the cell components of the tissue sample can all be stored in the same database.
All of the information accumulated by the workstation for one case, such as images, measurement results, patient data, preparation data, can be selected to be part of a report which can either be printed or signed out electronically via the network. The report provides a comprehensive picture of the case under evaluation and facilitates quality assurance and standardization.
During preprocessing/segmentation of the captured images, many different techniques/algorithms can be implemented for image analysis, particularly for quantitative video-microscopy in the field of cellular biology and pathology applications, by using multi-spectral imaging adapted to color cameras (i.e., RGB 3CCD cameras).
Effective analysis of microscopic images is essential in cellular biology and pathology, particularly for detection and quantification in genetic material (genes, messenger RNA) or the expression of this genetic information in the form of proteins, for example, gene amplification, gene deletion, gene mutation, number of messenger RNA molecules or protein expression analyses. Gene amplification is the presence of too many copies of the same gene in one cell, wherein a cell usually contains two copies, otherwise known as alleles, of the same gene. Gene deletion indicates that less than two copies of a gene can be found in a cell. Gene mutation indicates the presence of incomplete or non-functional genes. Messenger RNAs (mRNA) are molecules of genetic information, synthesized from gene reading, that serve as templates for protein synthesis. Protein expression is the production of a given protein by a cell. If the gene coding for this protein is up regulated or too many copies of the gene or mRNA are present, the protein may be over-expressed. If the gene is down regulated or deleted, the protein expression level may be low or absent.
Normal cellular behaviors are precisely controlled by molecular mechanisms involving a large number of proteins, mRNAs and genes. Gene amplification, gene deletion, and gene mutation are known to have a prominent role in abnormal cellular behaviors through abnormal protein expression. The range of cellular behaviors of concern includes behaviors as diverse as, for example, proliferation or differentiation regulation. Therefore, effective detection and quantification in gene amplification, deletion and mutation, mRNAs levels or protein expression analyses, is necessary in order to facilitate useful research, diagnostic and prognostic tools.
There are numerous laboratory techniques dedicated to detection and quantification in gene amplification, deletion and mutation, mRNA levels or protein expression analyses. For example, such techniques include Western, Northern and Southern blots, polymerase chain reaction ("PCR"), enzyme-linked immunoseparation assay ("ELISA"), and comparative genomic hybridization ("CGH") techniques. However, microscopy is routinely utilized because it is an informative technique, allowing rapid investigations at the cellular and sub-cellular levels, which may be implemented at a relatively low cost.
When microscopy is the chosen laboratory technique, the biological samples usually first undergo specific detection and revelation preparations. Once the samples are prepared, a human expert analyzes the samples with a microscope alone or with a microscope coupled to a camera and a computer, allowing both a more standardized and quantitative study. The microscope may be configured for fully automatic analysis, wherein the microscope is automated with a motorized stage and focus, motorized objective changers, automatic light intensity controls and the like.
The preparation of the samples for detection may involve different types of preparation techniques that are suited to microscopic imaging analysis, such as, for example, hybridization-based and immunolabeling-based preparation techniques. Such detection techniques may be coupled with appropriate revelation techniques, such as, for example, fluorescence-based and visible color reaction-based techniques.
In Situ Hybridization ("ISH") and Fluorescent In Situ Hybridization ("FISH") are detection and revelation techniques used, for example, for detection and quantification of genetic information amplification and mutation analyses. Both ISH and FISH can be applied to histological or cytological samples. These techniques use specific complementary probes for recognizing corresponding precise sequences. Depending on the technique used, the specific probe may include a chemical (ISH) marker or a fluorescent (FISH) marker, wherein the samples are then analyzed using a transmission microscope or a fluorescence microscope, respectively. The use of a chemical marker or a fluorescent marker depends on the goal of the user, each type of marker having corresponding advantages over the other in particular instances.
In case of protein expression analyses, further immunohistochemistry ("IHC") and immunocytochemistry ("ICC") techniques, for example, may be used. IHC is the application of immunochemistry to tissue sections, whereas ICC is the application of immunochemistry to cultured cells or tissue imprints after they have undergone specific cytological preparations, e.g. liquid based preparations. Immunochemistry is a family of techniques based on the use of specific antibody, wherein antibodies are used to specifically target molecules inside or on the surface of cells. The antibody typically, contains a marker that will undergo a biochemical reaction, and thereby experience a color change, upon encountering the targeted molecules. In some instances, signal amplification may be integrated into the particular protocol, wherein a secondary antibody that includes the marker stain follows the application of a primary specific monoclonal antibody.
In both hybridization and immunolabeling studies, chromogens of different colors are used to distinguish the different markers. As these markers may be cell compartment specific, this a priori knowledge can be used to automatically segment the cells (i.e. separates the nucleus masks from the cytoplasmic and or membrane masks). Overall, "colorimetric" algorithms are aimed to provide sample information to ease diagnosis and/or prognosis of the particular case. For illustration, the detection and quantification of the breast ER, PR and HER2 protein expression levels may be provided using a quantitative microscopy algorithm applied to immunohistochemistry (IHC) techniques.
In light of such image analysis techniques, however, there exists a need for improvements that facilitate flexibility in such analysis while providing a pathologist with accurate and useful information for allowing the pathologist to form an appropriate diagnosis and/or prognosis.
The above and other needs are met by the present invention(s) which, in one embodiment, provides a method of staining a sample for microscopy imaging whereby the image of the stained sample is configured to exhibit an optimum contrast between sub-cellular components for diagnosis by a pathologist. Such a method comprises staining a sample with a dye; determining a transmittance value of the dye from a microscopy image of the sample; forming an artificial image of the sample from the determined transmittance value of the dye; varying the transmittance value of the dye so as to form a series of artificial images; selecting one image, from the series of images, exhibiting the optimum contrast between sub-cellular components for the dye and determining the corresponding transmittance value of the dye in the one image; and varying staining of the sample with the dye so as to provide a stained sample having the transmittance value of the dye corresponding to the optimum contrast between sub-cellular components.
Another aspect of the present invention comprises a method of artificially staining a sample. Such a method includes staining a sample with a first dye; determining a transmittance value and an extinction coefficient of the first dye from a microscopy image of the sample; forming an artificial image of the sample from the determined transmittance value of the first dye; and substituting an extinction coefficient of a second dye for the extinction coefficient of the first dye so as to artificially stain the sample with the second dye.
Still another aspect of the present invention comprises a method of obtaining measurements of a sample from an image thereof. Such a method includes selecting a region of interest in the sample from an RGB image thereof segmenting the region of interest in the RGB image to identify any objects of interest therein; implementing feature extraction to determine measurements for the identified objects of interest; and determining cell scores with respect to at least one of marker localization and signal to noise ratio.
A further aspect of the present invention comprises a method of selecting a region of interest on a slide, wherein the region is positively contrasted from a surrounding thereof in a marker-only image corresponding to an RGB image of the sample, and the positively contrasted region includes at least one of a relatively larger nuclei and a relatively higher cell density than the surrounding. Such a method includes applying a low pass filter to a marker-only image of a sample, wherein the marker-only image is obtained through chromogen separation of the RGB image of the sample; determining a marker-only histogram of pixels in the marker-only image; and binarizing the marker-only image according to a threshold in the marker-only histogram so as to form a mask for discriminating between negative and positive regions of the sample.
Another aspect of the present invention comprises a method of segmenting a sample from an image thereof. Such a method includes determining a background component of an RGB image of the sample via a thresholding process; segmenting the image by creating a component image of at least one of a membrane, a cytoplasm, and a nucleus; refining the segmented image; and filtering any unwanted objects from the image.
Yet another aspect of the present invention comprises a method of determining optical density data for at least one dye staining a sample, for a high dye concentration, from an image obtained with a low bit resolution imaging device. Such a method includes capturing a series of images of the sample at different integration times; selecting a highest non-saturated intensity in each of a red, green, and blue channel of the imaging device; and reconstructing an optimized image of the sample using the highest non-saturated intensity levels in the red, green, and blue channels such that the optimized image is suitable for chromogen separation.
Another aspect of the present invention comprises a chromogen separation method for an image of a biological sample stained with four dyes obtained with a three channel imaging device. Such a method includes defining a priori known significant three dye combinations of the four dyes spatially collocated in the biological sample; obtaining an image of a sample stained with four dyes with an imaging device having a red, green, and blue channel, such that the image thereby includes a plurality of pixels each having a corresponding RGB triplet; projecting each RGB triplet onto an extinction coefficient plane where Ecr+Ecg+Ecb=1; determining the three dye combination of the four dyes in the extinction coefficient plane corresponding to each RGB triplet; and separating the image of the sample by tabulating an amount of pixels in the image corresponding to each three dye combination in the extinction coefficient plane.
