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1. A process for the preparation of 1,4-bis(hydroxymethyl)-2,3,5,6-tetrafluorobenzene comprising: a) fluorinating 2,3,5,6-tetrachloroterephthalonitrile to obtain 2,3,5,6-tetrafluoroterephthalonitrile; b) hydrogenating 2,3,5,6-tetrafluoroterephthalonitrile to give 1,4-bis(aminomethyl)-2,3,5,6-tetrafluorobenzene; and c) converting 1,4-bis(aminomethyl)-2,3,5,6-tetrafluorobenzene to 1,4-bis(hydroxymethyl)-2,3,5,6-tetrafluorobenzene. 2. A process according to claim 1 wherein step c) is performed by diazotisation of 1,4-bis(aminomethyl)-2,3,5,6-tetrafluorobenzene followed by in-situ hydrolytic decomposition of the resulting diazonium salt. 3. A process as claimed in claim 1 which comprises the further steps of i) halogenation of 1,4-bis(hydroxymethyl)-2,3,5,6-tetrafluorobenzene to give a 4-(halomethyl)-2,3,5,6-tetrafluoro-benzyl alcohol where halo is chloro or bromo and ii) hydrogenation of the 4-(halomethyl)-2,3,5,6-tetrafluorobenzyl alcohol to give to 4-methyl-2,3,5,6-tetrafluorobenzyl alcohol. 4. A process according to claim 1 which process comprises the further step of reacting 4-methyl-2,3,5,6-tetrafluorobenzyl alcohol with cis-Z 3-(2-chloro-1,1,1-trifluoro-2-propenyl)-2,2-dimethylcyclopropane carbonyl chloride to form tefluthrin. 5. A process according to claim 2 in which the step of converting 1,4-bis(aminomethyl)-2,3,5,6-tetrafluorobenzene to 1,4-bis(hydroxymethyl)-2,3,5,6-tetrafluorobenzene is followed by a hydrolysis reaction to convert ester by-products to the required 1,4-bis(hydroxymethyl)-2,3,5,6-tetrafluorobenzene. 6. A process according to claim 2 wherein the 2,3,5,6-tetrafluoroterephthalonitrile is hydrogenated in a carboxylic acid solvent and the hydrogenation mass is passed straight into the diazotisation stage (step c) after screening, such that no further acid is required. 7. A process according to claim 2 wherein the reaction mass containing the 1,4-bis(hydroxymethyl)-2,3,5,6-tetrafluorobenzene is adjusted to pH 7-10 and the 1,4-bis(hydroxymethyl)-2,3,5,6-tetrafluorobenzene is extracted into a solvent. 8. A process according to claim 3 wherein 1,4-bis(hydroxymethyl)-2,3,5,6-tetrafluorobenzene from step c) is extracted from the reaction mass in a solvent such as methyl isobutylketone (MiBK), the solvent removed under reduced pressure and a second solvent is added, the second solvent being suitable for the halogenation of 1,4-bis(hydroxymethyl)-2,3,5,6-tetrafluorobenzene to a 4-(halomethyl)-2,3,5,6-tetrafluoro-benzyl alcohol. 9. A process according to claim 3 wherein the 1,4-bis(hydroxymethyl)-2,3,5,6-tetrafluorobenzene from step c) is extracted directly into a solvent that is also used in the halogenation of 1,4-bis(hydroxymethyl)-2,3,5,6-tetrafluorobenzene to a 4-(halomethyl)-2,3,5,6-tetrafluoro-benzyl alcohol. |
Medicament dispenser |
A medicament dispenser comprising: (i) a housing having an outlet; (ii) a medicament container locatable within said housing; (iii) an electronic dose counter associated with said outlet, wherein said dose counter comprises a first sensor for directly detecting a medicament release dispensible from said medicament container through said outlet is disclosed. |
1. A medicament dispenser comprising: (i) a housing having an outlet; (ii) a medicament container locatable within said housing; (iii) an electronic dose counter associated with said outlet, wherein said dose counter includes a first sensor comprising an emitter and a detector for detecting a medicament release dispensible from said medicament container through said outlet, characterized in that the detector detects electromagnetic radiation in the infra red range. 2. A medicament dispenser according to claim 1, wherein said emitter emits electromagnetic radiation in the infrared range. 3. A medicament dispenser according to claim 1 wherein the electromagnetic radiation has a wavelength in the range of 0.95 μm to 0.35 μm. 4. A medicament dispenser according to claim 3, wherein the electromagnetic radiation has a wavelength of about 0.88 μm. 5. A medicament dispenser according to claim 1, wherein the emitter is selected from the group consisting of light emitting diode and laser. 6. A medicament dispenser according to claim 1, wherein the emitter further comprises a filter. 7. A medicament dispenser according to claim 6, wherein the filter is an optical filter. 8. A medicament dispenser according to claim 7, wherein the optical filter is a polarising filter. 9. A medicament dispenser according to claim 1, wherein the detector is selected from the group consisting of photodiode, phototransistor, light dependent resistor and bolometer. 10. A medicament dispenser according to claim 9, wherein the detector further comprises a filter. 11. A medicament dispenser according to claim 10, wherein the filter is an electronic filter. 12. A medicament dispenser according to claim 10, wherein the filter is an optical filter. 13. A medicament dispenser according to claim 12, wherein the optical filter is a polarising filter. 14. A medicament dispenser according to claim 1, wherein the detector is associated with an amplifier. 15. A medicament dispenser according to claim 14, wherein the amplifier is positioned close to the detector. 16. A medicament dispenser according to claim 14, wherein the amplifier is integrated with the detector. 17. A medicament dispenser according to claim 1, wherein the detector detects an increase in radiation compared to the amount of radiation emitted by the emitter. 18. A medicament dispenser according to claim 1, wherein the detector detects a decrease in radiation compared to the amount of radiation emitted by the emitter. 19. A medicament dispenser according to claim 17, wherein the increase or decrease in detected radiation is due to interference of radiation reaching the detector by the medicament release. 20. A medicament dispenser according claim 19, wherein the interference is due to absorption of radiation by the medicament release. 21. A medicament dispenser according claim 19, wherein the interference is due to scattering of radiation by the medicament release. 22. A medicament dispenser according claim 19, wherein the interference is due to reflection of radiation by the medicament release. 23. A medicament dispenser according claim 19, wherein the interference is due to refraction of radiation by the medicament release. 24. A medicament dispenser according claim 19, wherein the interference is due to diffraction of radiation by the medicament release. 25. A medicament dispenser according to claim 1, wherein the amount of radiation reaching the detector is maintained at a constant level by using an electronic feedback circuit to alter the level of radiation emitted by the emitter. 26. A medicament dispenser according to claim 1, wherein the first sensor further comprises a reflector to reflect radiation from the emitter to the detector. 27. A medicament dispenser according to claim 1, wherein the emitter emits radiation of more than one wavelength and the detector detects radiation of more than one wavelength. 28. A medicament dispenser according to claim 27, wherein the first sensor quantifies the concentration of medicament with the medicament release by measuring radiation at more than one wavelength. 29. A medicament dispenser according to claim 1, wherein the dispenser additionally comprises a second sensor for detecting a medicament release. 30. A medicament dispenser according to claim 29, wherein the second sensor comprises an emitter and a detector. 31. A medicament dispenser according to claim 29, wherein the medicament release passes the second sensor subsequent to passing the first sensor. 32. A medicament dispenser according to claim 1, wherein the dispenser further comprises a third sensor. 33. A medicament dispenser according to claim 32, wherein the third sensor is sensitive to parameter selected from the group consisting of electromagnetic radiation, magnetic field, light, motion, temperature, pressure, sound, oxygen concentration, carbon dioxide concentration and moisture. 34. A medicament dispenser according to claim 32, wherein the third sensor responds to actuation of the dispenser. 35. A medicament dispenser according to claim 29, wherein the first and/or second sensors are integral with the outlet. 36. A medicament dispenser according to claim 29, wherein the first and/or second sensors are reversibly attachable to the outlet. 37. A medicament dispenser according to claim 32, wherein the third sensor is integral with the housing. 38. A medicament dispenser according to claim 32, wherein the third sensor is reversibly attachable to the housing. 39. A medicament dispenser according to claim 1, wherein the dose counter is reversibly attachable to the housing. 40. A medicament dispenser according to claim 1, wherein the first sensor is located on the dose counter. 41. A medicament dispenser according to claim 1, wherein the dispenser further comprises one or more optical wave guides. 42. A medicament dispenser according to claim 41, wherein the one or more optical wave guides are located on the housing. 43. A medicament dispenser according to claim 41, wherein the optical wave guide is composed of an organic polymeric or inorganic glass fibre material. 44. A medicament dispenser according to claim 41, wherein the medicament dispenser comprises a first and a second optical wave guide per sensor. 45. A medicament dispenser according to claim 44, wherein the first optical wave guide channels radiation from the emitter to the outlet. 46. A medicament dispenser according to claim 44, wherein the second optical wave guide channels radiation from the outlet to the detector. 47. A medicament dispenser according to claim 1, wherein the emitter and detector are located on the same side of the outlet. 48. A medicament dispenser according to claim 47, wherein the radiation emitted from the emitter is reflected back to the detector by a reflective surface on the opposite side of the outlet to the emitter and detector. 49. A medicament dispenser according to claim 48, wherein the reflective surface is a surface of the outlet or is an additional component attached thereto. 50. A medicament dispenser according to claim 47, wherein the emitter and detector are integrated into a single component. 51. A medicament dispenser according to claim 1, wherein the first sensor is controlled by a digital or computational semi-conductor device. 52. A medicament dispenser according to claim 51, wherein the digital or computational semi-conductor device energises the first sensor and associated electronic components to detect and respond to a medicament release every 10 to 100 ms. 53. A medicament dispenser according to claim 51, wherein the sensor and associated electronic components are energised for 5 to 30 μs. 54. A medicament dispenser according to claim 51, wherein the digital or computational semiconductor device returns the sensor to low power mode after energising the sensor. 55. A medicament dispenser according to claim 1, wherein the medicament container is an aerosol container. 56. A medicament dispenser according to claim 55, wherein the aerosol container comprises a suspension of medicament in a propellant. 57. A medicament container according to claim 56, wherein the propellant is selected from the group consisting of HFA134a, HFA227, carbon dioxide or a mixture thereof. 58. A medicament dispenser according to claim 55, wherein the aerosol container comprises a solution of medicament in a solvent. 59. A medicament dispenser according to claim 1, wherein the medicament container is a dry-powder container. 60. A medicament dispenser according to claim 59, wherein the dry-powder container comprises a medicament and optionally excipient in dry-powder form. 61. A medicament dispenser according to claim 1, wherein the dispenser is actuable manually by the patient. 62. A medicament dispenser according to claim 1, wherein the dispenser is actuable by the application of non-mechanical energy to a coupling element. 