WO2005064308A1 - Apparatus for working up a solid biological specimen - Google Patents
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- WO2005064308A1 WO2005064308A1 PCT/EP2003/014739 EP0314739W WO2005064308A1 WO 2005064308 A1 WO2005064308 A1 WO 2005064308A1 EP 0314739 W EP0314739 W EP 0314739W WO 2005064308 A1 WO2005064308 A1 WO 2005064308A1
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- G—PHYSICS
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- G01N1/00—Sampling; Preparing specimens for investigation
- G01N1/28—Preparing specimens for investigation including physical details of (bio-)chemical methods covered elsewhere, e.g. G01N33/50, C12Q
- G01N1/30—Staining; Impregnating ; Fixation; Dehydration; Multistep processes for preparing samples of tissue, cell or nucleic acid material and the like for analysis
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- G—PHYSICS
- G01—MEASURING; TESTING
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- G01N1/28—Preparing specimens for investigation including physical details of (bio-)chemical methods covered elsewhere, e.g. G01N33/50, C12Q
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- G—PHYSICS
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- G01N1/28—Preparing specimens for investigation including physical details of (bio-)chemical methods covered elsewhere, e.g. G01N33/50, C12Q
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- G01N1/286—Preparing specimens for investigation including physical details of (bio-)chemical methods covered elsewhere, e.g. G01N33/50, C12Q involving mechanical work, e.g. chopping, disintegrating, compacting, homogenising
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Abstract
The invention is directed an apparatus to work up a solid biological specimen under standardized conditions and to collect data of said biological specimen, comprising: a documentation device for recording data of said biological specimen, a processing device to work up said biological specimen, and a preservation device to preserve said worked up biological tissue specimen.
Description
Apparatus for working up a solid biological specimen
The invention is directed to an apparatus for working up a solid biological specimen.
In the recent years, high throughput methods such as microarray techniques have been developed for analysis of gene expression or gene activity in tissue extracts. For producing a microarray, DNA sequences or oligonucleotides are printed on a solid support surface in a predetermined order using, for example, computer- controlled, high-speed robotics. Such DNA microarrays typically include representative sequences from genes of interest and can be used to generate an expression profile of a certain type of cells or of a tissue.
For establishing a gene expression profile of a certain tissue, mRNA has to be isolated from a respective tissue sample using standard techniques known by the skilled person. The isolated mRNA can be reverse transcribed into cDNA, for example, in the presence of fluorescence-tagged deoxyribonucleotides. The obtained fluorescent mixture of cDNA is then hybridised to a microarray of selected DNA probes. The fluorescence intensity of the cDNA molecules hybridised to the DNA probes can be quantified, for example, by a laser confocal scanning microscopy and image analysis. These techniques are known, for example, from Schena et al., Science 270, pp. 467-470, 1995; Schena, BioAssays 18, pp. 427-431 ; Soares, Current Opinion in Biotechnology 8, pp. 542-546, 1997; Ramsay, Nature Biotechnology 16, pp. 14-44, 1998; Service, Science 282, 396-399, 1998; US patent no. 5,700,637.
This approach allows to obtain a quantitative gene expression or gene activity profile for a large number of genes in a plurality of samples using one microarray.
These microarrays are already used for the routine prognostic screening of cancer patients. See, e.g., Nature Medicine 9, page 9, 2003.
A microarray allows to simultaneously screen a plurality of samples. A great advantage of this screening method is that the results of the various samples are directly comparable with each other since these samples have all been treated under identical conditions of preparation and measurement.
However, the significance of the results obtained using microarrays currently commercialised suffer from the fact that the obtained results strongly depend from the work up or preparation of the samples to be screened on a microarray. Phrased differently, although all incubation steps and measurements steps are identical for the samples screened on one microarray, the samples have a different "work up history" before applied to the microarray. Therefore, the results measured by microarray technology are often strongly influenced by the working up of the samples to be measured.
That is to say the obtained results do not reliably reflect, for example, the biochemical or clinical status of a patient examined but to a great extent the conditions under which the samples had been worked up.