Embodiments of the present invention thus meet the needs identified herein and provide significant advantages as further detailed herein.
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Having thus described the invention in general terms, reference will now be made to the accompanying drawings, which are not necessarily drawn to scale, and wherein:
FIGS. 3A1-3A2 and 3B1-3B2 show examples of automatically-selected regions of interest and subsequent sub-cellular segmentation according to one aspect of the present invention;
The present inventions now will be described more fully hereinafter with reference to the accompanying drawings, in which some, but not all embodiments of the inventions are shown. Indeed, these inventions may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will satisfy applicable legal requirements. Like numbers refer to like elements throughout.
The Microscope Imaging Platform
In a typical microscopy device for image acquisition and processing, the magnified image of the sample must first be captured and digitized with a camera. Generally, charge coupled device (CCD) digital cameras are used in either light or fluorescence quantitative microscopy. Excluding spectrophotometers, two different techniques are generally used to perform such colorimetric microscopic studies. In one technique, a black and white (BW) CCD camera may be used. In such an instance, a gray level image of the sample is obtained, corresponding to a monochromatic light having a wavelength specific to the staining of the sample to be analyzed. The specific wavelength of light is obtained either by filtering a white source light via a specific narrow bandwidth filter, or by directly controlling the wavelength of the light source, using either manual or electronic controls. Accordingly, using this technique, the analysis time increases as the number of colors increases because a light source or a filter must be selected for every different sample staining or every different wavelength. Therefore, many different images of the sample, showing the spectral response of the sample at different wavelengths, must be individually captured in a sequential order to facilitate the analysis. When multiple scenes or fields of view must be analyzed, the typical protocol is to automate the sequence in a batch mode to conserve processing time.
According to a second technique, a color CCD digital camera is used, wherein three gray level images of the sample are simultaneously captured and obtained. Each gray level image corresponds to a gray level image in each of the respective Red, Green and Blue channel (RGB) of the color CCD camera. When a color CCD digital camera is used, wherein three gray level images of the sample are simultaneously captured and obtained (each gray level image corresponds to a gray level image in each of the respective Red, Green and Blue channel (RGB)), chromogen separation techniques can be applied, which may allow the optical density of each molecular species (revealed by their associated chromogen or dye) to be evaluated in any location of the image (pixel). On the biological sample, markers and counter stains generally indicate the dyes to detect and quantify.
According to an arising third technique (e.g., using a JUMBOSCAN multispectral camera by Lumiere Technology), up to 13 gray level images of the sample can be simultaneously captured and obtained. This type of camera/scanner could increase the potential of chromogen separation techniques in the future by increasing the number of dyes that can be simultaneously solved for a given sample.
Regardless, the concentration of the molecular specie can be determined from a color image of the sample, where the color image includes 3 or more channels. In a video-microscopy system equipped with a 3CCD camera, the image should desirably be balanced and normalized according to an empty field white reference and a black field image, and then corrected for shading. Furthermore, the image should desirably be spatially corrected for chromatic aberrations, channel by channel. An optical density of the sample can then be computed in each of the red, green, and blue channels of the RGB image, at a particular pixel in the image, from the measured transmitted light. A corresponding optical density vector is thereafter formed for that pixel. The optical density vector is then multiplied by the inverse of a relative absorption coefficient matrix of the dyes present in the sample so as to form a resultant vector for the pixel, representing the optical density contributions from each dye. The relative absorption coefficient matrix comprises a relative absorption coefficient for each of the dye (marker(s) and counter stain(s)) used in the sample preparation protocol, in each of the red, green, and blue channels. The resultant vector thus comprises the concentration of the molecular species, as indicated by the marker(s), and by the counter stain(s), for that pixel.
Such imaging techniques, also known as multi-spectral imaging techniques, when adapted to color imaging (RGB camera), allow a real time (video rate) processing of the sample (typically 40 millisecond per frame), which provides a considerable advantage. In effect, for speed issues and real time processing, or displaying purposes in case of the use of an RGB camera, the acquisition through the different channels is performed in parallel and look-up tables (LUT) can be generated which map the RGB color input values to pre-computed concentrations and/or transmittance of each of the participating dyes.
Such techniques are discussed in more detail, for example, in U.S. Patent Application Publication Nos. US 2003/0091221A1 (Method for quantitative video-microscopy and associated system and computer software program product) and US 2003/0138140A1 (Method for quantitative video-microscopy and associated system and computer software program product), both to Marcelpoil et al. and assigned to Tripath Imaging, Inc, also the assignee of the present invention, the contents of which are incorporated herein in their entirety by reference.
The Lambert-Beer Law
The microscopic imaging platform is configured to analyze the sample in accordance with the Lambert-Beer law. The Lambert-Beer law generally describes a proportionality that can be observed between the concentration of molecules in a solution (the concentration of the "molecular specie" or the "sample") and the light intensity measured through the solution. The Lambert-Beer law is typically expressed as:
This proportionality relationship defined by the Lambert-Beer law has been verified under the several conditions including, for example, monochromatic light illuminating the sample, low molecular concentration within the sample, generally no fluorescence or light response heterogeneity (negligible fluorescence and diffusion) of the sample, and lack of chemical photosensitivity of the sample. The Lambert-Beer law may have additional requirements, however, such as, for instance, correct Koehler illumination of the sample under the microscope.
Koehler illumination is offered on almost all state-of-the-art microscopes, and provides even illumination in the image plane, while allowing for effective contrast control. Koehler illumination is typically critical for densitometry analysis. Correct Koehler illumination is provided, for example, by a two-stage illuminating system for the microscope in which the source is imaged in the aperture of the sub-stage condenser by an auxiliary condenser. The sub-stage condenser, in turn, forms an image of the auxiliary condenser on the object. An iris diaphragm may also be placed at each condenser, wherein the first iris controls the area of the object to be illuminated, and the second iris varies the numerical aperture of the illuminating beam.
The Lambert-Beer law has an additive property such that, if the sample comprises several light-absorbing molecular species, for example, s1 and s2, having respective concentration C1 and C2, the OD of a sample of thickness l (in solution, l1=l2=l) can be expressed as:
To accurately measure the concentration of given species imaged under a microscope, the measurements of the optical densities performed at different wavelengths should correspond to the same portion of the sample. That is, the system can be physically corrected for chromatic aberration or, otherwise, the correction can be made through another methodology such as software.
The natural dispersion power of glass causes a simple lens to focus blue light at a shorter distance than red light. That is, a simple lens has different focal lengths for light of different wavelength (different colors). Two phenomena occur as a direct consequence:
In systems with high quality objectives (apochromatic objectives), chromatic aberration is corrected. If chromatic aberration is otherwise structurally not well corrected, a software-based method for correcting lateral chromatic aberration can be implemented as follows:
Once the microscope has been set in Koehler illumination mode for image acquisition, and any chromatic aberrations have been addressed or apochromatic objectives used, the additive property of the Lambert-Beer law can be used to perform chromogen separation using linear algebraic equations.
More particularly, the additive property of the Lambert-Beer law can also be expanded to a situation in which the scene is analyzed in a color image environment, such as, for example, generated by a RGB camera having separate red, green, and blue channels. In such an example, the marker dye (or "dye 1") would exhibit absorption coefficients, ε1r, ε1g, and ε1b, in the red, green and blue channels, respectively. Note that the analysis of the image in each of the red, green, and blue channels essentially comprises analyzing a red representation of the image across the red spectrum, a green representation of the image across the green spectrum, and a blue representation of the image across the blue spectrum. Accordingly, the counter stain (or "dye 2") would exhibit absorption coefficients, ε2r, ε2g, and ε2b, in the red, green and blue channels, respectively. Therefore, according to the additive property of the Lambert-Beer law, analysis of the sample in the RGB environment would lead to the system of three equations for the optical density thereof:
In such a situation, the three dyes may comprise, for instance, one marker dye and two counter stains, or two marker dyes and one counter stain, or even three separate marker dyes. This property of the Lambert-Beer law might be expanded to include an even greater plurality of dye combinations. However the chromogen separation procedure described herein focuses on making use of a fast color-image capture device with 3 channels, such as for example a 3CCD RGB camera, for multi-spectral imaging of biological markers. Therefore, due to the 3 distinct information channels (R, G, B) only three equations can be used in any location.