63. A medicament dispenser according to claim 1, wherein the dispenser is actuable by the application of mechanical energy to a coupling element. 64. A medicament dispenser according to claim 62, wherein the coupling element is one or more shape memory alloy wires. 65. A medicament dispenser according to claim 1, wherein the dispenser is actuable by the application of non-mechanical energy to a drive means. 66. A medicament dispenser according to claim 1, wherein the dispenser is actuable by the application of mechanical energy to a drive means. 67. A medicament dispenser according to claim 1, wherein the medicament container contains a medicament selected from the group consisting of albuterol, salmeterol, flucticasone propionate, beclomethasone dipropionate and salts and solvates and any mixtures thereof. 68. A medicament dispenser according to claim 1, wherein the outlet comprises a mouthpiece for inhalation therethrough. 69. A medicament dispenser according to claim 1, wherein the dispenser additionally comprises a communicator for communication to enable transfer of data from the dose counter to an electronic data management system. 70. A medicament dispenser according to claim 69, wherein the data management system is a local data management system. 71. A medicament dispenser according to claim 69, wherein the dispenser further comprises a communicator for wireless communication with a gateway to a network computer system to enable transfer of data between the network computer and the electronic data management system. 72. The use of a medicament dispenser as claimed in claim 1, for dispensing medicament to a patient. 73. A method of dispensing medicament to a patient, said method comprising the use of a medicament dispenser as claimed in claim 1. 74. A housing for receipt of a medicament container, the housing comprising: (i) an outlet for dispensing medicament therethrough; and (ii) an electronic dose counter associated with the outlet, wherein said dose counter includes a first sensor comprising an emitter and a detector for detecting a medicament release dispensible through said outlet, characterized in that the detector detects electromagnetic radiation in the infra red range. 75. A housing for receipt of a medicament container, the housing comprising: (i) an outlet for dispensing medicament therethrough; and (ii) a first and second strand of optical wave guide associated therewith, wherein said first and second strand of optical wave guide are associable with an electronic dose counter including a first sensor for detecting medicament release through said outlet. |
<SOH> BACKGROUND OF THE INVENTION <EOH>Medicaments for treating respiratory disorders are frequently administered as dry powder formulations through the mouth and nose. Dry powder inhalation devices, or inhalers, are used in the administration of these drugs, inhalation by the patient resulting in uptake of a specified dosage of medicament through the nose or mouth. The drug may be stored as a dry powder within a reservoir in the body of the inhaler, a metering chamber being utilised to administer a specified dose of medicament. Alternatively, more sophisticated inhalation devices employ medicament carriers, such as individual capsules or blister packs/strips containing defined doses of powdered drug. It is also known to use for such therapy medicaments which are contained in an aerosol and are administered to a patient by means of an inhalation device. The aerosol containers used in such inhalation devices are designed to deliver a predetermined dose of medicament upon each actuation and are known as Metered Dose Inhalers (MDIs); see Peter Byron, Respiratory Drug Delivery, CRC Press, Boca Raton, Fla. (1990) for a general background on this form of therapy. Mechanical and electrical dose indicating devices, which typically count the number of doses delivered from or remaining in the medicament dispenser, are frequently used in dry powder inhalers and MDIs to enable patients to determine how much medicament is available in the dispenser for future use. One problem associated with both mechanical and electrical dose counters is that they may, on occasions, give false readings. Thus the electronic dose counter disclosed in U.S. Pat. No. 5,020,527 employs a mechanical trigger, which may be actuated without release of the medicament, thereby giving a false reading. Other forms of triggers are also known, particularly the use of sensing means to detect actuation of the dispenser. U.S. Pat. No. 5,544,647 discloses a range of sensors which may be used to detect and record actuation of MDIs. Typical sensors include pressure switches which are sensitive to either physical contact with a movable element of the device or to the inward breath of the patient. Other examples include sensors which are responsive to light, such as reflected or emitted light, or optical sensors which recognise reference points on the container or housing. These sensors are designed to detect movement of the aerosol container following actuation of the device by being aligned to a reference point or a light source, such as a LED. Sensors which are responsive to electromagnetic radiation, such as fluctuations in electromagnetic fields caused by movement of the container, are also disclosed within this document. WO 95/07724 describes a dry powder inhaler with an electronic dose counter which employs a series of sensors to validate actuation of the inhaler. The inhaler uses magnetically responsive proximity reed switches to detect medicament loading within the device, and a thermistor sensor to detect temperature changes due to inhalation by the patient. A general problem encountered with dose counters in the art, such as those described above, is that they are dependent upon sensors which do not directly detect the medicament release from the dispenser. All of the sensors used in the art are arranged to sense some feature associated with actuation of the device, such as movement of the container/housing or pressure/temperature changes due to inhalation. This indirect method of sensing medicament release can lead to false readings being registered on the dose counter, if for example the sensor is activated without release of medicament. Accidental activation or triggering of the sensor may, for example, result from partial movement of the container or from interference with light received by the sensor. Similarly, a blockage or only partial release of the drug from either an MDI or dry powder inhaler would lead to a false reading registering on the dose counter. |
<SOH> SUMMARY OF INVENTION <EOH>It is an object of the present invention to provide direct sensing means by which release of a medicament can be detected and recorded on a dose counter. It is a further object of the present invention to provide a means of confirming or validating medicament release from a medicament dispenser. |
Latch device for securing cargo containers together and/or to vehicle decks |
A cargo container hold down device that includes a housing defined by a base which forms a planar surfacing thereabout on which cargo container corner fittings results in the applied relation on the container relative to the supporting structure or platform involved. The hold down device includes a flanged end which engages a cargo container corner casting aperture opening or an appropriate aperture and utilizes the structure for retention of the hold down device so the opposite side of the hold down device is allowed to automatically engage and disengage with a cargo container corner fitting as necessary to achieve proper handling and transport of cargo containers. |
1. A cargo container hold down arrangement for cargo containers of generally parallelepiped configuration, the four corners of the underside of which are each equipped with a corner fitting for purposes of securing the container to a support that is horizontally disposed, and with such container fittings being disposed in co-planar relation and respectively each defining a similar locking opening and a planar bearing surfacing that are respectively disposed adjacent such openings of the respective fittings, with a container securement device for each of the respective corner fittings for securing the cargo container to a platform, said securement devices each comprising: a shear block defining a front side, a top side, and a back side, with said shear block forming a base portion defining a planar force transmitting surfacing portion that extends to eitherside of the same, and a projecting portion that is generally normal to the planar bearing surfacing; said shear block further defining an internal chamber that in the projecting portion of said shear block is open at said front side of the same; said shear block base portion also defining a second force transmitting surfacing portion for engagement with such support, and including a latch member pivotally mounted in said chamber, for movement therein in a plane that is normally disposed relative to said front and rear sides of said shear block, and that is about a pivot axis that is normal of such plane; said latch member including a nose portion having an upper cam surfacing means for engagement by the bearing surfacing of a correspondingly located container mounted fitting, and an under cam surfacing means for engagement by the bearing surfacing of such correspondingly located container mounting fitting for removal of such container from such platform; resilient means for biasing said latch member to dispose said nose portion thereof exteriorly of said shear block opening in said front side thereof when said member cam surfacing means are not in use, said resilient means having, a resilient member interposed between said latch member and said base portion opposite the latch member tail portion; means for effecting deflection of said latch member about said pivot axis to within a housing on engagement of a container being lowered with said latch member nose upper cam surfacing means, and means for effecting deflection of said latch member within the housing on engagement of a correspondingly located container corner fitting of a container being removed from such platform and about a separate axis spaced frontwise from and parallel to said pivot axis of said latch member, said separate axis is disposed adjacent the level of said second force transmitting surfacing portion. 2. The securement device set forth in claim 1, wherein the top and back sides of said shear block are imperforate. 3. A container securement device for each respective corner fitting of a lower side of a cargo container of parallelepiped configuration for securing the cargo container to a platform, said securement device comprising: a shear block defining a front side, a top side, and a back side; said shear block forming a base portion defining a planar force transmitting surfacing portion that extends to either side of the same, and a projecting portion that is generally normal to the planar bearing surfacing; said shear block further defining an internal chamber that in the projecting portion of said shear block is open at said front side of the same; said shear block base portion also defining a second force transmitting surfacing portion for engagement with such support, and including a latch member pivotally, but unpinned, mounted in said chamber, for movement therein in a plane that is normally disposed relative to said front and rear sides of said shear block, and that is about a pivot axis that is normal of such plane; said latch member including a nose portion having an upper cam surface; said upper cam surface engaging a first bearing surfacing of a correspondingly located container mounted fitting, said latch member also including an under cam surface; said under cam surface engaging a second bearing surfacing of such correspondingly located container mounting fitting for removal of such container from such platform; a resilient member biasing said latch member to dispose said nose portion thereof exteriorly of said shear block opening in said front side thereof when said member cam surfaces are not in use; said resilient member being interposed between said latch member and said base portion opposite the latch member tail portion; a first deflector associated with said resilient member; said first deflector moving said latch member about said pivot axis to within a housing on engagement of a container being lowered with said latch member nose upper cam surface; a second deflector associated with said resilient member; said second deflector moving said latch member within the housing on engagement of a correspondingly located container corner fitting of a container being removed from such platform and about a separate axis spaced from and parallel to said pivot axis of said latch member. 