Moreover, the pathological status of a patient is often strongly influenced by the medical history of the patient from which the biological specimen is isolated. For example, the development of cancer or metabolic disease states is often caused by external factors such as consumption of drugs, nicotine, alcohol, sugar, etc. or daily working or life conditions and so on. However, this specific information is not available when providing scientists with biological specimens of diseased tissue. Therefore, the results obtained by analysing respective biological specimens cannot be fully or correctly understood.
For these reasons it is rather difficult, if not impossible, to compare results obtained from different tissues of various patients worked up separately under different conditions and wherein, furthermore, no medical information of said patients, from whom the respective tissues had been isolated, is available and to elucidate the molecular defects responsible for the respective pathological conditions or status of said patients.
Consequently, there is a demand to obtain biological specimen under standardised conditions for research, clinical and diagnostic purposes.
The object underlying the present invention is solved by providing an apparatus to work up a solid biological specimen under standardised conditions and to collect data of said biological specimen, comprising a documentation device for recording data of said biological specimen, a processing device to work up said biological specimen, and a preservation device to preserve said worked up biological tissue specimen.
The term "biological specimen" is meant to designate any biological specimen after having been isolated from its natural environment, such as the body of an animal or a human being. The surgical operation is not covered by the invention.
The term "processed biological specimen" is meant to designate a biological specimen which has been worked up, for example by cutting, stamping or chopping to a final seize in which the material is to be preserved.
Pursuant to the present invention, the biological specimen is solid. Therefore, the apparatus of the present invention is not able to process liquid specimens such as urine or blood.
The term "solid" in connection with "biological sample" covers any biological material which can be taken from the animal or human body. Preferably, the solid biological specimen is a biological tissue taken, for example, from organic tissue, fatty tissue, muscle tissue or blood vessels of an animal or human being.
The apparatus of the invention allows to work up solid biological samples under defined conditions. After the biological sample has been taken, for example, from a patient by surgical operation, the sample can be automatically processed with the apparatus of the present invention. Thereby, deviations of the work up between various biological specimens are minimised or, preferably, eliminated.
Consequently, the molecular differences found later between the biological specimens, processed with the apparatus of the invention, are not caused by the of work up process. This means that the molecular differences found between the processed biological specimens give a hint with respect to the molecular reasons of a disease state. Therefore, the processed biological specimen are particular useful for the identification and validation of diagnostic and therapeutic markers for research, diagnostic and/or therapeutic purposes.
The apparatus of the invention greatly facilitates the work up of a large number of biological specimens under standardised conditions. A great deal of processed biological specimens is a prerequisite to statistically evaluate the results obtained with the various processed biological specimens.
In other words, the apparatus of the present invention enables a high-throughput processing of isolated biological specimens and the preparation of processed biological specimens with high accuracy. Therefore, the apparatus of the invention can also be classified as "high-throughput apparatus for processing of solid biological specimens and collecting of data".
Current methods or devices for tissue collection and storage do not adequately address the issue of standardisation by either being focused on collecting basically one tissue specimen at a time such as biopsy for diagnosis by a pathologist or by being focused only on optimising freezing of an obtained tissue specimen. The present invention, however, provides an apparatus which allows to work up a plurality of tissue specimens within a short period of time under standardised conditions. The processed biological specimens, therefore, are uniquely qualified for comparative molecular analysis of, for example, biological tissues obtained from different patients.
Preferred embodiments of the invention are described in dependent claims.
Pursuant to an embodiment of the invention the apparatus further comprises a timer to control and/or to record the period of time of the operations performed by the documentation device, processing device and/or preservation device.
A timer is advantageous to control the time for documenting the biological specimen and/or for processing of the biological specimen until the processed biological specimen is preserved. Preferably, the period of time for each process step is recorded. Depending on the type of biological specimen to be documented, processed and preserved the period of time can be appropriately selected.
It is preferred that the total period of time for the complete work up is as short as possible to avoid any detrimental effects such as degradation of bio-molecules, for example, of RNA, especially mRNA, or proteins in the biological specimen. Moreover, the post-translational modifications such as phosphorylation, sulphation or glycosylation of proteins shall not be altered during the work up of the biological specimen.
Preferably, the whole work up process is completed within less than 25 minutes, particularly preferred within less than 20 minutes. Pursuant to another embodiment the work up does not last longer than 15 minutes. Especially preferred, the whole process is completed within about 10 minutes or less such as 5 minutes.