In applying the Lambert-Beer law to a digital microscopy system, it is difficult and complex, inaccurate, or sometimes not possible to measure the thickness l of the sample. Consequently, the concentration C of the molecular specie can be extended and examined as the product of l and C (l·C), and the results treated accordingly. For example, where the concentration of one dye is being compared to the concentration of another dye in a particular sample, the sample thickness term will be common to both concentrations and thus it becomes less important to determine the sample thickness as an absolute and accurate value. Therefore, it will be understood that an accurate determination of the thickness is usually not required, but assumed constant and therefore generally negligible in the analysis disclosed herein.
The application of the Lambert-Beer law to the digital microscopy system also recognizes that the Lambert-Beer law can be expressed as:
Therefore, for a prepared sample examined by the digital microscopy system, the appropriate relation is expressed as:
Since the light source intensity remains substantially constant over time, or can be easily re-evaluated, the reading of the light intensity in any pixel can therefore be translated into a measure of the relative transmittance at the pixel location for each of the red, green, and blue channels. Once Io and I are known, the corresponding OD can be computed.
Any location on the field of view where a unique dye is present (the only absorbing material) allows the relative extinction coefficients of the dye to be measured for the different RGB channels. Because in equation (1), l·C is equal for each of the RGB channels at a given location, if both l and C are known at this particular location the exact extinction coefficient can be computed as being OD/(l·C). The absorption coefficient ε in each of the red, green, and blue channels can thus be consequently extracted as being:
Consequently if the absolute concentration of the dye remains unknown, it is still possible to compute arbitrary (or relative) dye concentrations in any pixel, with a known absolute error factor equal to (l·C).
Because l is unique at a given pixel location and can arbitrarily be set to 1, equations 6, 7, and 8 may be rewritten as follow where C1, C2 and C3 are related to l.
When all the extinction coefficients have been evaluated for different dyes, and optical densities are known from the reading of the image data, solving these equations to extract C1, C2 and C3 just involves solving a set of linear equations.
Solution of Linear Algebraic Equations/Matrices
A set of linear algebraic equations appear, for example, as:
If M<N, there is effectively fewer equations than unknowns. In this case there can be either no solution, or else more than one solution vector x.
If N=M then there are as many equations as unknowns, and there is a good chance of solving for a unique solution set of xj′s.
If M>N that there are more equations than unknowns, and there is, in general, no solution vector x to equation (1), the set of equations is said to be over determined. In such a case, the most appropriate solution will be considered in general as the one fitting the best all the equations (i.e., the solution minimizing the sum of reconstruction errors).
Equation (19) can thus be written in matrix form as
The solution of the matrix equation A·x=b for an unknown vector x, where A is a square matrix of coefficients, and b is a known right-hand side vector, usually requires the determination of A−1 which is the matrix inverse of the matrix A.
In applying these concepts to the present case, the determination of the absorption coefficient ε matrix for different dyes may be performed independently of sample evaluation and stored for further application to samples treated with at least one of the respective dyes. Computing solutions for all possible pixel values allows substantially real time processing. Since, in the chosen example of an 8 bit 3CCD color image acquisition device, the measured light intensity I of a sample ranges between limits of 0 and 255 in each of the red, green, and blue channels, all possible gray values (with respect to the original light intensity Io) may be pre-computed (2563 in case of an 8 bit RGB system) and stored, for example, within the computer. Thus, for a sample stained with a particular dye, the transmitted light intensity I (or the optical density OD) can be measured at a pixel in each of the red, green, and blue channels and then compared to the previously stored gray values and the absorption coefficient ε matrix for that particular dye to thereby determine the dye concentration C (or an estimate thereof as the product l·C) at that pixel. In this regard, there are [256(red)×256(green)×256(blue)]=2563 solutions to compute, giving rise to a 16 megabyte (raw data) look-up table (LUT) for each of the dyes. Gray value resolutions exceeding 8 bits per channel will lead to larger LUTs (i.e., >1 gigabyte if 10 bits per channel).
Electronic Staining
According to one aspect of the present invention, gray levels or RGB transmittance values of an artificial image resulting from any combination of the previously-examined dyes can be generated since there are not anymore unknown variables. As such, for a particular pixel and its solved dye concentrations, the single dye images would correspond to the following Black and White (BW) or RGB pixel intensities:
When this process is applied to each pixel of a captured digital image, an artificial picture of the same field of view can be generated using only the respective contribution of any of the constituent dyes. As such, if the extinction coefficients of one dye are exchanged with the extinction coefficients of another dye, it is then possible to simulate how the same artificial image corresponding to a given marker only would be seen through a microscope, if the dye used to reveal this marker is changed to a secondary dye.
Furthermore, using the additive property of the Lambert-Beer law, it is also possible, as shown in
More particularly,
Measurement Strategy
According to another aspect of the present invention, a measurement strategy can be based upon and can make use of the chromogen separation technique(s) described above in many aspects, from allowing only the marker of interest to be specifically measured, to the e-staining capabilities which allow segmentation-optimized contrasted images to be generated.
Obtaining measurement results from the acquired image includes several steps: 1) selecting the region of interest (tumor region); 2) segmentation to identify the objects of interest in the image; and 3) feature extraction to calculate the various measurement features for the identified objects and affect cell scores based upon, for example, their marker localization and signal to noise ratio.
1) Region of Interest Pre-Selection
In order to reduce the workload for the pathologist, a pre-selection methodology was developed for automatically delineating the potential region of interest within the field of view that will be the region used for analysis, wherein any excluded part is thus excluded from the analysis. Such a pre-selection methodology generally requires two a priori factors:
Consequently, a large low pass filter may be applied to the marker-only image resulting from the chromogen separation technique(s) applied to the RGB field of view. The marker-only histogram is measured (avoiding background regions based upon the luminance image), and then the image is binarized according to the best threshold in the histogram that could discriminate two classes (negative and positive regions). Any small holes are filled to smooth the final mask. The mask is outlined on the top of the original RGB field of view image to allow acceptance/rejection by the pathologist, as shown in
2) Segmentation Strategy
The segmentation strategy includes the following steps:
Various examples of such segmentation are shown, for example, in FIGS. 3A1-3A2 and 3B1-3B2, respectively. More particularly, FIG. 3A1 shows a PSMB9 (cytoplasmic marker) example of automatic definition of the region of interest followed by sub-cellular segmentation in FIG. 3A2. Within the region of interest, automatically defined cells have been segmented, such that the nucleus masks appear in blue and the cytoplasm boundaries appear in red, while background pixels are shown in black. FIG. 3B1 illustrates a HER2 (membrane marker) example of automatic definition of the region of interest followed by sub-cellular segmentation in FIG. 3B2. Within the region automatically defined, cells have been segmented, such that nucleus masks appear in blue and the membrane appears in green, while background pixels are shown in black. One skilled in the art will appreciate, however, that additional image processing steps or refinements may, in some instances, be needed to adapt such generic algorithms to tissue or marker specificities.
2a) Background Determination
The first segmentation step is to divide the image content into fore- and background. Since the imaging platform is designed to support bright field microscopy, objects will appear darker than the bright background. To create a background mask for an image, the image is converted into a luminance image and a background threshold level is calculated. Every pixel having a luminance value above the background threshold level is considered to belong to the background. Conversely, any pixel with luminance less than the threshold belongs to the foreground which has to be processed further in the following steps.
Determining this background threshold value involves smoothing the luminance image and calculating the histogram of the smoothed image. The histogram is then scanned, beginning at the higher end, for a local minima to be used for the threshold value. The search is limited when an arbitrary 90% transmission is reached, which translates, for the case of 8-bit images, into the value of 230.
2b) Cell Component Image Creation
In the next segmentation step, cell component images for the nucleus and cytoplasm are created using chromogen separation techniques previously described. The separation is initiated according to the specification of the optical density contribution of each dye to the specific cell component. Those component images are then used as input for subsequent nucleus and cytoplasm segmentation steps. The component images are based upon e-staining capabilities and generate images which best contrast the targeted cell compartment from neighboring regions.
2c) Membrane Segmentation
Membrane segmentation is performed using the following steps:
Membrane segmentation is performed first to facilitate further nucleus segmentation, since membranes are generally expected to separate nuclei from one another.
2d) Nucleus Segmentation
In the beginning of the nucleus segmentation process, both the mean and median pixel values of the nucleus component image are calculated under consideration of the background mask. The greater of those values is used to create an initial nucleus mask through thresholding the nucleus component image with this value. Any pixel having a value higher than this threshold is set to the threshold value so that only pixels having a lower value remain with their original value in this initial nucleus mask. If membrane masks are available, any potential nucleus mask pixel falling within a membrane mask is deleted.