4. A latch device for securing cargo containers comprising: a housing having a cavity opening and an internal pocket, a latch movably carried in the housing; a retainer holding a spring in place so as to urge said latch into a locked position; said latch is pivotally mounted in said chamber in an unpinned manner, for movement about a pivot axis, said latch has a projecting leg having a latch surface such that said latch pivots about said axis through motion within said internal housing pocket imparted through the contacting between latch first and second surfaces and an internal housing pocket at an under surfaces and over surface, respectively. 5. The latch device of claim 4 further comprising: said latch member including a nose portion having an upper cam surface; said upper cam surface adapted for engaging a bearing surfacing of a correspondingly located container mounted fitting, and an under cam surface; said under cam surface adapted for engaging a surface of a container mounting fitting for removal of such container from a platform. 6. The latch device of claim 5 further comprising: said housing, latch, retainer and spring being held together in relation to one another so that said latch is first inserted into a cavity opening of said housing and then positioned into said internal pocket. 7. The latch device of claim 6 further comprising: said spring is mounted in said cavity opening of said housing with a first end of the spring being positioned on a protrusion of said latch and the opposite end of said spring abutting said retainer in said cavity opening. 8. The latch device of claim 7 further comprising: said latch device is assembled with an appropriate assembly force is applied to said retainer compressing said spring so as to push retainer into cavity opening past first and second tabs and and four internal nubs; said retainer is then rotated to become aligned with said first and second tabs and said four internal nubs wherein the assembly force that has been applied to said retainer is removed thereby resulting in said retainer backing out of said housing cavity and bearing against said tabs which prevents complete removal of said retainer. 9. The latch device of claim 8 further comprising: said four internal nubs trap said retainer in a desired position holding the parts together and preventing said retainer from rotating and inadvertently aligning itself with said housing cavity thereby allowing the parts to come loose. 10. The latch device of claim 4 further comprising: an integral attachment adapted to receive a tether to be attached to said housing to secure said latch device to a deck of a vehicle to deter theft or loss of said latch device when it is desired for it to be removed from an appropriate structure and surface from a vehicle deck but yet remain with the vehicle. 11. The latch device of claim 4 further comprising: said latch device operates in absence of any pin, bolt or fastener retaining said latch in said housing. 12. The latch device of claim 11 further comprising: said latch has a substantially vertical line of action corresponding to the line of clearance of the container corner casting with said nose of said latch; said latch is contoured and functionally matched to fit within the internal contours of said housing and is be restrained therein by the resulting geometry, such that latch surface contacts and pivots in internal housing pocket at said undersurface and said undersurface is displaced as far away and to the left of said line of action thereby minimizing the mechanical force advantage of said spring during the engagement motion of the corner casting, thereby aiding in obtaining low applied forces and smooth engagement motion of latch. 13. The latch device of claim 12 further comprising: said device is a deck mountable device. 14. The latch device of claim 12 further comprising: said device has a twist lock container engagement. 15. The latch device of claim 12 further comprising: said device is one of a class of deck mounted or twist lock devices. |
<SOH> BACKGROUND OF THE INVENTION <EOH>The invention relates to container securement devices, and more particularly, to improvements in cargo container securement devices of the type that provides automatic securement and release of a cargo container. The device is mountable and demountable on a deck or frame of a vehicle so that the device can be adapted to different load conditions including a different mix of containers of different length and the like while having unused devices not interfere with the flush mounting of long containers. |
<SOH> BRIEF DESCRIPTION OF THE PREFERRED EMBODIMENT <EOH>A device for securing cargo containers to a vehicle deck and/or two cargo containers together comprising a housing containing a latch mechanism that extends outwardly from the housing to engage a cargo container corner casting. The other side of the housing has two flanges projecting therefrom in a generally “T” shaped plan form. In the case where two cargo containers are to be secured together, the flanges are inserted into the aperture of a cargo containers corner fitting manually and oriented in such a manner as to prevent its removal. The appropriate corner fitting of the other cargo container is brought into contact with the exposed end of the device's latch mechanism that extends outwardly from the housing to engage the cargo container corner casting and secure the two cargo containers together. When appropriate force is exerted to pull the two cargo containers apart, the devices latch mechanism that extends outwardly from the housing will automatically retract into the devices housing allowing the two cargo containers to be separated. In the case where a cargo container is to be secured to a deck or frame of a vehicle, the flanges are inserted into the aperture of a deck or frame of a vehicle manually and oriented in such a manner as to prevent its removal. The appropriate corner fitting of the cargo container is brought into contact with the exposed end of the device latch mechanism that extends outwardly from the housing to engage the cargo container corner casting and secure it to the deck or frame of a vehicle. When appropriate force is exerted to pull the cargo container off of the deck, the devices latch mechanism that extends outwardly from the housing will automatically retract into the devices housing allowing the cargo container to be removed. |
Telephone directory assistane method and telephone directory assistance system |
This telephone directory assistance system accepts a request for a telephone number of a registrant, and judges whether the registrant is registered in a telephone number data base. When the registrant is registered in the telephone number data base, the telephone directory assistance system judges whether a message from the inquirer is transmitted to the registrant without informing the telephone number to the inquirer based on a telephone number disclosing condition registered in the telephone number data base. Then, in a case of transmission, the inquirer is caused to input a message and the inputted message is informed to the registrant. |
1. A method for informing a telephone number of a registrant to an inquirer, comprising: accepting a request for a telephone number of the registrant from the inquirer; judging whether the registrant is registered in a telephone number data base; judging whether an information from the inquirer is transmitted to the registrant at least without informing the telephone number of the registrant to the inquirer, corresponding to a disclosing condition registered in the data base when the registrant is registered in the telephone number data base; and causing the inquirer to input information and the registrant to be capable of being informed of the input information when informing the telephone number of the registrant. 2. The method according to claim 1, wherein the method includes requesting the inquirer for a message as the information, recording the message and causing the recorded message to be capable of being played back to the registrant. 3. The method according to claim 2, wherein the method includes calling the registrant and notifying the recorded message to the registrant when a terminal of the registrant is a conventional telephone set. 4. The method according to claim 2, wherein the method includes notifying the registrant that the message is recorded and causing the registrant to access the recorded message when a terminal of the registrant is a cellular phone. 5. The method according to claim 1, wherein the method includes requesting the inquirer for a message in a form of a character signal inputted by a push button operation as the information and informing the inputted message to the registrant. 6. The method according to claim 5, wherein the inputted message is converted to an audible sound and informing the registrant of the audible sound. 7. The method according to claim 1, wherein the method includes requesting the inquirer to transmit an e-mail as the information and causing the registrant to receive the transmitted e-mail. 8. The method according to any one of claims 1 to 7, being capable of setting one of a first condition and a second condition for each of the registrants, the first condition always informing the telephone number, the second condition always refusing to inform the telephone number in response to the request for the telephone number from the inquirer, as the disclosing condition registered in the data base. 9. The method according to any one of claims 1 to 7, wherein the request for the telephone number of the registrant is accepted by accessing an old telephone number of the registrant. 10. A system informing a telephone number of a registrant to an inquirer, comprising: a data base in which at least a telephone number of a registrant and a disclosing condition on whether an information from the inquirer is transmitted to the registrant without informing the telephone number to the inquirer, are corresponding to each other; and means for informing the information from the inquirer to a terminal of the registrant. 11. The system according to claim 10, wherein the informing means records a message as the information from the inquirer, and cause the recorded message to be capable of being played back to the registrant. 12. The system according to claim 11, wherein the terminal of the registrant is a conventional telephone set, and wherein the informing means calls the registrant and notify the recorded message to the registrant. 13. The system according to claim 11, wherein the terminal of the registrant is a cellular phone, and wherein the informing means notifies the registrant that the message is recorded and cause the registrant to access for playback of the recorded message from the cellular phone. 14. The system according to claim 10, wherein the informing means informs the registrant of a message in a form of a character signal inputted by a push button operation as the information from the inquirer. 15. The system according to claim 14, wherein the inputted message is converted to an audible sound and the audible sound is informed to the registrant. 