The maximum deviation of time between the various work up processes is less than 10 percent, preferably less than 5 %, based on the whole period of time.
It is particularly preferred that the maximum deviation between the different work up processes is not more than ±1 minute, preferably no more than ± 0,5 minute.
Preferably, the documentation device comprises a camera for taking an image or picture of said biological specimen. According to another embodiment of the invention, the camera is an electronic or a digital camera, such as a photographic or a video camera.
The documentation can occur twice. The first documentation by camera can be effected after the biological specimen has been taken from its natural environment. Preferably, the biological specimen is documented a second time by camera after the biological specimen has been processed by the processing device. Pursuant to a preferred embodiment, the second documentation by camera is effected before preservation.
It is of course also possible to use a video camera, preferably a digital video camera, and to record the - preferably complete - work up process.
The documentation is preferably effected by digital camera so that the pictures can be stored, for example, on a magnetic or optic data carrier as a data set assigned to the particular processed biological specimen.
Pursuant to a preferred embodiment of the invention, the documentation device comprises a balance for weighing and recording the weight of said biological specimen.
When making pictures or images of the biological specimen or processed biological specimen the specimen can be simultaneously weighed.
It is also preferred when the documentation device comprises means for measuring further parameters of the biological specimen such as temperature or pH of the biological specimen.
It is, for example, possible to also record the length and width of the specimen by optical means and to calculate automatically by computer the area of the specimen. In case the biological specimen is a tumour tissue, the area of the central tumour and of the peripheral tumour can be recorded and/or calculated. It is also contemplated to record how and where the biological specimens are cut or stamped. These data can be valuable at a later point in time when the processed biological specimen are used for research, diagnostic or clinical purposes.
Pursuant to another embodiment of the invention, the processing device processes said biological specimen according to predetermined sequence of operations.
The apparatus can have various options how the biological specimens are to be handled and/or processed. For example, it is possible to skip one or more of the devices. If, for example, the biological specimen shall merely been processed it is possible to omit the documentation at the very beginning and to directly process and preserve the biological specimen. It is also possible to document only the processed biological specimen before preservation in order to save time, i.e. to shorten the complete process.
In the latter case the biological specimen is directly processed by the processing device. After having finished the processing operation the processed biological specimen can be documented by the documentation device for taking pictures or images, and optionally weighing the processed biological specimen. Then, the processed biological specimen is transported to the preservation device for preserving the processed biological specimen.
It is preferred that the processing device cuts or stamps said biological specimen to a provide a processed biological specimen of a predetermined weight or seize or height or area of said biological specimen.
The biological specimen is normally surgically obtained and cut to an appropriate seize. The biological specimen can then be put on transportation means, for example, a conveyor and transported into the apparatus to be documented by the documentation and/or processed by the processing device. It is of course possible to
use other technical solutions to bring the biological specimen into the apparatus of the invention.
The processing device can cut the biological specimen with a cutter or stamp or punch the biological specimen with a stamp or puncher, respectively.
When documenting the biological specimen, it is arranged, for example, on a flexible grate or grid or on any other suitable substratum and, optionally, temporarily locked in position using, for example holders, fasteners or clamps. After having documented the biological specimen, the processing device is processing the biological specimen.
Thereafter, the processed biological specimen can be documented again by the documentation device. The cut or stamped biological specimen are then taken, for example, by a gripping device and transported to the preservation device.
That is to say, pursuant to a preferred aspect of the invention the biological specimen is documented and processed at the same place. However, it is also possible to perform the documentation and processing of the biological specimen at different places within the apparatus. In the latter case transportation means are required to transport the biological sample from the documentation device to the processing device.
Preferably, the predetermined area of the biological specimen comprises non- diseased or diseased areas of said biological specimen.
The non-diseased area is preferably a healthy area of the biological specimen. The non-diseased or healthy biological specimens can be used later as controls with respect to diseased biological specimens for research, clinical or diagnostic purposes.
Preferably, the biological specimen is a biological tissue such as an organic tissue, a fatty tissue or a blood vessel. Generally, any solid material from an animal or a human being can be documented, processed and preserved with the apparatus of the invention.