This preliminary or initial nucleus mask is then low-passed with a kernel of 1.5 times the expected nucleus size to prepare the initial nucleus mask for a watershed transformation or segmentation procedure. The output of the watershed segmentation procedure is combined with the initial nucleus mask so that only mask pixels are set where the watershed image has catchment basins and the initial nucleus mask has a pixel value below the threshold value. The resulting nucleus mask is then finalized by a clean-up step including filling holes having an area less than about one-fifth of the expected nucleus size, and removing objects that are smaller than about one-fourth of the expected nucleus size.
2e) Cytoplasm Segmentation
The cytoplasm segmentation process uses a two-way approach to create the cytoplasm mask. Both ways use the nucleus mask created in the previous step as the starting point. First, the nucleus mask is inverted and distance-transformed. The first potential cytoplasm mask is created by binarizing the output of the distance transform such that all pixels within the expected cell size are included in the resulting mask. In order to mask only the foreground, the resulting first potential cytoplasm mask is then combined with the background mask. For the second potential cytoplasm mask, the nucleus mask is again inverted and then watershed-transformed. Both the first and second potential cytoplasm masks are then combined to create the final cytoplasm mask.
2f) Segmentation Refinement
Once both the nucleus and cytoplasm segmentation masks have been established, those masks are further refined using the knowledge of the combined masks. Starting with the cytoplasm mask, each segmented object in the cytoplasm mask is identified and is associated with a labeled image, wherein each object is identified by a unique pixel value. Due to the watershed transformation in the cytoplasm segmentation, the labeled objects are separated from each other. As such, the labeled image is dilated once in order to reconnect the labeled objects.
The labeled image is then used to refine the nucleus mask. That is, each labeled object is binarized using an individual threshold. For each labeled object, the process is as follows:
Next, holes in the nucleus mask having an area smaller than about one-fifth of the expected nucleus size are filled. To prevent under-segmentation, the mask is first distance transformed and then watershed transformed to split up potentially merged nuclei.
Finally, the nucleus mask is cleared of artifacts by removing all objects smaller than about one-third of the expected nucleus size. Once the refined nucleus mask is determined, the cytoplasm segmentation procedure is repeated and results in a refined cytoplasm mask.
For Her2neu segmentation, an additional step of membrane removal is performed, which deletes any membrane mask located within about 3 pixels of a nucleus mask, so as to facilitate discrimination of a cell membrane from a nucleus membrane.
2g) Filtering of Unwanted Cells
The last processing step in the segmentation procedure involves filtering of unwanted cells. For this procedure, each object in the refined cytoplasm mask is labeled. Also, the acquired FOV image is chromogen separated into the dye images for the marker and the counter stain. For each identified object, a bounding rectangle is determined and, if the object is positioned closer than a certain distance to any image border, the object is no longer taken into account and discarded so as to prevent processing of cells extending beyond the image border. If the cell passes this criterion, its key measurement features, such as densitometry, texture, shape, contextual information, are calculated. Further examples (non-inclusive) include:
Each feature is computed for the nucleus, the cytoplasm, and/or the entire cell, as well as for each of the luminance, marker dye(s) and counter stain dye(s).
Using the mean transmittance determined from the Mean OD, another pass/fail criterion is applied to the cell. That is, if the cell's mean transmittance is higher than a threshold value specified in the segmentation setup, the cell is not considered any further and discarded.
3a) Cell Scoring
Based upon the features evaluated for each cell, a score can be attributed to that cell depending on the marker intensity and signal to noise ratio thereof in the targeted compartment. A cell is considered positive when the marker content of that cell in the marker-specific targeted-compartment optical density (intensity) is significantly higher than in neighboring compartments. For instance, if the marker is a nucleus marker, the contrast, or signal to noise ratio, is computed from the marker-specific optical density measure in the nucleus versus the residual optical density measured over the cytoplasm. Because the background noise is not specific by definition, the overall background mean optical density is measured over all of the cytoplasm compartment of the cells within the selected region of interest.
To facilitate optimum correlation with the pathologist's know-how, the contrast required to designate a cell as being positive can be adapted from strong to weak, since some pathologists consider only very intense nuclei as being positive, while other pathologists consider any faint positive staining as being positive. Such a subjective positive determination based on contrast level may also be affected by the particular pathology being considered.
Accordingly, as shown in
3b) Overall Score
An overall score can be attributed to a case that reflects, for that case, the information requested by the pathologist to establish his diagnosis/prognosis.
In case of the ER and/or PR tests, the overall score requested by the pathologist is the percentage of positive cells within the tumor region. Therefore, once the pathologist is confident in his diagnosis/prognosis of the proposed region of interest (automatically proposed or manually drawn), the percentage of positively-scored cells is reported.
Integration Concept
To further investigate the OD contribution of the different dyes when concentrations are very high and bit-wise limitations of the camera are reached, a strategy based upon time integration (shutter speed) of the camera can be implemented. That is, the same field of view is imaged with the same camera, but with different integration times. As shown in
Breaking the 3D Limit Using RGB Input: 4D Chromogen Separation
One example of such a procedure for 4D chromogen separation is provided by a combination of 4 dyes for a modified PAP procedure, as shown in
With respect to the nature of the respective dyes, there are two accepted 3 dye configurations among the 4 possible configurations of the 3 dyes, as shown in FIGS. 7B1 and 7B2, respectively, wherein these two 3 dye configurations are each highlighted by a surrounding triangle. From a priori knowledge, it is known to be unlikely that all 4 dyes will be significantly present at the same geographical location with respect the sample. Therefore, chromogen separation in this instance considers only 3 dyes configurations where the 3 dyes could be co-located with respect to the sample. More particularly, Eosin and Green are mainly cytoplasmic dyes which stain cells with different cytoplasmic attributes. Consequently, these dyes are not likely to be present at the same location with respect to the sample even though, due to the location of the Hematoxylin between the Eosin and Green dyes in this extinction coefficient plane, a mixture of Eosin and Green could be mistaken with Hematoxylin (but is very unlikely to be mistaken for DAB).
Thus, in order to solve the 4D problem, the chromogen separation procedure is applied by looking for each RGB triplet of this FOV where, at the XY location thereof, the corresponding stain would be located, the XY location being the location in the extinction coefficient plane where EcR+EcG+EcB=1. In this plane, the surrounding 3D configuration, or by default the closest 3D configuration, is determined and used to solve the equations for optical density for the 3 corresponding dyes, while the remaining dye's optical density is set to 0. One skilled in the art will note that most of the XY locations of the investigated RGB triplets should lay within one of the 2 accepted 3 dye configurations.
Ultra-Fast Adaptation of the Scanner to Search for Positive (DAB) Cells in a Modified PAP Environment
The discussed aspects of 4D chromogen separation and e-staining may, in some instances, combine to form another aspect of the present invention. More particularly, in continuation of the above example directed to the use of DAB and Hematoxylin, a scanner can be implemented that is capable of reading modified PAP slides (a DAB positive rare event solution), as shown in
Taking RGB Distortion into Consideration
To accommodate and/or compensate for RGB distortion due to the image path, electronics, and/or staining variations, a modification of the chromogen separation can be considered. That is, imaging biological material stained with only one dye demonstrates that the extinction coefficient model, which can be calculated from each RGB triplet within the source FOV, varies slightly around the averaged accepted measure. Consequently when a dye mixture is present, multiple solutions of dye mixtures could be de facto accepted or acceptable. Different sources of noise could be responsible for such RGB distortion. For example, acquiring the image with a CMOS camera instead of a 3CCD camera could be one factor.
To compensate for these distortions, the dye-respective contribution solution for a given RGB triplet and a given multiple dye model is computed in a slightly different manner. More particularly, the RGB triplet under investigation is considered as the center of a ball in the RGB space having a given radius r. All triplets within this ball are investigated for their dye contribution solutions, and the solutions are averaged for each dye for all of the RGB triplets that satisfy the dye combination model. If no RGB triplet belongs to the dye combination model, the nearest RGB triplet within the ball to the dye combination model is retained as best potential candidate solution.
Dynamic Procedures
Traditionally, all algorithms or computational procedures used in quantitative microscopy applications are implemented or built into the system by software engineers. As such, each software release generally includes a limited set of algorithms, which cannot be changed without modification of the software ("software upgrades").
For example, an application may calculate the percent of positive cells on a slide by calculating the ratio of the number of cells having a mean optical density (MOD) of a marker stain in the cell nucleus greater than a threshold value to the total number of cells on the slide. In a traditional application, the threshold value may be configurable, but the formula used to calculate the ratio remains fixed; it will always compare the number of cells over a certain threshold to the total number of cells. Even if a procedure or algorithm allows the threshold value to vary based on other extracted features, the formulas used to determine the threshold are still fixed.