16. The system according to claim 10, the informing means informs the registrant of a message in a form of an e-mail as the information from the inquirer. 17. The system according to any one of claims 10 to 16, wherein the system is capable of setting one of a first condition and a second condition for each of the registrants, the first condition always informing the telephone number, the second condition always refusing to inform the telephone number in response to the request for the telephone number from the inquirer, as the disclosing condition registered in the data base. 18. The system according to any one of claims 10 to 16, wherein the telephone number of the registrant and the telephone number of the inquirer are corresponds to each other in the data base, and the system further comprising: means for accepting a request for a telephone number of the registrant from the inquirer; means for judging whether the registrant is registered in the telephone number data base; means for judging whether the information from the inquirer is transmitted to the registrant at least without informing the telephone number of the registrant to the inquirer, corresponding to a disclosing condition registered in the data base when the registrant is registered in the telephone number data base; means for causing the inquirer to input information and the registrant to be capable of being informed of the inputted information when informing the telephone number of the registrant. 19. The method according to claim 8, wherein the request for the telephone number of the registrant is accepted by accessing an old telephone number of the registrant. 20. The system according to claim 17, wherein the telephone number of the registrant and the telephone number of the inquirer are corresponds to each other in the data base, and the system further comprising: means for accepting a request for a telephone number of the registrant from the inquirer; means for judging whether the registrant is registered in the telephone number data base; means for judging whether the information from the inquirer is transmitted to the registrant at least without informing the telephone number of the registrant to the inquirer, corresponding to a disclosing condition registered in the data base when the registrant is registered in the telephone number data base; means for causing the inquirer to input information and the registrant to be capable of being informed of the inputted information when informing the telephone number of the registrant. |
<SOH> BACKGROUND ART <EOH>In the telephone directory assistance service of this kind, a person, who owns his/her telephone number (registrant), can select disclosure or private. For example, when a certain registrant does not want to make his/her telephone number known to others, the registrant registers his/her telephone number as private and this prevents the telephone number from being known by others via the telephone directory assistance service, so that the registrant's privacy is protected. |
<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG. 1 is a view showing the schematic entire configuration of a first embodiment to which the present invention is applied; FIG. 2 is a view showing the configuration of a telephone number data base; FIG. 3 is a view showing the configuration of a message box; FIG. 4 is a view showing the entire configuration of this system including an information processing unit; FIG. 5 is a flowchart (No.1) showing an operation when an inquirer gains access to an old telephone number and automatically receives service from the system; FIG. 6 is a flowchart (No.2) showing an operation when an inquirer gains access to an old telephone number and automatically receives service from the system; FIG. 7 is a flowchart (No. 3) showing an operation when an inquirer gains access to an old telephone number and automatically receives service from the system; FIG. 8 is a schematic diagram showing the entire configuration of a second embodiment of the present invention; FIG. 9 is a block diagram showing the configuration of a changer data base; FIG. 10 is a block diagram showing the configuration of an inquirer data base; FIG. 11 is a schematic block diagram showing an address inquiry system; FIG. 12 is a flowchart showing the registration process of changer information; FIG. 13 shows an example of an interface screen for explaining the registration of the changer information; FIG. 14 shows an example of the interface screen for explaining the registration of the changer information; FIG. 15 shows an example of the interface screen for explaining the registration of the changer information; FIG. 16 shows an example of the interface screen for explaining the registration of the changer information; FIG. 17 shows an example of the interface screen for explaining the registration of the changer information; FIG. 18 is a first flowchart showing the process of registration of inquirer information and inquiry about a new address; FIG. 19 shows an example of an interface screen for explaining the registration of inquirer information; FIG. 20 shows an example of the interface screen for explaining the registration of the inquirer information; FIG. 21 shows an example of the interface screen for explaining the registration of the inquirer information; FIG. 22 shows an example of the interface screen for explaining the registration of the inquirer information; FIG. 23 is a block diagram showing the configuration of an inquirer terminal in which special-purpose software for inquiry is installed; FIG. 24 is a second flowchart showing registration of inquirer information and the process of inquiry about the new address; FIG. 25 shows an example of an interface screen for explaining the inquiry process in which the special-purpose software for inquiry is used; FIG. 26 shows an example of the interface screen for explaining the inquiry process in which the special-purpose software for inquiry is used; FIG. 27 shows an example of the interface screen for explaining the inquiry process in which the special-purpose software for inquiry is used; FIG. 28 shows an example of the interface screen for explaining the inquiry process in which the special-purpose software for inquiry is used; FIG. 29 is a third flowchart showing the process of registration of inquirer information and inquiry about the new address; FIG. 30 shows an example of an interface screen for explaining an inquiry operation by an address inquiry system; FIG. 31 shows an example of the interface screen for explaining the inquiry operation by the address inquiry system; FIG. 32 shows an example of the interface screen for explaining the inquiry operation by the address inquiry system; FIG. 33 shows an example of the interface screen for explaining the inquiry operation by the address inquiry system; FIG. 34 shows an example of the interface screen for explaining the inquiry operation by the address inquiry system; FIG. 35 shows an example of the interface screen for explaining the inquiry operation by the address inquiry system; FIG. 36 shows an example of the interface screen for explaining the inquiry operation by the address inquiry system; FIG. 37 shows an example of an interface screen for explaining another embodiment of the present invention; FIG. 38 shows an example of the interface screen for explaining the inquiry operation by the address inquiry system; and FIG. 39 shows an example of the interface screen for explaining the inquiry operation by the address inquiry system. detailed-description description="Detailed Description" end="lead"? |
Software development |
A method of developing software capable of performing a task is disclosed. The task comprises at least one task step required to perform the task. The task step has a resultant effect. The method comprises: recording a use case comprising one or more scenarios, the or each scenario comprising one or more further steps; recording said scenario or one of said scenarios as a main success scenario such that the resultant effect of said main success scenario is the same as the resultant effect of said task step. Also disclose is the re-use of use cases which have been stripped of context-specific information. Such information may be included in a reference to the re-used use case. |
1. A method of developing software capable of performing a task, said task comprising at least one task step required to perform said task, the task step having a resultant effect, wherein the method comprises: recording a use case comprising one or more scenarios, the or each scenario comprising one or more further steps; recording said scenario or one of said scenarios as a main success scenario such that the resultant effect of said main success scenario is the same as the resultant effect of said task step. 2.-63. (canceled) |
Bridge for attaching auxiliary lenses |
An auxiliary spectacle apparatus is provided wherein auxiliary lenses have a mechanical bridge fastener for releasably engaging the bridge portion of the primary frames in a manner which provides security of attachment in all directions. |
1-21. (canceled) 22. An auxiliary spectacle apparatus, comprising: (a) two auxiliary lenses; (b) a hole in each lens; (c) an auxiliary bridge extending between and connecting said auxiliary lenses to each other; (d) an attachment for attaching said auxiliary bridge to a primary spectacle; and (e) lens rivets extending from said auxiliary bridge through said holes to secure said lenses to said bridge; wherein said lens rivets extend rearward from said auxiliary bridge. 23. An auxiliary spectacle apparatus as claimed in claims 22, wherein said auxiliary bridge is Polyflex™ plastic or memory plastic. 24. An auxiliary spectacle apparatus as claimed in claim 22, wherein said lens rivets terminate in a bulb. 25. An auxiliary spectacle apparatus as claimed in claim 22, further comprising at least two holes in each lens and at least two lens rivets extending from each side of said auxiliary bridge through said holes to secure said lenses to said bridge. 26. An auxiliary spectacle bridge as claimed in claim 22, wherein said lens rivets terminate in a cap. 27. An auxiliary spectacle bridge, comprising a bridge having: (a) lateral ends; (b) an attachment for attaching said auxiliary spectacle to a primary spectacle; and (c) lens rivets extending horizontally from said lateral ends; wherein said lens rivets extend rearward from said auxiliary bridge. 28. An auxiliary spectacle bridge as claimed in claim 27, wherein said auxiliary bridge is Polyflex™ or memory plastic. 29. An auxiliary spectacle bridge as claimed in claim 27 wherein said lens rivets terminate in a bulb. 30. An auxiliary spectacle bridge as claimed in claim 27, wherein said lens rivets terminate in a cap. 31. A spectacle bridge and lenses comprising: (a) two lenses; (b) a bridge having: (i) lateral ends; (ii) lens rivets extending horizontally from said lateral ends; wherein said lens rivets have a distal end of said lens rivet spread against said lenses. 32. An spectacle bridge as claimed in claim 31, wherein said lens rivets extend rearward from said bridge. 33. An spectacle bridge as claimed in claim 31, wherein said bridge is a bridge for auxiliary spectacles. 34. A spectacle apparatus, comprising: (a) a primary frame adapted for fitting on a wearer's head, said primary frame having a primary bridge medial in said primary frame; (b) a ridge extending forward from said primary bridge; (c) two auxiliary lenses; (d) an auxiliary bridge extending between and connecting said auxiliary lenses to each other; (e) an upper projection extending rearward from said auxiliary bridge and a lower projection extending rearward from said auxiliary bridge; wherein said upper projection and said lower projection of said auxiliary bridge are configured such that there is an upper face, a lower face, and lateral faces, collectively configured to form a snug interference with said ridge which is correspondingly configured. 