The biological specimen can comprise healthy tissue, peripheral diseased tissue, central diseased tissue and blood vessels. For example, the diseased area of said biological specimen can comprise neoplastic tissue, peripheral tumour tissue or
central tumour tissue. The non-diseased area can be healthy tissue or non-tumour tissue.
According to an embodiment of this invention the neoplastic tissue is selected, but not limited to, from the group consisting of colonic carcinoma, rectocolonic carcinoma, pancreatic carcinoma, mammary carcinoma, prostatic carcinoma, broncho carcinoma, gastric carcinoma, ovary carcinoma and cervical carcinoma.
Pursuant to another embodiment of the invention, the preservation device comprises means for chemical preservation of said processed biological specimen.
In the preservation device the processed biological specimen can be stored in appropriate containers such as plastic tubes. The plastic tubes can be filled with a chemical fixation agent, like formaldehyde or glutaric dialdehyde, if a chemical fixation is desired. In this case the cut, stamped or punched (processed) biological specimen can simply be transferred by a gripping means and immersed in the fixation agent. Since the volume of the processed biological specimens is preferably about 1 mm3, 3 mm3, 50 mm3, 200mm3, 0.5 cm3, 1 cm3, 2 cm3 or 4 cm3 the samples are rapidly preserved.
Pursuant to another embodiment of the invention tissue cuts are prepared from the chemically preserved processed biological specimen which can be used for histological analysis. It is preferred that the tissue cuts can be used for immuno histological analyses.
It also possible pursuant to another embodiment of the invention that the preservation device comprises means for cryo-preservation of said processed biological specimen.
If the processed biological specimen shall not be chemically modified, the processed biological specimens can be cryo-preserved. In the latter case, the tubes are preferably cryo-tubes. When the processed biological specimens have been put into cryo-tubes, the cryo-tubes are normally shock frozen in a cryogenic medium. The cryogenic medium can be, for example, liquid nitrogen (-196°C) or a carbon dioxide alcohol mixture (about -80°C). Preferably, liquid nitrogen is used as cryogenic medium. It is, however, also possible to use a freezer for cryo-preservation. The container can be, for example, a 1.5 ml, 5 ml or 10 ml cryo-tube.
Since the volume of the processed biological specimen is preferably about 1 mm3, 3 mm3, 50 mm3, 200mm3, 0.5 cm3, 1 cm3, 2 cm3 or 4 cm3 the samples are deep frozen within seconds.
It is also possible to use a step-wise freezing operation wherein the processed biological specimen is frozen according to a given temperature gradient, preferably in the presence of a preservation medium. In the latter case the cryo-tubes are put in a freezing block which is cooled down using a computer controlled program. This can ensure viability of the processed biological specimens.
The processed biological specimens can also at first preserved using a preservation agent, such as a chemical preservation agent, and subsequently be cryo-preserved.
The preservation device can also comprise means for labelling of said processed biological specimen. The label is normally applied to the container containing the respective processed biological specimen.
It is preferred when the inventive apparatus including said documentation device, processing device and/or preservation device comprises heating and/or cooling means to adjust the temperature to a predetermined value.
In order to have standardised conditions through both the winter and the summer time, it is preferred to have a constant temperature in the documentation device, the processing device and the preservation device as well as in any optional additional device. Preferably, the temperature is the same in the whole apparatus, i.e. the various devices have the same temperature, thereby simplifying the construction of the apparatus.
Preferably, the inventive apparatus including the documentation device, processing device and/or preservation device is heat insulated. A heat insulation facilitates the adjustment of the temperature in the apparatus of the invention. Any insulation material known by the skilled person can be used.
The present invention is also directed to an apparatus which can comprise a data processing and/or data recording unit to assign measured or obtained data and/or additional data to each processed biological specimen.
The data such as the pictures or images or video recordings can be stored on data carrier. Preferably the data are automatically assigned to the processed biological specimen.
For example, the tubes containing the processed biological specimen can be labelled with adhesive labels carrying preferably an automatically readable code such as a bar code. The automatically readable code can also be applied directly to the containers. The automatically readable code, e.g. bar code, can later be read automatically using a reader so that the stored data are assigned to the correct processed biological specimen.