Accordingly, another aspect of the present invention comprises a methodology whereby the algorithms or procedures are configured to be dynamic (i.e., producing results based on formulas entered by a user). That is, instead of the algorithms or procedures being coded directly into the software, the software can evaluate the formulas to be used at actual analysis runtime. More particularly, a quantitative microscopy application implementing such dynamic algorithms first calculates or otherwise determines a general set of features at several levels, including a slide level, a TMA core level, a field level, and a cellular level. Such general features can then be aliased, thus defining different "variables" that may be combined in various forms with each other using, for example, standard mathematical operations, to form higher level features, or to define functions. As such, at analysis runtime, the application would load the list of aliased features and applicable formulas. When a formula is needed in the analysis, that formula is dynamically evaluated and the aliased features used to alter the formula as necessary. If a formula is frequently recalculated, or is sufficiently complex, such a formula or portion thereof may be precompiled to speed execution.
Such a method thus allows the set of algorithms or procedures implemented by the application to be updated, added to, or otherwise modified, in the field, without requiring any external modification to the software. As such, the application provides flexibility to the users, since new functionality can be created, as necessary and/or desired, without requiring any complex external software development. Such functions can, for example, generate numeric scores for the slides, cores, fields, or cells. In addition or in the alternative, such functions may provide a filtering capacity. As an example of the application of such functions, a user may define a function that calculates a percent positive, as described above, wherein the dynamic formulas may also be used to define a function that allows a display to highlight 'positive' cells, fields, or cores. Such dynamic formulas can also be used, for example, to define ranges for expected normal values, or named bins such as '0', '1+', '2+', etc.
Many modifications and other embodiments of the inventions set forth herein will come to mind to one skilled in the art to which these inventions pertain having the benefit of the teachings presented in the foregoing descriptions and the associated drawings. Therefore, it is to be understood that the inventions are not to be limited to the specific embodiments disclosed and that modifications and other embodiments are intended to be included within the scope of the appended claims. Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.
Patent Citations
Non-Patent Citations
Referenced by
Original Image


text:
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Mother deerhound, collie, whippet. 25 inch to top of shoulder. David Platt blood line. Father Suluki, whippet. 22 inch to top of shoulder. Both parents can be seen. Very good temperament on both dogs. Great with kids. 9 pups in total. 3xdogs 1xbitch
- DOB:05 Sep 2014
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0 miles | Pontllanfraith, Caerphilly£150,130 2 days ago


text:
Birmingham, Ala., Mayor Convicted Of Corruption
Listen to the Story
A federal jury convicted the mayor of Birmingham, Ala., on bribery and corruption charges Wednesday. Larry Langford was removed from office, and he faces years in prison.
Copyright © 2009 NPR. For personal, noncommercial use only. See Terms of Use. For other uses, prior permission required.
STEVE INSKEEP, host:
Alabama's largest city, a center of industry, Birmingham, has a new mayor today. That's because a federal jury convicted Larry Langford on bribery and corruption charges yesterday, ousting him from office.
Tanya Ott reports from member station WBHM in Birmingham.
TANYA OTT: Larry Langford was raised in a housing project in segregated Birmingham but he went on to become one of the most powerful politicians in town. He's flamboyant. He made a pitch to have Birmingham host the 2020 Olympics. He has also held Bible sessions in city hall. But now, he is a convicted felon. A jury decided that while he was a Jefferson County commissioner, Langford accepted nearly a quarter million dollars in designer clothes, jewelry and cash from an investment banker and a lobbyist. In exchange Langford funneled millions of dollars in county bond deals to the banker. Glennon Threatt is Langford's defense attorney.
Mr. GLENNON THREATT (Defense Attorney for Larry Langford): Two hundred plus exhibits and seven days of testimony, and a jury that deliberates for two hours - and I'll let y'all do the math on how much time they spent going through all the documentation and evidence.
OTT: The defense argued the cash and clothes were gifts from long time friends. The banker and the lobbyist pleaded guilty and testified against him. After the verdict, Langford vowed to appeal.
Mr. LARRY LANGFORD (Former Governor, Alabama): I'm not the first person who has ever gone on trial for something that they didn't do. It happens. But if you expect to see me crying and head drop, you picked a wrong one, I'm not yet.
OTT: Langford claims a Republican appointed U.S. attorney targeted him because he is a Democrat. And that there was no hope of a black man getting a fair jury trial in Alabama.
Mr. JIM PHILLIPS (Attorney At Law): It's sort of like the last refuge of a scoundrel to claim politics or race following a conviction in a fair trial.
OTT: Jim Phillips is acting U.S. attorney for this case. His office has prosecuted several former county commissioners, white and black, Republican and Democratic.
Mr. PHILLIPS: I don't believe that Alabama or Jefferson County is any worse than other counties or other states. Part of the reason that you've seen these cases is the FBI, the Internal Revenue Service, law enforcement has aggressively conducted their investigations. and anytime you have that, you're naturally going to have more folks brought to trial.
OTT: Phillips says this should be a warning to other elected officials who might be on the take. Larry Langford faces decades of prison time.
For NPR News, I'm Tanya Ott in Birmingham, Alabama.
Copyright © 2009 NPR. All rights reserved. No quotes from the materials contained herein may be used in any media without attribution to NPR. This transcript is provided for personal, noncommercial use only, pursuant to our Terms of Use. Any other use requires NPR's prior permission. Visit our permissions page for further information.
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The Ritz-Carlton Orlando, Grande Lakes Names David Serus Exec. Chef
Wednesday March 19th, 2014 - 10:11AM KBY
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ORLANDO—David Serus has been appointed executive chef at The Ritz-Carlton Orlando, Grande Lakes, where he will oversee all culinary operations at the 582-room property.
Serus has worked for The Ritz-Carlton Hotel Co. since 2002 and most recently served as executive chef at The Ritz-Carlton, Dove Mountain in Marana, AZ. Prior to that, he was executive chef at The Ritz-Carlton, Washington, DC, for four years and held culinary leadership roles at The Ritz-Carlton, Penha Longa, Portugal; The Ritz-Carlton, Sarasota, FL; and The Ritz-Carlton, Half Moon Bay, CA.
Serus is originally from Le Mans, France and is a Master Chef of France, Maître Cuisiniers de France, one of only six in Florida.
Serus will continue the resort's commitment to a sustainable cuisine philosophy as he partners with The Ritz-Carlton Orlando Chef de Cuisine Mark Jeffers to open the hotel's new casual dining restaurant, Highball & Harvest, in late summer.
Grande Lakes Orlando is a 500-acre resort with a 582-room Ritz-Carlton and 1,000-room JW Marriott Hotels.
Tags: David Serus • The Ritz-Carlton Orlando • Grande Lakes • Hospitality • Brands • F+B • Brands •
For the past few years, the talk of The Lodging Conference in Phoenix had been focused on the economic recovery, solid industry projections and "cautious optimism." With the word cautious no longer necessary, the economic outlook took a backseat this year to the seemingly unending parade of new lifestyle brands.
Crowne Plaza Charlotte Executive Park Unveils $10-Million Reno »
Paramount Lodging Advisors Sells Two Terre Haute Hotels
Mission Capital Advisors Arranges $20M Loan for Three Marriott-Branded Hotels
American Hotel Income Properties REIT LP Acquires Portfolio for $41M
Renovated Mahekal Beach Resort to Open December 2014
Fairfield by Marriott to Open in El Salvador in 2016
Renaissance Dallas Hotel Opens LEED Silver Certified Event Space
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will this mod be in english ???
Enderal - The Shards of Order is a total conversion in development for Skyrim and the sequel to Nehrim: At Fate's Edge by SureAI. The story of Enderal is not set in the Elder Scrolls world of Tamriel, but takes place in its own universe, creating a new, interesting world completely unrelated to Skyrim with a complex, dark storyline and thousands of secrets to discover.
3 comments by SureAI on Nov 18th, 2014
Hello everyone,
As some of you might already know, we're using Articy Draft, a gamedesign/storywriting-tool from Nevigo since the early stages of development.
Recently, they've interviewed us about the experiences we made with Articy, and published a little showcase on their blog, which can be read here. Those who look carefully enough might even spot some new screenshots!
Once again, a big thanks to Nevigo, who sold us their software for special conditions and thus facilitate the development progress a lot! :)
All the best,
will this mod be in english ???
It will be translated for sure, but voice-overs in English ?, i don't know. In one video you hear, english voice-overs and, in another they speak in German.
You can look these video's up, here or on youtube
OMG I love SureAI! Wonderful game changing mods that sometimes makes you think that you're playing a whole different new game! I love all of your mods, forever 10/10 mods, Tracking this!
Need more enderal updates :)
next year on earliest, (heard in recent video).
What i would like to know is can we install the mod manually ?
and will it work with the add on content installed ?