35. A spectacle apparatus as claimed in claim 34, comprising said protrusions on both said projections, said protrusions configured for releasably engaging said primary bridge. 36. A spectacle apparatus as claimed in claim 34 wherein said ridge has a ridge face which extends laterally and said auxiliary bridge has an rearward auxiliary bridge face which extends laterally and said faces are configured such that an interference fit between said faces prevents rotation between said primary spectacle and said auxiliary bridge. 37. A spectacle apparatus as claimed claim 34, wherein said protrusion is beveled. 38. A spectacle apparatus, comprising: (a) a primary frame adapted for fitting on a wearer's head, said primary frame having a primary bridge medial in said primary frame; (b) a ridge extending forward from said primary bridge; (c) two auxiliary lenses; (d) an auxiliary bridge extending between and connecting said auxiliary lenses to each other; (e) an upper projection extending rearward from said auxiliary bridge and a lower projection extending rearward from said auxiliary bridge and at least one said projection is elastic; and (f) at least one protrusion on at least one of said projections; wherein the lateral shape of said projections and the corresponding lateral shape of said ridge prevents horizontal movement of the apparatus when assembled. 39. A spectacle apparatus as claimed in claim 38, comprising said protrusions on both said projections, said protrusions configured for releasably engaging said primary bridge. 40. A spectacle apparatus as claimed in claim 38 wherein said ridge has a ridge face which extends laterally and said auxiliary bridge has an rearward auxiliary bridge face which extends laterally and said faces are configured such that an interference fit between said faces prevents rotation between said primary spectacle and said auxiliary bridge. 41. A spectacle apparatus as claimed in claim 38, wherein said protrusion is beveled. |
<SOH> BACKGROUND OF THE INVENTION <EOH>A spectacle frame having an attachable one-piece slide-on rim is disclosed in U.S. Pat. No. 4,070,103 to Meeker. In Meeker, a spectacle frame includes a magnetic material secured to the front face of the frame for facilitating attachment of an auxiliary frame. The lens rim cover also includes a magnetic strip for engaging with the magnetic material of the spectacle frame. Other typical auxiliary eyeglass attachments are disclosed in U.S. Pat. No. 5,416,537 to Sadler, U.S. Pat. No. 5,737,054 to Chao, U.S. Pat. No. 5,975,961 to Ku, Canadian patent application No. 2,180,714 to Chao, Canadian patent application No. 2,235,897 to Chao, Canadian patent application No. 2,236,025 to Ku, Canadian patent application No. 2,223,088 to Madison, U.S. Pat. No. 5,568,207 to Chao, Canadian patent No. 2,223,295 to Chao, German patent application No. DE 43 16 698 to Karp, PCT application No. WO 026718 to Zelman, Canadian patent application No. 2,235,917 to Chao, U.S. Pat. No. 6,053,611 to Ku, U.S. Pat. No. 6,542,177 to Nishioka, and PCT application no. WO 9009611 to Stemme. In all cases, the auxiliary lenses are attached to the frames by magnetic materials. The use of magnets to attach auxiliary lenses has several drawbacks. The strength of magnets weakens over time. In addition, magnetic attachment means are only effective in association with selected metal frames, unless magnets are embedded in the frames of the eyeglasses. This requires cavities in the frames for engaging with the magnetic members such that the strength of the frames comprised. Also, there is some literature which suggests that magnets placed near the body may alter body chemistry or physiology. U.S. Pat. No. 6,053,611 to Ku teaches auxiliary glasses with magnets located on upper and lower flanges which extend backwardly to the primary bridge, which is also equipped with upper and lower magnets corresponding to the auxiliary glasses magnets. The insertion of four magnets into this confined space is difficult and therefor costly. Also, as discussed above, there are several other drawbacks associated with the use of magnets in eyeglasses. As the strength of the magnets weakens, the design taught by Ku will become ineffective. One magnet-free method of attaching auxiliary lenses that has attempted to address these problems is the ColorClip™ system. This system provides for holes drilled at various places around the outer perimeter of the auxiliary lenses. Soft plastic clips are then inserted into the holes. A similar system, ECLIPS, requires that the lenses be scored, coated with primer and glue, and rely on metal clips on the auxiliary spectacles. In both systems, the clips engage the primary spectacles. The use of these clip systems creates the risk that drilling, scoring, gluing or attaching the clips will damage the auxiliary lenses in positions, such as the upper, lower and lateral portions of the lenses, that tend to impair vision. Furthermore, each auxiliary lens must be separately attached to and removed from the primary frames. In use, the presence of the clips on the lenses may obscure vision. Also, many wearers consider the clips to be unsightly or unappealing. Thus, it would be desirable to have a means for attaching auxiliary lenses to primary spectacles which did not rely on magnets, and did not require placement of clips on the lenses. |
<SOH> SUMMARY OF THE INVENTION <EOH>The present invention provides a spectacle apparatus having: (a) a primary frame adapted for fitting on a wearer's head, the primary frame having a primary bridge medial in the primary frame; (b) a ridge extending forward from the primary bridge; (c) an indentation on a horizontal surface on the ridge; (d) two auxiliary lenses; (e) an auxiliary bridge extending between and connecting the auxiliary lenses to each other; and (f) an upper projection extending rearward from the auxiliary bridge and a lower projection extending rearward from the auxiliary bridge and (g) at least one protrusion on at least one of the projections, the protrusion configured for releasably inserting into the indentation, and the at least one the projection is elastic. In one embodiment the spectacle apparatus has protrusions on both the projections, and the protrusions are configured for releasably inserting into at least one indentation on the ridge. In another embodiment, there are protrusions on both the projections, and the protrusions extend laterally in correspondence with at least one the indentation for releasably inserting into the indentation. In a further embodiment, the at least one protrusion extends laterally in correspondence with the indentation for releasably inserting into the indentation. In another embodiment, the indentation on the ridge extends laterally. The indentation on the ridge can be a hole through the ridge. In an embodiment, the ridge has a ridge vertical face which extends laterally and the auxiliary bridge has a rearward vertical auxiliary bridge face which extends laterally and the faces are configured such that an interference fit between the faces prevents horizontal rotation between the primary spectacle and the auxiliary bridge. In another embodiment, the ridge has a horizontal ridge face which extends laterally and at least one projection has a projection face which extends laterally and the faces are configured such that an interference fit between the faces prevents vertical rotation between the primary spectacle and the auxiliary bridge. In a further embodiment, the ridge has a horizontal ridge face which extends laterally and at least one projection has a projection face which extends laterally and the faces are configured such that an interference fit between the faces prevents vertical rotation between the primary spectacle and the auxiliary bridge. The protrusion may be beveled. The auxiliary bridge may be made from Polyflex™ plastic or memory plastic. The invention also provides an auxiliary spectacle apparatus, comprising: (a) two auxiliary lenses; (b) a hole in each lens; (c) an auxiliary bridge extending between and connecting the auxiliary lens to each other; (d) an attachment for attaching the auxiliary spectacle to a primary spectacle; and (e) lens rivets extending from the auxiliary bridges through the holes to secure the lenses to the bridge. In a further embodiment, the lens rivets extend rearward from the auxiliary bridge. The lens rivets may terminate in a bulb. The lens rivets may terminate in a cap. The invention also provides an auxiliary spectacle bridge, comprising a bridge having: (a) lateral ends; (b) an attachment for attaching the auxiliary spectacle to a primary spectacle; and (c) lens rivets extending horizontally from the lateral ends. In a further embodiment, the lens rivets extend rearward from the auxiliary bridge. |
Means for detecting pathological transformation of the app protein and their uses |
A method of intra-articular drug delivery may include selecting an attachment zone in a synovial joint; affixing a drug release device in the attachment zone, the drug release device comprising a base affixable in the attachment zone, a sustained-release drug carrier, and a drug, the device positioned so that the device releases the drug into the synovial fluid of the synovial joint, and so that agitation of the synovial fluid facilitates elution of the drug from the drug release device. |
1. A method of intra-articular drug delivery, comprising: selecting an attachment zone in a synovial joint; and affixing a drug release device in the attachment zone, the drug release device comprising a base affixable in the attachment zone, a sustained-release drug carrier, and a drug, the device positioned so that the device releases the drug into the synovial fluid of the synovial joint, and so that agitation of the synovial fluid facilitates elution of the drug from the drug release device. 2. The method of claim 1, wherein the attachment zone comprises a non-articulating portion of bone and/or cartilage within the synovial joint. 3. The method of claim 2, further comprising removing the bone and/or cartilage in the attachment zone to create a void, and so inserting the drug release device into the void that at least one surface of the drug release device is in communication with the synovial fluid. 4. The method of claim 3, wherein the drug release device is so inserted that its surface in communication with the synovial fluid is about flush with surrounding bone and/or cartilage. 5. The method of claim 2, wherein the attachment zone comprises a band of bone and/or cartilage adjacent to an articulating surface within the synovial joint. 6. The method of claim 5, wherein the band extends from about 0.5 millimeters to about 1 centimeter away from the articulating surface. 7. The method of claim 5, further comprising removing the bone and/or cartilage in the attachment zone to create a void, and so inserting the drug release device into the void that at least one surface of the drug release device is in communication with the synovial fluid. 8. The method of claim 7, wherein the drug release device is so inserted that its surface in communication with the synovial fluid is about flush with surrounding bone and/or cartilage. 9. The method of claim 1, wherein the synovial joint is a hip joint, and the attachment zone comprises a non-articulating portion of bone and/or cartilage within the hip. 10. The method of claim 9, wherein the attachment zone comprises a band of bone and/or cartilage adjacent to at least one of a femoral head, and an acetabulum. 11. The method of claim 1, wherein the synovial joint is a knee joint, and the attachment zone comprises a non-articulating portion of bone and/or cartilage within the knee. 12. The method of claim 11, wherein the attachment zone comprises a band of bone and/or cartilage adjacent to at least one of a tibial plateau, a femoral condyle, a patellofemoral area, the medial rim of a femoral trochlea, the lateral rim of a femoral trochlea, and the periphery of an intercondylar notch. 13. The method of claim 1, wherein the synovial joint is a shoulder joint, and the attachment zone comprises a non-articulating portion of bone and/or cartilage within the shoulder. 14. The method of claim 13, wherein the attachment zone comprises a band of bone and/or cartilage adjacent to at least one of the anatomical neck of a humerus, a glenoid cavity, and a glenoid neck. 15. The method of claim 1, wherein the synovial joint is an arthroplastic joint comprising at least one prosthesis, and the attachment zone comprises a non-articulating portion of bone and/or cartilage within the joint. 16. The method of claim 15, wherein the attachment zone comprises a band of bone and/or cartilage adjacent to the at least one prosthesis. 17. The method of claim 1, wherein the drug release device is forcefully injected by gun. 18. The method of claim 1, wherein the drug release device comprises threads on its outer surface, and the drug release device is affixed by drilling a hole in the attachment zone and screwing the drug release device into the hole. 19. A method of intra-articular drug delivery, comprising: step for selecting a para-articular attachment zone in a synovial joint; step for creating a void in the para-articular attachment zone; and step for implanting in the void a drug-release means for sustainedly releasing a drug into the synovial fluid of the synovial joint. 20. A sustained-release intra-articular drug delivery device, comprising: a base, so sized and shaped as to be affixable in an attachment zone of a synovial joint; and a sustained-release drug carrier coupled to the base, the carrier including a drug, the carrier so formed as to elute the drug into synovial fluid, upon implantation of the device in a joint, sufficient to sustain a therapeutically effective concentration of the drug in the synovial fluid for at least 8 hours. |