It is of course also possible that additional data are added to the data obtained during the work up of the biological specimen.
The additional data can be data sets which can comprise information of the human or non-human being such as sex, age, weight, ethnic background, occupation, environment, family medical background, complaints, prior diseases, allergies, children's diseases, infectious diseases, tropical diseases, habit of living, eating or sleeping, excretion habits of stool and urine, diagnostic and prognostic test results, symptoms, drug exposure, therapeutic agent exposure, result of treatment regimens, incompatibilities of medicaments, history of alcoholism, drug or tobacco use, time of death, cause of death, medication history, intake of anaesthetics for surgery, surgical procedure, and/or medical follow-up information such as survival time or development of metastases.
It is further preferred that the data sets can comprise information relating to the biological specimen, such as, histological characterisation such as acute or chronic inflammation, thromboses, tumour type, tumour grade, tumour size, written documentation of tumour, photographic documentation of tumour, electronic documentation of tumour, and/or accrual information or information about the collection of the biological specimens.
The data set can be a comprehensive data collection comprising any relevant information about the patient and/or the biological sample.
The medical, biological and/or clinical information supplements significantly the scientific results obtained by with the processed biological specimen in research or diagnostics. This additional information can provide the missing link to understand the pathological condition of the patient. Due to the standardised working up of the biological specimens reliable information can be obtained, for example, by array or microarray analyses.
Another embodiment of the invention is directed to an apparatus comprising an interface for connection with a computer or a handheld. The interface facilitates data transfer from and to the apparatus of the invention.
Preferably, the apparatus of the present invention is a table top apparatus or a mobile apparatus having rollers. Since the apparatus of the invention is preferably used in the operating room where the biological sample is taken from an animal or human being, it is preferred that the apparatus is moveable or mobile to move it quickly into the operating room or out of the operating room. Another possibility is to use the apparatus of the invention as a table top version.
An embodiment of the apparatus of the invention is schematically illustrated by the Figure 1. The embodiment is given for exemplary purposes only and is not intended to limit the scope of invention.
In Figure 1 the biological specimen isolated from a patient in an operating room is put on a transportation means such as a conveyor and transported into the apparatus wherein the apparatus is heat insulated and the temperature is kept, for example at 15°C. The biological specimen is arranged on a lattice. Then the biological specimen is then documented by taking digital images with a digital camera (documentation device). After having taken the images the biological specimen is cut by a stamp or puncher (processing device) on the grid. The stamped or punched biological specimen (processed biological specimen) is then documented again by digital imaging using the digital camera (documentation device). Thereafter, the processed biological specimen is transferred by a gripping device (not shown) into 1 ,5 ml cryo- tubes. The cryo-tubes arranged in a rack are then immersed in liquid nitrogen (preservation device), and stored at -196°C. The rack can then be taken out manually and stored in liquid nitrogen or a freezer somewhere else. The total time between isolation (surgical operation) of the biological specimen and preservation took 10 minutes.
Claims
1. An apparatus to work up a solid biological specimen under standardised conditions and to collect data of said biological specimen, comprising: a documentation device for recording data of said biological specimen, a processing device to work up said biological specimen, and a preservation device to preserve said worked up biological tissue specimen.
2. The apparatus pursuant to claim 1 , further comprising: a timer to control and/or to record the period of time of the operations performed by the documentation device, processing device and/or preservation device.
3. The apparatus pursuant to claim 1 or claim 2, wherein the documentation device comprises a camera for taking an image of said biological specimen.
4. The apparatus pursuant to claim 3, wherein the camera is an electronic or a digital camera.
5. The apparatus pursuant to claim 4, wherein the camera is a photographic or a video camera.
6. The apparatus pursuant to any one of the preceding claims, wherein the documentation device comprises a balance for weighing and recording the weight of said biological specimen.
7. The apparatus pursuant to any one of the preceding claims, wherein the documentation device comprises means for measuring further parameters of the biological specimen such as temperature or pH.
8. The apparatus pursuant to any one of the preceding claims, wherein the processing device processes said biological specimen according to predetermined sequence of operations.
9. The apparatus pursuant to any one of the proceeding claims, wherein the processing device cuts or stamps said biological specimen to a provide a processed biological specimen of a predetermined weight or seize or height or area of said biological specimen.