Enderal. SureAI is one of the most ambitioned teams I know which has created one of the best Total conversions I've ever played. I'm looking foward to see an absolutly awesome game wich creates an even better experience than the original Skyrim and I can't wait to be in the fantastic univers of Vyn!
Can you do something about picking up readable items, like books and notes, to not open by just the "use" key when in third or first person view? Can you make it how it is when the readable item is in another inventory (container, sack, npc, etc.)?
When there are more than 10 or 15 books that I want to pick up, it gets very annoying that it opens first, and only then gives the possibility to take it. :/
Always good to hear! :)
Promote Enderal - The Shards of Order on your homepage or blog by selecting a button and using the HTML code provided (more).


text:
In a move that seems almost too petty to believe, it has now been confirmed that the official WWE account on Twitter is no longer following CM Punk after he walked out before Monday Night Raw this week. The decision could have been made by someone in the marketing or technology department as opposed to Vince McMahon or Triple H.
WWE has been pushing the wrestlers to use Twitter more often, especially on weekends, in order to get the fans talking more about the performers and company. The belief is that management has noticed how much of a buzz Ryback has been able to create through the social media website.
During a recent interview, Stephanie McMahon touted the WWE app by revealing that it has been downloaded more than eight million times.
Some last minute replacements were added to Royal Rumble 2014. Initially, Xavier Woods and Wade Barrett were given spots in the big match, but WWE officials decided to remove them and replace them with JBL and El Torito instead. The feeling backstage was that the fans would react better to those the latter two performers.
Batista won Royal Rumble 2014 by eliminating Roman Reigns in the end. Other contestants during the match were Alberto Del Rio, Alexander Rusev, Antonio Cesaro, Big E Langston, CM Punk, Cody Rhodes, Damien Sandow, Dean Ambrose, Dolph Ziggler, El Torito, Erick Rowan, Fandango, Goldust, Great Khali, Jack Swagger, JBL, Jey Uso, Jimmy Uso, Kane, Kevin Nash, Kofi Kingston, Luke Harper, R Truth, Rey Mysterio, Ryback, Seth Rollins, Sheamus and the Miz.
To play up their story line, El Torito posted a tweet, where he shows his affection towards WWE announcer Renee Young.


text:
Wild River State Park
Wild River State Park is located along 18 miles of the beautiful St. Croix River. The park attracts people who enjoy camping, hiking, horseback riding, canoeing, interpretive programs, self-guided trails, and cross-country skiing and snowshoeing. Day visitors can enjoy a leisurely paddle down the St. Croix River from the Sunrise river access to the southern park river access.
The park provides opportunities for semi-modern camping, group camping, equestrian camping, backpack camping, and canoe camping. Visitors who want modern amenities can reserve the guest house which provides a living room, dining room, kitchen, and fireplace. The park also has six camping cabins which include bunkbeds, a table, and benches.
An all-season trail center is a great spot to relax after hiking or cross-country skiing on the 35-mile trail system. A visitor center with exhibits and environmental education programs is open year-round.
Tell me more about this park's wildlife, history, geology and landscape.
Visitor Alert!
Winter Trails Update
Wild River received over a foot of snow 11/10. We have had a little bit of light fluffy snow since then. As of 11/21, our current snow pack is around 10". All ski trails have been rolled/packed at least once. We set some track 11/21, and combed the large section of the Advanced Loop also. Skiing should be best Saturday vs. Sunday this weekend.
Overall trails are in fair to good early season condition, with trails in the open in fair to poor condition. We have also cut vegetation on some trail edges, so a few trails will have plant debris until we get more snow.
The Old Logging Trail, River Trail and Mitigwaki Loop were tracked 11/21. The Sunrise Trail was packed 11/20. The Dry Creek Trail, and Deer Creek, Pioneer and Little Advanced loops were packed 11/18.
Snowshoers and winter hikers are welcome on the Amik's Pond, River Terrace or Goose Creek loops only. Watch trail signs for designated uses. Your cooperation is appreciated!
Ski and snowshoe rental will be available at the Trail Center 11/22 beginning at 10 a.m. Park roads and parking lots have been cleared of snow from the November 10 storm. Please use caution as roads remain narrow, and there are rough or slippery sections also. A limited number of electric and non-electric campsites are plowed out and available for winter camping.
Water Off in Campground
The outside water spigots, shower buildings and dump station in the regular campground are closed for the season. Camping is allowed year-round, including electric campsites. There are outhouses in the campground. Water is available on the outside of the office building.
Horse Trails Closed
Horse trails are closed so we can make preparations for the winter ski season. Thanks for another great riding season at Wild River! We'll see you in May.
Using a GPS Unit to Find the Park?
If you are using a GPS unit to direct you to the park, you must type in the park address to get to the park headquarters and main use area. Take exit #147 from I-35. We are located 15 miles east of North Branch off County Road 12.
Campsite Numbers Changed
Campsites in the main campground were renumbered in Spring 2013 (physical site locations are the same). Revised campground map.
Park Notes
Be fascinated. Check out the naturalist programs and other activities scheduled at the park.
Virtual Tour:
Take a virtual tour. It's a great tool to help you plan your next trip to the park! Panoramic tour | Snapshot tour
Why Visit Wild River State Park?
Listen to a brief overview of park staff and visitors' favorite features and reasons to visit the park. (MP3, 3.25MB)
Trumpeter Swans
Maple Syruping
Teacher Resources
Requested Naturalist Programs Available
Prairie restoration project at Wild River state park
A Vanished Forest: outdoor exhibit visitors' guide and teaching ideas.
Nevers Dam...The Lumberman's Dam (30 pages, 1 MB) - An illustrated history of a St. Croix River logging era landmark
Geocaching Adventures at the park
Overview of all the geocaching opportunities at the park
Wild River State Park (Way)Points of Interest
Wild River State Park History Cache 1
Gift Cards
Purchase a Minnesota State Parks Gift Card.
Don't move firewood!
Burning non-local firewood can spread invasive species, and it's against Minnesota state law. Learn more. Always buy your firewood at the park, or from an approved local vendor. Find firewood vendors for Wild River State Park.
Bird Checklist at Wild River State Park.
Park Highlights
Best time to contact the park:
Daily, 9 a.m. - 4 p.m.
39797 Park Trail
Center City, MN 55012
tel: 651-583-2125
Park Naturalist: 651-583-2925
email: firstname.lastname@example.com
Getting There
From I-35, take State Highway 95 to County Road 12. Drive 3 miles on County Road 12 to the park entrance.
Do not rely on a GPS unit to find the park's main entrance! GPS units direct you to the geographic center of the park (Sunrise Landing area), not to the main park entrance. Please consult a map or call the office if you need additional driving directions.


text:
2012-03-19 17:10:00
Jared McCann is by no means a household name, but if all goes as planned for the 15-year-old, his road to fame will begin this April when he is expected to be chosen in the top 10 of the OHL Priority Draft.
The Stratford, Ont., native had 54 goals and 103 points in 52 games this season with the London Junior Knights and helped the team capture its league championship.
The win also qualified the Junior Knights for the OHL Cup where THN's Ryan Kennedy caught up with McCann to discuss the pressure of playing in front of so many scouts, bonding with teammates and more.
REPORTER: Ryan Kennedy | PRODUCER: Ted Cooper
AdvertisementThis Week - Subscribe Now
Do you think former Devils star goalie Martin Brodeur will sign a contract with the Blues after practicing with them this week?


text:
Hey guys.
I just got the trinket Haromn's Talisman from 6th boss in SoO. It has a certain chance to procc a multistrike which deals damage equivilent to 33% off the original attacks damage. (I can't post links, haven't made 10 posts on AJ yet). It also proccs some agility for 10 seconds (0.92 proccs / minute).
Anyone got any opinions on this, or is there anyone who's tested it already?
PvE trinket; Haromn's Talisman for MM, opinions?
Started by AJEEeu, Oct 27 2013 11:58 AMTrinket Hunter Marksmanship
2 replies to this topic
Posted 27 October 2013 - 11:58 AM
Posted 27 October 2013 - 12:36 PM
PvE trinkets are horrible in PvP. Their effectiveness is divided by around 3 in a PvP enviromnent.
The proc will probably only do about 10% damage and the agi proc will be about 3k I'm guessing.
The proc will probably only do about 10% damage and the agi proc will be about 3k I'm guessing.
Posted 27 October 2013 - 01:03 PM
PvE trinkets get downscaled (atm ilvl 500), proccs get half effect but double duration, so it's 8,5% chance for multistrike and 3588 agi for 20 seconds. But atm there seems a bug (maybe intended) for the SoO trinkets, that the duration of the buffs not gets doubled, so the trinkets are useless.