<SOH> INTRODUCTION <EOH>Pain and disability from arthritis, joint degeneration, and surgery have been treated by a combination of oral medications or intra-articular injections of steroid compounds designed to reduce inflammation. In addition, other devices, such as hyaluronic acid products, have been injected to provide visco-supplementation. Unfortunately, these approaches have significant systemic side effects or are not effective for extended periods of time. In order to provide local or regional blockade for extended periods, clinicians currently use local anesthetics administered through a catheter or syringe to a site where the pain is to be blocked. This requires repeated administration where the pain is to be blocked over a period of greater than one day, either as a bolus or through an indwelling catheter connected to an infusion pump. These methods have the disadvantage of potentially causing irreversible damage to nerves or surrounding tissues due to fluctuations in concentration and high levels of anesthetic. In addition, anesthetic administered by these methods are generally neither confined to the target area, nor delivered in a linear, continuous manner. In all cases, analgesia rarely lasts for longer than six to twelve hours, more typically four to six hours. In the case of a pump, the infusion lines are difficult to position and secure, the patient has limited, encumbered mobility and, when the patient is a small child or mentally impaired, they may accidentally disengage the pump. In part, this disclosure describes implantable devices that may be used to deliver drugs to a joint. |
<SOH> SUMMARY <EOH>In one aspect, this disclosure describes devices and methods for delivering drugs to the synovial fluid of a joint by locally implanting a drug delivery device. In certain embodiments, the device is positioned in such a way that agitation of synovial fluid facilitates elution of the drug from the device. In one aspect, a method of intra-articular drug delivery includes selecting an attachment zone in a synovial joint and affixing a drug release device in the attachment zone. Exemplary suitable attachment zones include intra-articular regions of the synovial joint where there is no interfacing articular cartilage. In certain instances, an attachment zone may include intra-articular regions of bone that are non-load-bearing and optionally removed from the articulation surface. In certain embodiments, the drug release device includes a base affixable in the attachment zone, a sustained-release drug carrier, and a drug. The device may be positioned, in certain applications, so that the device releases the drug into the synovial fluid of the synovial joint, and further, so that agitation of the synovial fluid may facilitate elution of the drug from the drug release device. In a further aspect, a method of providing a therapeutic to a skeletal articulation includes identifying a safe zone of the articulation and coupling a therapeutic elution apparatus in the safe zone. Exemplary safe zones include non-load-bearing regions in or around the articulation. In certain embodiments, the therapeutic elution apparatus includes a body couplable in the safe zone, and a therapeutic dispersed in a controlled-release binder. The apparatus may be positioned, in certain applications, so that it releases the therapeutic into the articulation environment. In another aspect, a drug delivery device includes a base and a sustained-release drug carrier coupled to the base. In certain embodiments, the base may be so sized and shaped as to be capable of affixation in an attachment zone of a synovial joint. Typically, the carrier includes a drug to be eluted in vivo, often into the synovial fluid upon implantation of the device in a joint. In certain applications, the carrier may be so formed as to elute the drug into synovial fluid sufficient to sustain a therapeutically effective concentration of the drug in the synovial fluid for at least 8 hours. In yet another aspect, a wide range of therapeutic drugs are contemplated, including but limited to antiinflammatories, antiinfectives, analgesics, and anesthetics. A wide range of drug carrier materials are contemplated, including but not limited to polymers, such as polytetrafluoroethylene, polyfluorinated ethylenepropylene, polylactic acid, polyglycolic acid, silicone, and mixtures thereof. In still another aspect, a drug delivery device may be delivered by a wide variety of methods, such as by placement into a drill site, or forceful injection by gun. In an embodiment, a method of intra-articular drug delivery may include selecting an attachment zone in a synovial joint, and affixing a drug release device in the attachment zone, the drug release device comprising a base affixable in the attachment zone, a sustained-release drug carrier, and a drug, the device positioned so that the device releases the drug into the synovial fluid of the synovial joint, and so that agitation of the synovial fluid facilitates elution of the drug from the drug release device. In any preceding embodiment, the attachment zone may include a non-articulating portion of bone and/or cartilage within the synovial joint. Any preceding embodiment may further include removing the bone and/or cartilage in the attachment zone to create a void, and so inserting the drug release device into the void that at least one surface of the drug release device is in communication with the synovial fluid. In any preceding embodiment, the drug release device may be so inserted that its surface in communication with the synovial fluid is about flush with surrounding bone and/or cartilage. In any preceding embodiment, the attachment zone may include a band of bone and/or cartilage adjacent to an articulating surface within the synovial joint. In any preceding embodiment, the band may extend from about 0.5 millimeters to about 1 centimeter away from the articulating surface. In any preceding embodiment, the synovial joint may be a hip joint, and the attachment zone may include a non-articulating portion of bone and/or cartilage within the hip. In any preceding embodiment, the attachment zone may include a band of bone and/or cartilage adjacent to at least one of a femoral head, and an acetabulum. In any preceding embodiment, the synovial joint may be a knee joint, and the attachment zone may include a non-articulating portion of bone and/or cartilage within the knee. In any preceding embodiment, the attachment zone may include a band of bone and/or cartilage adjacent to at least one of a tibial plateau, a femoral condyle, a patellofemoral area, the medial rim of a femoral trochlea, the lateral rim of a femoral trochlea, and the periphery of an intercondylar notch. In any preceding embodiment, the synovial joint may be a shoulder joint, and the attachment zone comprises a non-articulating portion of bone and/or cartilage within the shoulder. In any preceding embodiment, the attachment zone may include a band of bone and/or cartilage adjacent to at least one of the anatomical neck of a humerus, a glenoid cavitym and a glenoid neck. In any preceding embodiment, the synovial joint may be an arthroplastic joint comprising at least one prosthesis, and the attachment zone comprises a non-articulating portion of bone and/or cartilage within the joint. In any preceding embodiment, wherein the attachment zone may include a band of bone and/or cartilage adjacent to the at least one prosthesis. In any preceding embodiment, the drug release device may be forcefully injected by gun. In any preceding embodiment, the drug release device may include threads on its outer surface, and the drug release device may be affixed by drilling a hole in the attachment zone and screwing the drug release device into the hole. In any preceding embodiment, the drug release device may include a base, so sized and shaped as to be affixable in an attachment zone of a synovial joint, and a sustained-release drug carrier coupled to the base, the carrier including a drug, the carrier so formed as to elute the drug into synovial fluid, upon implantation of the device in a joint, sufficient to sustain a therapeutically effective concentration of the drug in the synovial fluid for at least 8 hours. |
Food grade transglutaminase inhibitor and uses thereof |
Transglutaminase inhibitor containing composition obtainable from milk, in particular from a whey fraction obtainable from skimmed milk by forming a curd from the milk, separating the curd from the whey in a centrifugation step followed by subjecting the whey to an ultrafiltration step or, alternatively, by subjecting the skimmed milk to a diafiltration step, a method for the production of a transglutaminase inhibitor and the use of the transglutaminase inhibitor in the production of food or pharmaceutical compositions and to the use in the preparation of a medicament for the treatment of pathologies. |