10. The apparatus pursuant to claim 9 wherein the predetermined area of the biological specimen comprises non-diseased or diseased areas of said biological specimen.
11. The apparatus pursuant to claim 10 wherein said diseased area of said biological specimen comprises peripheral diseased tissue or central diseased tissue.
12. The apparatus pursuant to claim 10 wherein said diseased area of said biological specimen comprises peripheral tumour tissue or central tumour tissue.
13. The apparatus pursuant to any one of the proceeding claims, wherein the preservation device comprises means for chemical preservation of said processed biological specimen.
14. The apparatus pursuant to any one of the proceeding claims, wherein the preservation device comprises means for cryo-preservation of said processed biological specimen.
15. The apparatus pursuant to any one of the proceeding claims, wherein the preservation device comprises means for labelling of said processed biological specimen.
16. The apparatus pursuant to any one of the proceeding claims wherein the apparatus including said documentation device, processing device and preservation device comprises heating and/or cooling means to adjust the temperature to a predetermined value.
17. The apparatus pursuant to any one of the proceeding claims wherein apparatus including said documentation device, processing device and preservation device is heat insulated.
18. The apparatus pursuant to any one of the proceeding claims, wherein the apparatus comprises a data processing and/or data recording unit to assign measured data and/or additional data to each processed biological specimen.
19. The apparatus pursuant to any one of the proceeding claims, wherein the apparatus comprises an interface for connection with a computer or a handheld.
20. The apparatus pursuant to any one of the proceeding claims, wherein the apparatus is a table top apparatus or a mobile apparatus.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/EP2003/014739 WO2005064308A1 (en) | 2003-12-22 | 2003-12-22 | Apparatus for working up a solid biological specimen |
| AU2003294937A AU2003294937A1 (en) | 2003-12-22 | 2003-12-22 | Apparatus for working up a solid biological specimen |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/EP2003/014739 WO2005064308A1 (en) | 2003-12-22 | 2003-12-22 | Apparatus for working up a solid biological specimen |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2005064308A1 true WO2005064308A1 (en) | 2005-07-14 |
Family
ID=34717116
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP2003/014739 WO2005064308A1 (en) | 2003-12-22 | 2003-12-22 | Apparatus for working up a solid biological specimen |
Country Status (2)
| Country | Link |
|---|---|
| AU (1) | AU2003294937A1 (en) |
| WO (1) | WO2005064308A1 (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5125240A (en) * | 1989-08-04 | 1992-06-30 | Cryo-Cell International, Inc. | Storage apparatus, particularly with automatic insertion and retrieval |
| US5817032A (en) * | 1996-05-14 | 1998-10-06 | Biopath Automation Llc. | Means and method for harvesting and handling tissue samples for biopsy analysis |
| US6251516B1 (en) * | 1994-03-01 | 2001-06-26 | The United States Of America As Represented By The Department Of Health And Human Services | Isolation of cellular material under microscopic visualization |
| US6349264B1 (en) * | 1996-10-07 | 2002-02-19 | Lab Vision Corporation | Method and apparatus for automatic tissue staining |
-
2003
- 2003-12-22 WO PCT/EP2003/014739 patent/WO2005064308A1/en active Application Filing
- 2003-12-22 AU AU2003294937A patent/AU2003294937A1/en not_active Abandoned
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5125240A (en) * | 1989-08-04 | 1992-06-30 | Cryo-Cell International, Inc. | Storage apparatus, particularly with automatic insertion and retrieval |
| US6251516B1 (en) * | 1994-03-01 | 2001-06-26 | The United States Of America As Represented By The Department Of Health And Human Services | Isolation of cellular material under microscopic visualization |
| US5817032A (en) * | 1996-05-14 | 1998-10-06 | Biopath Automation Llc. | Means and method for harvesting and handling tissue samples for biopsy analysis |
| US6349264B1 (en) * | 1996-10-07 | 2002-02-19 | Lab Vision Corporation | Method and apparatus for automatic tissue staining |
Also Published As
| Publication number | Publication date |
|---|---|
| AU2003294937A1 (en) | 2005-07-21 |
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