Also tagged with one or more of these keywords: Trinket, Hunter, Marksmanship
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Book this hotel and collect nights after your stay
Situated near the beach in Biloxi, Econo Lodge Biloxi Beach North is close to Miramar Park, Beauvoir-The Jefferson Davis Home and Presidential Library, and Cavalier Field. Also nearby are Hiller Park and Keesler Air Force Base.
Hotel Features.
Guests are served a complimentary breakfast. In addition to an outdoor pool, Econo Lodge Biloxi Beach North features RV/bus/truck parking. Complimentary wireless Internet access is available in public areas. Self parking is complimentary.
Amenities in air-conditioned guestrooms at Econo Lodge Biloxi Beach North include hair dryers and irons/ironing boards. Guests can use the in-room complimentary wireless high-speed Internet access. Televisions are equipped with cable channels. All accommodations provide phones along with free local calls (restrictions may apply).
Deposit: USD 150 per stay (cash only)
|Food and drink
|Things to do
|Home comforts
|Freshen up
|Be entertained
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|Food and drink
No star rating available
No star rating available
No star rating available
No star rating available
Deposit: USD 150 per stay (cash only)
We have included all charges provided to us by this hotel. However, charges can vary, for example, based on length of stay or the room you book.
We are now watching this hotel on your travel dates
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NewsMarch 31 2014
Sobriety Checkpoints Planned
Posted by Lucy
PIERRE, S.D. – The South Dakota Highway Patrol has sobriety checkpoints scheduled for Lyman County during the month of April. Other counties on the schedule include: Beadle, Brookings, Charles Mix, Codington, Custer, Davison, Edmunds, Hamlin, Harding, Hughes, Kingsbury, Lawrence, Lincoln, Minnehaha, Pennington, Roberts, Spink, Stanley and Union.
- Transportation Secretary visits South Dakota rail rehab project
- National Gas Average Nears Four-Year Low
- Schaefer re-elected to third term in House
- Growing rural communities
- Schaefer re-elected to third term in House
- Thune to Hold Transportation Roundtable With Secretary Foxx in Rapid City and Oacoma
- Reliance residents express concerns with rezoning in city limits
- Election results
- Lyman wins in first round playoff game against Stanley Co.
- Lyman to host openning round of football playoffs
- Hunting begins


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I asked earlier this week if we should have a giveaway in celebration of so much fun at HSN and the brand NEW Glitter and Glow Materials at Square1Masterpiece.com So here it is! Use the Rafflecopter app below and leave a review of ANY Megan Elizabeth Products or your experience with AboveRubiesStudio.com and you will be entered to win! There are also a few other "bonus" ways to win as well using the app HERE! a Rafflecopter giveaway {Read More}
$45 Value Mystery Prize Giveaway
HSN Prep! New Layout Tutorial and GIVEAWAY!
Hey all I'm so excited to be heading back to HSN on August 5! Make sure you time in between 1am and 10pm and get in on some exclusive FABULOUS deals!!!! I have a fun tutorial showing some of the simple things I'm going to have on display during the HSN show! We also have an awesome giveaway! Check this out! Glue Arts is hosting two giveaways! One here on AboveRubiesStudio and another on their website! We will announce winners {Read More}
Would you Like to WIN? Want to Go Shopping With Me?
**Second Video Repaired – Sorry about That! Now go WIN!** It is the FIRST day of spring and I am cramming a LOT into today! I have TWO videos today – ONE is my personal "home party" that I can't wait for you to hear more about – and the second is instructions for a FUN Spring Frolic Virtual Shopping trip I have been talking about for a few weeks! I know I could spread this out – but I {Read More}
CTO: Scrapbooking Dance Layout & Win a Mini Theme Kit!
Hello Everyone Thank you for coming over today to check out the Echo Park Mini Kits particularly the Le Ballet Du Grande kit. This kit is great for the dancers in your life, ballet, jazz, or just girly fun! I am going to create a layout with this mini kit today and show making a simple folded rosette in the process for an extra embellishment. You can pick up all the Echo Park mini kits for under $6.00 each at {Read More}
CHA Goodies Giveaway Winner
With over 315 comments the winner of the CHA the goodies bag is: RITA: OMG! Every thing looks wonderful. My favorite Viva…….what a beautiful display. I use their pens all the time and they are great. Thank you for showing so many of the new products. Congratulations Rita! Please use the form to verify your address and email that you commented with HERE. You have 14 days to claim your prize! Thanks and Congrats again Rita!!! Enjoy the Moments Everyone {Read More}
CHA Ustream Winter 2013 Giveaway!
I'm BACK from CHA! And I have goodies to share! Last night I did a quick Ustream to share ALL the goodies from CHA that I brought home and I have a giveaway for you!!! I hope you enjoy this fun little video and SPECIAL Announcement!!! Video streaming by Ustream Just leave a comment and share this post with your friends to be entered to WIN! Videos from CHA will be posted all week long and I hope you {Read More}
Are You The Selected Few? See Who Won What!
Today is ALL about the Winners from our 12 days of Black Friday! Lots of great stuff CONGRATS and SO EXCITED! If your name is listed as a winner below PLEASE contact us using this form found HERE within 14 days. Please include your name, mailing address and email address. We will verify the the identity of each and send your prize within 5 business days. All winners were selected at complete random using the Rafflecopter Giveaways Application. Day 1 {Read More}
12 Days of Black Friday Prizes and Giveaways
2 AMAZING Specials and Deals today the FINAL day of the best 12 days here ever! SPECIAL OF THE DAY! WIN THIS TODAY! Today is the GRAND PRIZE day so do NOT miss out on winning the Cricut Mini thanks to Tanner Bell Designs!!! Please make sure you do all that you can to share, enter and WIN! Good Luck and Enjoy! a Rafflecopter giveaway Feel free to come {Read More}
Black Friday Extravaganza Day 11 Prizes and Specials
SPECIAL OF THE DAY! LOWEST POSSIBLE PRICE we could go EVER with the PINK Megan Elizabeth Nesting Dies! For this 12 Days sale ONLY $14.99 for ALL 3 DIE SETS TOGETHER! MSRP on this bundle is $53.97 – what a HUGE savings so get them while they LAST! Available at this price only at shop.AboveRubiesStudio.com WIN THIS TODAY! Since we are on day 11 – win the HUGE Megan Elizabeth MEGA {Read More}
Day 10 Black Friday Extravaganza Prizes and Specials
Cruising Right Along! What has been your favorite thing so far? What posts have you loved? How have you been inspired by our Christmas Tutorials these past few days? **Vido will be up later, Megan is traveling. Thank you all so much for understanding! ** SPECIAL OF THE DAY! ALL 10 Megan Elizabeth Ink Edgerz for the INCREDIBLE Price of only $7.99 – CORRECTION! Only $6.97!!! WIN THIS TODAY! Get your own set of all 10 Ink Edgerz in todays giveaway! {Read More}


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To mark IDC Herzliya's 20th anniversary, we spent a day following Prof. Uriel Reichman, IDC's founder and president, and Jonathan Davis, VP for External Relations, around its delightful campus.
A panel of experts advised the Dutch government to return only one painting out of 189 claimed by relatives of a Holocaust-era art collector.
The Advisory Commission on Restitution Requests, Cultural Goods and World War II asserted that descendants of the art collector Nathan Katz and his brother, Benjamin, failed to prove that the brothers had been in possession of some of the 188 paintings they claimed, or that the brothers were pressured by Nazi occupation forces into selling the paintings.
The committee, in a report published Jan. 24, advised the government to return only one painting, "Portrait of a Man with a High Hat," which is currently on display at the Museum Gouda near Utrecht. The painting is the work of the 17th century Dutch master Ferdinand Bol.
Relatives of the brothers, who have made several claims since 2004 for the return of the artwork, say they owned all 189 paintings. Many of the works, they claimed, were stolen by the Nazis and then came to be in the possession of Dutch authorities.
Nathan Katz died in 1949 and his brother in 1962.
About the Author:
If you don't see your comment after publishing it, refresh the page.
The bounties of war? I don't know all the circumstances, but It seems that in this case, there is some evidence the paintings are stolen property. If it turns out to be true, then return the paintings – they are not yours.
"The Dutch government has for many years followed an anti-Semitism-promoting immigration policy."
A quote from an article. Like America, Britain and France it doesn't screen or even demand that immigrants be loyal to their adopted country. Instead they're allowed to bring their fascist jew-hating, infidel hating ideologys with them and allows them to promote these same ideologies with the help of groups like CAIR and most universities.
People need to read:
The Professors: The 101 Most Dangerous Academics in America by David Horowitz.