1. Transglutaminase inhibitor containing composition obtainable from milk. 2. Transglutaminase inhibitor containing composition according to claim 1 obtainable from a whey fraction obtainable from skimmed milk by forming a curd from the milk, separating the curd from the whey in a centrifugation step followed by subjecting the whey to an ultrafiltration step. 3. Transglutaminase inhibitor containing composition according to claim 1, obtainable by subjecting skimmed milk to a diafiltration step. 4. Transglutaminase inhibitor according to claim 26, wherein the filtrate obtained from the ultrafiltration step or from the diafiltration step is further subjected to a concentration step. 5. Transglutaminase inhibitor according to claim 2, wherein the concentration step comprises lyophilisation. 6. Transglutaminase inhibitor according to claim 26, wherein the whey fraction is at least partially further purified in a purification step, comprising gel filtration and/or ion exchange chromatography. 7. Transglutaminase inhibitor according to claim 5, wherein the purification comprises the removal of at least part of the lactose. 8. Transglutaminase inhibitor according to claim 2, wherein curd is formed by the acidification of the milk with food grade acid or by the addition of acid generating micro-organisms. 9. Transglutaminase inhibitor according to claim 2, wherein the milk is acidified to a pH of 2.8-5.2, preferably 3-5, more preferably 4.0-4.6. 10. Transglutaminase inhibitor according to claim 26, whereby the milk is derived from domestic animals, preferably cow, goat, sheep, deer, ass, reindeer, or humans. 11. Transglutaminase inhibitor according to claim 10, whereby the milk has been heat treated at a temperature lower than 80° C. 12. Transglutaminase inhibitor according to claim 1, having a molecular weight in the order of magnitude of about 200 Dalton. 13. Method for obtaining a transglutaminase inhibitor containing composition from milk, in particular from a whey fraction, comprising the steps of forming a curd from the milk, separating the curd from the whey in a centrifugation step. 14. Method for obtaining a transglutaminase inhibitor containing composition comprising subjecting skimmed milk to a diafiltration step. 15. canceled. 16. canceled. 17. canceled. 18. Method of preparing a medicament, comprising the step of utilizing a transglutaminase inhibitor containing composition according to claim 1 in the preparation of a medicament for the treatment of Alzheimer's disease, haemophilia, apoptosis, celiac disease, Huntington's disease, dermatological afflictions, cataract, spinobulbar atrophy (Kennedy's disease), (spino) cerebellar ataxia, dentatorubral-pallidoluysian atrophy, inflammatory diseases of the central nervous system, including multiple sclerosis, rheumatoid arthritis, diabetes such as insulin dependent diabetes mellitus, tetanus and other Clostridium related pathologies, Rett's syndrom, HIV infections and inflammatory processes. 19. Method of preparing a medicament for the treatment of Alzheimer's disease, haemophilia, apoptosis, celiac disease, Huntington's disease, dermatological afflictions, cataract, spinobulbar atrophy (Kennedy's disease), (spino) cerebellar ataxia, dentatorubral-pallidoluysian atrophy, inflammatory diseases of the central nervous system, including multiple sclerosis, rheumatoid arthritis, diabetes such as insulin dependent diabetes mellitus, tetanus and other Clostridium related pathologies, Rett's syndrom, HIV infections and inflammatory processes, comprising the step of utilizing a transglutaminase inhibitor containing a composition obtainable by a method of subjecting skimmed milk to a diafiltration step, or controlling the activity of transglutaminase in the cross-linking of proteins. 20. Method of controlling the activity of transglutaminase in the cross-linking of proteins, comprising the step of utilizing a transglutaminase inhibitor containing composition according to claims 1. 21. Method of controlling the activity of transglutaminase in the cross-linking of proteins, comprising the step of utilizing a transglutaminase inhibitor containing composition obtainable by a method of subjecting skimmed milk to a diafiltration step, or by controlling the activity of transglutaminase in the cross-linking of proteins. 22. Method for the production of food, comprising the step of utilizing a transglutaminase inhibitor containing composition according to claim 1. 23. Method for the production of food, comprising the step of utilizing a transglutaminase inhibitor containing composition obtainable by a method of subjecting skimmed milk to a diafiltration step, or by controlling the activity of transglutaminase in the cross-linking of proteins. 24. Pharmaceutical composition comprising the transglutaminase inhibitor containing composition according to claim 1. 25. Pharmaceutical composition comprising the transglutaminase inhibitor containing composition obtainable by a method of subjecting skimmed milk to a diafiltration step, or by controlling the activity of transglutaminase in the cross-linking of proteins. 26. Transglutaminase inhibitor containing composition according to claim 1, obtainable: from a whey fraction obtainable from skimmed milk by forming a curd from the milk, separating the curd from the whey in a centrifugation step followed by subjecting the whey to an ultrafiltration step; or by subjecting skimmed milk to a diafiltration step. 27. Transglutaminase inhibitor according to claim 6, wherein the purification comprises the removal of at least part of the lactose. |
Aminoglycosides as antibiotics |
The present invention provides aminoglycosides and pharmaceutical compositions that include the aminoglycosides. The aminogylcosides are useful to treat or prevent infectious diseases (e.g., bacterial infections) in a mammal (e.g., human). |
1. A compound of formula (I): wherein: R1 is thio, sulfinyl, sulfonyl, a direct bond, or C═X, wherein X is O or S; R2 is (C1-C12)alkyl, (C6-C10)aryl (C1-C12)alkyl, heteroaryl (C1-C12)alkyl, or (C3-C8)cycloalkyl (C1-C12)alkyl; wherein any alkyl, aryl, heteroaryl, or cycloalkyl is substituted with one or more amino or hydroxy; R3 is a direct bond or C═X, wherein X is O or S; R4 is (C1-C12)alkyl optionally substituted with one or more NRaRb, wherein Ra and Rb are each independently hydrogen, (C1-C12)alkyl, or (C6-C10)aryl (C1-C12)alkyl; wherein any alkyl or aryl of R4, Ra or Rb is optionally substituted with one or more amino, hydroxy, or guanidinyl; R5 is hydroxy, halo, or hydrogen and R6 is a direct bond; or R5 is (C1-C12)alkyl optionally substituted with one or more NRcRd, wherein Rc and Rd are each independently hydrogen, (C1-C12)alkyl, or (C6-C10)aryl (C1-C12)alkyl, wherein any alkyl or aryl of R5, Rc or Rd is optionally substituted with one or more amino, hydroxy, or guanidinyl, and R6 is oxy, thio, or C═X, wherein X is O or S; R7 is hydrogen, halo, or hydroxy; R8 is hydrogen or hydroxy; and R9 is hydrogen or hydroxy; wherein any alkyl is optionally interrupted with one or more oxy, thio, sulfinyl, or sulfonyl; and wherein any alkyl, aryl, heteroaryl, or cycloalkyl is optionally substituted on carbon with one or more halo, cyano, nitro, trifluoromethyl, hydroxy, (C1-C6)alkoxy, mercapto, oxo, thioxo, or NReRf, wherein Re and Rf are each independently hydrogen, (C1-C12)alkyl, or (C6-C10)aryl (C1-C12)alkyl; or a pharmaceutically acceptable salt thereof. 2. The compound of claim 1 wherein R1 is sulfonyl, a direct bond, or C═X, wherein X is O or S. 3. The compound of claim 1 wherein R2 is hydrogen, (C1-C12)alkyl, or (C6-C10)aryl (C1-C12)alkyl, wherein any alkyl or aryl is substituted with one or more amino and wherein any alkyl is optionally substituted with one or more hydroxy or mercapto. 4. The compound of claim 3 wherein the (C1-C8)alkyl is terminally substituted with an amino or the aryl of (C6-C10)aryl (C1-C12)alkyl is substituted with an amino. 5. The compound of claim 1 wherein R1R2 is hydrogen or a group of the formula: wherein n is 0 to about 6; R10 is sulfinyl, sulfonyl, a direct bond, or C═X wherein X is O or S; and R11 is hydroxy, mercapto, or NRgRh, wherein Rg and Rh are each independently hydrogen, (C1-C8)alkyl, or (C6-C10)aryl (C1-C8)alkyl. 6. The compound of claim 1 wherein R3 is a direct bond. 7. The compound of claim 1 wherein R3 is C═X, wherein X is S or O. 8. The compound of claim 1 wherein R4 is (C1-C12)alkyl substituted with one or more NRaRb, wherein Ra and Rb are each independently hydrogen, (C1-C12)alkyl, or (C6-C10)aryl (C1-C12)alkyl; wherein any alkyl is optionally substituted with one or more hydroxy or mercapto. 9. The compound of claim 1 wherein R4 is (C1-C12)alkyl substituted with one or more NRaRb, wherein Ra and Rb are each independently hydrogen, (C1-C12)alkyl, or (C6-C10)aryl (C1-C12)alkyl; wherein any alkyl or aryl of R4, Ra or Rb is substituted with one or more amino or guanidinyl. 10. The compound of claim 1 wherein R3R4 is a group of the formula: wherein Ri is hydrogen, Rj is wherein R12 is sulfinyl, sulfonyl, a direct bond, or C═X, wherein X is S or O; R13 is sulfinyl, sulfonyl, a direct bond, or C═X, wherein X is S or O; R14 is hydrogen, hydroxy, mercapto, or NRiRj, wherein Ri and Rj are each independently hydrogen, (C1-C8)alkyl, or (C6-C10)aryl(C1-C8)alkyl; and m is 0 to about 8. 11. The compound of claim 10 wherein Ri is (CH2)n—NH2, wherein n is 2 to about 8; or Ri is guanidinyl. 12. The compound of claim 10 wherein Rj is hydrogen or a group of the formula: wherein R15 is C═X, wherein X is O or S; R16 is hydrogen, hydroxy or amino; and q is 2. 13. The compound of claim 1 wherein R5 is hydroxy, halo, or hydrogen and R6 is a direct bond. 14. The compound of claim 1 wherein R5 is (C1-C12)alkyl optionally substituted with one or more oxo or NRmRn, wherein Rm and Rn are each independently hydrogen, (C1-C12)alkyl, or (C6-C10)aryl (C1-C12)alkyl, wherein any alkyl or aryl of R5, Rm or Rn is optionally substituted with one or more amino or guanidinyl, and R6 is oxy, thio, or C═X, wherein X is O or S. 15. The compound of claim 1 wherein R5R6 is hydrogen, hydroxy, flouro, or a group of the formula: wherein Ro is hydrogen, Rp is wherein R17 is sulfinyl, sulfonyl, a direct bond, or C═X, wherein X is S or O; R18 is sulfinyl, sulfonyl, a direct bond, or C═X, wherein X is S or O; R19 is hydrogen, hydroxy, mercapto, or NRqRs, wherein Rq and Rs are each independently hydrogen, (C1-C8)alkyl, or (C6-C10)aryl(C1-C8)alkyl; and p is 0 to about 6. 16. The compound of claim 1 wherein R5R6 is hydroxy. 17. The compound of claim 1 wherein R7 is hydrogen, fluoro, or hydroxy. 18. The compound of claim 1 wherein R7 is hydrogen. 19. The compound of claim 1 wherein R8 is hydroxy or hydrogen. 20. The compound of claim 1 wherein R8 is hydroxy. 21. The compound of claim 1 wherein R9 is hydroxy or hydrogen. 22. The compound of claim 1 wherein R9 is hydroxy. 23. The compound of claim 1 which is or a pharmaceutically acceptable salt thereof. 24. The compound of claim 1 which is or a pharmaceutically acceptable salt thereof. 25. The compound of claim 1 which is or a pharmaceutically acceptable salt thereof. 26. The compound of claim 1 which is or a pharmaceutically acceptable salt thereof 27. The compound of claim 1 which is or a pharmaceutically acceptable salt thereof. 28. The compound of claim 1 which is or a pharmaceutically acceptable salt thereof. 29. The compound of claim 1 which is or a pharmaceutically acceptable salt thereof. 30. The compound of claim 1 which is or a pharmaceutically acceptable salt thereof. 31. The compound of claim 1 which is or a pharmaceutically acceptable salt thereof. 32. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier or diluent. 33. The pharmaceutical composition of claim 32 further comprising one or more additional antibiotic agents. 34. The pharmaceutical composition of claim 33 wherein the additional antibiotic agent kills or effectively inhibits the growth of one or more of the following bacterium: Escherichia coli; Pseudomonas spp.; Proteus spp.; Bacteroides spp.; Haemophilus influenzae; Klebsiella spp.; Enterobacter spp.; Neisseria gonorrhoeae; Acinetobacter; Citrobacter spp.; Serratia marcescens; Branhamella (Moraxella) catarrhalis; Morganella morganii; Providencia stuartii; Salmonella spp.; Shigella spp.; Campilobacter spp.; Staphylococcus aureus; Staphylococcus epidermidis; Enterococcus faecalis; Streptococcus pyogenes; Streptococcus (alpha-hemolytic); Streptococcus pneumoniae; and Enterococcus faecium. 35. The pharmaceutical composition of claim 33 wherein the additional antibiotic agent is an aminoglycoside, β-lactam antibiotic, cephalosporin, macrolide, miscellaneous antibiotic, penicillin, tetracycline, antifungal, antimalarial agent, antituberculosis agent, antiviral, leprostatic, miscellaneous anti-infective, quinolone, sulfonamide, urinary anti-infective, nasal antibiotic, ophthalmic antibiotic, ophthalmic antiviral, ophthalmic quinalone, ophthalmic sulfonamide, skin and mucous membrane antibiotic, skin and mucous membrane antifungal, skin and mucous membrane antiviral, skin and mucous membrane miscellaneous anti-infective, skin and mucous membrane scabicide and pedulicide, skin and mucous membrane antineoplast, nitrofuran, or oxazolidinone. 36-41. (canceled) 42. A method for preventing or treating a bacterial infection in a mammal comprising administering to the mammal in need of such prevention or treatment a compound of claim 1. 