Ivory Towers On Sand: The Failure of Middle Eastern Studies in America by Martin Kramer.
Muslim Mafia by Gaubatz and Sperry.
Because They Hate by Brigitte Gabriel.
Infiltration: How Muslim Spies and Subversives have Penetrated Washington by Paul Sperry.
American Jihad: The Terrorists Living Among Us by Steven Emerson.
Stop the Ilamization of America: A Practical Guide to the Resistance by Pamela Geller.
Invasion: How America Still Welcomes Terrorists, Criminals and Other Foreign Menaces to Our Shores by Michelle (the hottest woman on the planet) Malkin.
The Haj by Leon Uris.
The Source by James Michener.
"Slavery, Terrorism and Islam" and "Holocaust in Rwanda" by Peter Hammond.
The Legacy of Islamic Antisemitism by Andrew G. Bostom
The Legacy of Jihad by Andrew G. Bostom MD
A Concise History of the Crusades by Thomas F. Madden
The Book of Jewish Knowledge by Nathan Ausubel.
The New Moody Atlas of the Bible by Barry J. Beitzel
The Al Qaeda Reader by Raymond Ibrahim.
Reliance of the Traveller: A Classic Manual of Islamic Sacred Law.
Sahih al-Bukhari (With Sheikh Humaid's article on Jihad).
The Koran: Pickthall.
The Quran: Yusuf Ali: Translated by Prof. Syed Vickar Ahmed.
Holy Qur'an with Commentary: Maulana Muhammad Ali.
The Second Message of Islam by Mahmoud Mohamed Taha.
Vince Flynn's "Term Limits" as a solution to our political problems.
Taken Into Custody by Stephen Baskerville and The War Against Boys by Christina Hoff Sommers.
Mean Justice: A true account of a prosecutor's power and betrayel by Edward Humes.
The Man by Irving Wallace.
Oh yeah, "Justice Not Vengeance" by Somon Wiesenthal. About how Nazi war criminals got away with it thanks to……well, everybody.
This is not the first time they do this in Holland because in Rotterdam , where unfortunately I was born a museum acted like their nose was bleeding and keep stolen Jewish art so everyone thinks here they can follow in their footsteps way not? They got away with it to.So maybe a good thing to give the Jewish children a little monument after all this years to shut everybody's mouth about more things like a bank in Dordrecht practically gave Jewish things they gave them to watch over.
to get rid of it and I did not hear a word being spoken!
Happy Birthday Rob.
Comments are closed.
Hamas snipers fired from Gaza at an IDF routine patrol operating along the security fence early afternoon on Thursday. No injuries were reported, and the vehicle was damaged. The IDF responded with an artillery shell aimed at the source of fire.
Jacob Richman found this amusing mistake in the store. Do we eat these "extra crispy" soap nuts, or wash the dishes with them?
For every terrorist cell Israel announces it has captured, there are many more kept under wraps.
On Monday evening, tTwo Arab MKs hurled epithets at MKs David Rotem and Feiglin from the podium. Here is Feiglin's response.
Most significantly, both sides made progress until they talked about the status of Jerusalem.
If the Shin Bet had not stopped the terrorist cells in its tracks, they would have caused a mass catastrophe.
Thanksgiving is an American secular holiday that most Jews have no problem celebrating due to its lack of overt religious symbols (unlike the American holidays right before and after it). Still, there are always holdouts for some reason or another. Let's hear what you do…
MK Miri Regev said the law is a difficult and complicated one, and it requires a serious discussion about its downsides, and therefore shouldn't be rushed into implementation.
The Navy has selected Captain Or Cohen to become the first woman appointed as an IDF Navy ship's commander.
Three Gazans were captured overnight when they crossed over the security fence into Israel.
Over 200 hair salons across Israel took part in the annual nationwide drive to collect hair for the Zichron Menachem Cancer Support in Israel in partnership with Pantene Products Israel.
In 2014, cruise ship traffic to Israel decreased by almost two-thirds in comparison with the year before.
U.S. Supreme Court Ruth Bader Ginsburg had heart surgery on Wednesday, Nov. 26.
"The Israeli government is not interested in the collapse of the Palestinian Authority," said Arbell, a guest scholar at the Brookings Institution who teaches at American University here. "There may be faults in Abbas and the leadership and in what they're doing, but they're still the safest bet."
Shas head Aryeh Deri said this evening on Radio Kol Chai that if Netanyahu met his two non-negotiable conditions, Shas could join the coalition.
The man, a resident of Beit Safafa, tried on three different occasions last week to burn down the section of the hospital building where he worked.
The documents, some of which were also found in a deserted apartment in Jerusalem, reportedly had belonged to a member of the prosecution team.
Only 49 US States have a Chabad House. Is this holding back the Moshiach?
The Netherlands will not recognize Palestinian statehood right now because it would not help restart peace talks with Israel, Dutch Foreign Minister Bert Koenders said.
The task force will aim at keeping Americans from joining ISIS and other radical Muslim murder gangs.
Her tweet proves a baroness can be a twit.
Charley Levine, a top public relations professional in Israel and well known in Ango-Israeli circles, has died.
New York police have arrested a 23-year-old Brooklyn man was arrested for assaulting an Orthodox Jewish couple in Manhattan this summer. A police department spokesman confirmed to JTA that Mustafa Mashni was charged with assault, as first reported on the Jpupdates website. The victims, in their 20s, were walking on the Upper East Side at […]
A Canadian university professor was charged in Paris on Saturday in the deadly 1980 synagogue bombing in Paris that killed four and injured more than 40. The arraignment of Hassan Diab came hours after he arrived in Paris after being extradited from Canada following a six-year fight to prevent it. Canada's Supreme Court last week […]
Printed from: http://www.jewishpress.com/news/dutch-stolen-art-committee-dismisses-katz-familys-188-claims-2/2013/01/27/
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Sheep & Equipment Exchange is a free listing for ISIA members. Ads are placed in the Lamb & Wool Newsletter and in this online listing. One ad per membership, which must be limited to 50 words. Ads may run in four issues of the Lamb & Wool newsletter (date in parenthesis indicates first issue) and may be re-submitted for an additional four issues. Send ad information along with name, address, phone and email to Claudia Putnam at: email@example.com by the 15th of the month for publication in the following month's newsletter. Newsletter is published 11 times/year with a July/August issue.
Sheep, Equipment and Exchange
11/14 For Sale: Bred Ewes for Sale:Ultrasounded for lambing dates and fetal numbers. Check our web page on club lamb page or facebook . Vander Linden Livestock . Kenny Vander Linden 641-891-2471 or Les Vander Linden 641-891 5946 Email: email@example.com
10/14 For Sale: Dorper and White Dorper rams: registered and commercial; also Ile de France percentage rams. All are hardy/easy care, well muscled, out of season breeding, excellent growth on forage only. Purebred Karakachan puppies, great guardians, quiet and gentle.S Mitcham, 3061 160th Street, Sumner, 563-578-5665, firstname.lastname@example.com;www.ccdorpers.com; FaceBook
10/14 For Sale: Priefert 6x6 kennel panels, 4 with doors,
9 plain panels plus connectors, will configure in a line or in a square. Special ordered from http://www.priefert.com/products/kennels/kennels/premier-kennel-components/kf441
Great kennels for working dogs or as a holding pen for sheep. Iowa City.
Jenn 319-321-3699 or email@example.com
10/14 For Sale: Fall born 2 year old registered Polypay ram. RR scrapie tested. NSIP data: maternal index, top 25%, weaning weight, top 2%, and post weaning weight top 7% of the Polypay breed. Sand Prairie Polypays, Howard Lindaman, 2041 180th Street, Marshalltown, Iowa 50158. Phone: 641 752 3490.
9/14 For Sale: Prolific, productive, profitable registered Finnsheep ram and ewe lambs. Also Finn x Dorset x Ile de France commercial ewe and ram lambs. NSIP flock with written health status guarantee. Mormon Trail Farms, Greenfield, Iowa, 641-745-2323 (h), 641-221-0551 (c) firstname.lastname@example.com.
8/14 For Sale: Registered Suffolk RR Rams ready for breeding. Bloodline consists of Ruby Mountain on the sire side and Corson, Lansing on the dam side, will work as terminal sires for commercial producers. Several registered Suffolk ewe lambs, all will have at least one R gene. Newton, IA (641) 792-2323. (641) 521-7981
8/14 For Sale: Cormo/CVM 2014 lambs (ram's fleece won Grand Champion at the Iowa State Fair 2014) $175. Pictures available & posted on facebook Still Water Fiber Farm. Contact Mary Parks 515-681-2361


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