43. The method of claim 42 wherein the bacterial infection is caused by one or more of the following bacterium: Escherichia coli; Pseudomonas spp.; Proteus spp.; Bacteroides spp.; Haemophilus influenzae; Klebsiella spp.; Enterobacter spp.; Neisseria gonorrhoeae; Acinetobacter; Citrobacter spp.; Serratia marcescens; Branhamella (Moraxella) catarrhalis; Morganella morganii; Providencia stuartii; Salmonella spp.; Shigella spp.; Campilobacter spp.; Staphylococcus aureus; Staphylococcus epidermidis; Enterococcus faecalis; Streptococcus pyogenes; Streptococcus (alpha-hemolytic); Streptococcus pneumoniae; and Enterococcus faecium. 44. The method of claim 42 further comprising administering one or more additional antibiotic agents. 45. The method of claim 44 wherein the additional antibiotic agent effectively kills or effectively inhibits the growth of one or more of the following bacterium: Escherichia coli; Pseudomonas spp.; Proteus spp.; Bacteroides spp.; Haemophilus influenzae; Klebsiella spp.; Enterobacter spp.; Neisseria gonorrhoeae; Acinetobacter; Citrobacter spp.; Serratia marcescens; Branhamella (Moraxella) catarrhalis; Morganella morganii, Providencia stuartii; Salmonella spp.; Shigella spp.; Campilobacter spp.; Staphylococcus aureus; Staphylococcus epidermidis; Enterococcus faecalis; Streptococcus pyogenes; Streptococcus (alpha-hemolytic); Streptococcus pneumoniae; and Enterococcus faecium. 46. The method of claim 44 wherein the additional antibiotic agent is an aminoglycoside, β-lactam antibiotic, cephalosporin, macrolide, miscellaneous antibiotic, penicillin, tetracycline, antifungal, antimalarial agent, antituberculosis agent, antiviral, leprostatic, miscellaneous anti-infective, quinolone, sulfonamide, urinary anti-infective, nasal antibiotic, ophthalmic antibiotic, ophthalmic antiviral, ophthalmic quinalone, ophthalmic sulfonamide, skin and mucous membrane antibiotic, skin and mucous membrane antifungal, skin and mucous membrane antiviral, skin and mucous membrane miscellaneous anti-infective, skin and mucous membrane scabicide and pedulicide, skin and mucous membrane antineoplast, nitrofuran, or oxazolidinone. 47. The method of claim 42 wherein the mammal is a human. |
<SOH> BACKGROUND OF THE INVENTION <EOH>Antibiotics are low-molecular weight antimicrobial agents that are produced as secondary metabolites by microorganisms that inhabit soil. For instance, Penicillium and Cephalosporium produce beta-lactam antibiotics (e.g., penicillin, cephalosporin, and their relatives). Actinomycetes (e.g., the Streptomyces species) produce tetracyclines, aminoglycosides (e.g., streptomycin and its analogs), macrolides (e.g., erythromycin and its analogs), chloramphenicol, ivermectin, rifamycins, and most other clinically-useful antibiotics that are not beta-lactams. Bacillus species (e.g., B. polymyxa and Bacillus subtilis ) produce polypeptide antibiotics (e.g. polymyxin and bacitracin), while B. cereus produces zwittermicin. The modern era of antibiotic therapy began with Fleming's 1929 discovery of penicillin, and Domagk's 1935 discovery of synthetic sulfonamides. Spurred by the need for antibacterial drugs during World War II, penicillin was isolated, purified and injected into experimental animals. The substance was found to not only cure infections, but also to possess low toxicity. This finding marked the beginning of the era of antibiotic use in human drug therapy and the intense search for similar antimicrobial agents of low toxicity that could be used to treat infectious diseases. The rapid isolation of streptomycin, chloramphenicol and tetracycline followed, and these and several other antibiotics were in clinical usage by the 1950's. Antibiotics are used therapeutically to treat bacterial infections. Several types of antibiotics, classified according to their mechanism of action, are currently employed. The known types of antibiotics include, e.g., cell wall synthesis inhibitors, cell membrane inhibitors, protein synthesis inhibitors, and inhibitors that bind to or affect the synthesis of DNA or RNA. Cell wall synthesis inhibitors, such as beta lactam antibiotics, generally inhibit some step in the synthesis of bacterial peptidoglycan. Penicillin is generally effective against non-resistant streptococcus, gonococcus and staphylococcus. Amoxycillin and Ampicillin have broadened spectra against Gram-negative bacterias. Cephalosporins are generally used as penicillin substitutes, against Gram-negative bacteria, and in surgical prophylaxis. Monobactams are generally useful for the treatment of allergic individuals. Cell membrane inhibitors disorganize the structure or inhibit the function of bacterial membranes. Polymyxin, produced by Bacillus polymyxis, is a cell membrane inhibitor that is effective mainly against Gram-negative bacteria and is usually limited to topical usage. Protein synthesis inhibitors include the tetracyclines, chloramphenicol, the macrolides (e.g. erythromycin) and the aminoglycosides (e.g. streptomycin ). Aminoglycosides have been used against a wide variety of bacterial infections caused by Gram-positive and Gram-negative bacteria. Aminoglycosides bind to the bacterial RNA in manifestation of their activity. Davis, B. D. Microbiol. Rev. 1987, 51, 341-350. Mingeot-Leclercq, M.-P.; Glupczynski, Y.; Tulkens, P. M. Antimicrob. Agents Chemother. 1999, 43, 727-737. Moazed, D.; Noller, H. F. Nature 1987, 327, 389-394. Shaw, K. J., Rather, P. N.; Hare, R. S.; Miller, G. H. Microbiol. Rev. 1993, 57, 138-163. Streptomycin has been used extensively as a primary drug in the treatment of tuberculosis. Gentamicin is active against many strains of Gram-positive and Gram-negative bacteria, including some strains of Pseudomonas aeruginosa. Kanamycin is active at low concentrations against many Gram-positive bacteria, including penicillin-resistant staphylococci. The structures of two aminoglycoside antibiotics, paromomycin and gentamicin C 1a , bound to the template sequences of ribosomal RNA (rRNA), have been determined recently by NMR. Fourmy, D.; Recht, M. I.; Blanchard, S. C.; Puglisi, J. D. Science 1996, 274, 1367-1371; (a) Fourmy, D.; Recht, M. I.; Puglisi J. D. J. Mol. Biol. 1998, 277, 347-362; (b) Fourmy, D.; Yoshizawa, S.; Puglisi, J. D. J. Mol. Biol. 1998, 277, 333-345; (c) Recht, M. I.; Fourmy, D.; Blanchard, S. C.; Dahlquist, K. D.; Puglisi, J. D. J. Mol. Biol. 1996, 262, 421-436; (d) Yoshizawa, S.; Fourmy, D.; Puglisi, J. D. EMBO J. 1998, 17, 6437-6448. These and other studies show that the neamine-class of aminoglycosides bind specifically to the A-site region on the 16S subunit of rRNA. Hence, neamine serves as a minimal structural motif for such binding. Fourmy, D.; Recht, M. I.; Blanchard, S. C.; Puglisi, J. D. Science 1996, 274, 1367-1371; Kotra, L. P.; Haddad, J.; Mobashery, S. Antimicrob. Agents Chemother. 2000 (in press)). As such, aminoglycosides are a suitable class of compounds that could be effective antibiotics. Neamine itself is a poor antibiotic and is not clinically useful. However, clinically useful aminoglycosides include, e.g., gentamicin, amikacin and neomycin. These compounds, however, face the possibility of clinical obsolescence because of the function of aminoglycoside-modifying enzymes, such as what already happened with kanamycins. (Wright, G. D.; Berghuis, A. M.; Mobashery, S. Aminoglycoside antibiotics: Structures, functions and resistance; Rosen, B. P., Mobashery, S., Eds.; Plenum Press: New York, 1998; pp. 27-69. The tetracyclines are protein synthesis inhibitors that consist of eight related antibiotics which are all natural products of Streptomyces, although some can now be produced semisynthetically. Tetracycline, chlortetracycline and doxycycline are the best known. The tetracyclines are broad-spectrum antibiotics with a wide range of activity against both Gram-positive and Gram-negative bacteria. Tetracyclines have some important uses, such as in the treatment of Lyme disease. Chloramphenicol is a protein synthesis inhibitor that has a broad spectrum of activity but it exerts a bacteriostatic effect. It is effective against intracellular parasites such as the rickettsiae. It is infrequently used in human medicine except in life-threatening situations (e.g. typhoid fever). Macrolide antibiotics, such as erythromycin, are protein synthesis inhibitors that are active against most Gram-positive bacteria. Some antibiotics affect the synthesis of DNA or RNA, or can bind to DNA or RNA so that their messages cannot be read. For example, nalidixic acid is a synthetic quinoloid antibiotic which is active mainly against Gram-negative bacteria. The main use of nalidixic acid is in treatment of lower urinary tract infections (UTI). In addition, the rifamycins has greater bactericidal effect against the bacteria that causes tuberculosis than other anti-tuberculosis drugs and is also useful for treatment of tuberculosis meningitis and meningitis caused by Neisseria meningitidis. Growth factor analogs are structurally similar to bacterial growth factors, but do not fulfill their metabolic functions in cells. For example, sulfonamides have been extremely useful in the treatment of uncomplicated UTI caused by E. coli, and in the treatment of meningococcal meningitis. The worldwide exploitation of antibiotics to treat infectious diseases has grown dramatically over the last forty years. In 1954, two million pounds of antibiotics were produced in the United States. Today, the figure exceeds 50 million pounds. According to the Centers Disease Control (CDC), humans consume 235 million doses of antibiotics annually. Widespread misuse or overuse of antibiotics has fostered the spread of antibiotic resistance and has contributed to the development of a serious public health problem. Antibiotic resistance occurs when bacteria that cause infection are not killed by the antibiotics taken to stop the infection. The bacteria survive and continue to multiply, causing more harm. For example, the bacterium Staphylococcus aureus is a major cause of hospital acquired infections that, historically, responded satisfactorily to the antibiotic vancomycin. Recently, however, many strains of S. aureus have been found to be resistant to vancomycin. Moreover, the death rate for some communicable diseases such as tuberculosis have started to rise again, in part because of increases in bacterial resistance to antibiotics. The development of new drugs is an essential component to strategies designed to reverse the problem of bacterial resistance, particularly in treating infectious diseases (e.g., bacterial infections). Accordingly, there is a need to identify additional compounds to treat infectious diseases (e.g., bacterial infections). The compounds can preferably be administered orally. |
<SOH> SUMMARY OF THE INVENTION <EOH>The present invention provides compounds (e.g., aminoglycosides) that are useful to treat or prevent infectious diseases (e.g., bacterial infections). The compounds are orally available and/or intravenously available. The compounds kill or effectively inhibit the growth of one or more Gram positive bacteria and/or one or more Gram negative bacteria. For example, the compounds of the present invention can effectively kill or effectively inhibit the growth of one or more of the following bacterium: Escherichia coli; Pseudomonas spp., Proteus spp.; Bacteroides spp.; Haemophilus influenzae; Klebsiella spp.; Enterobacter spp.; Neisseria gonorrhoeae; Acinetobacter; Citrobacter spp.; Serratia marcescens; Branhamella (Moraxella) catarrhalis; Morganella morganii; Providencia stuartii; Salmonella spp.; Shigella spp.; Campilobacter spp.; Staphylococcus aureus; Staphylococcus epidermidis; Enterococcus faecalis; Streptococcus pyogenes; Streptococcus (alpha-hemolytic); Streptococcus pneumoniae; and Enterococcus faecium. The present invention provides a compound of formula (I): wherein: R 1 is thio, sulfinyl, sulfonyl, a direct bond, or C═X, wherein X is O or S; R 1 is hydrogen, (C 1 -C 12 )alkyl, (C 6 -C 10 )aryl (C 1 -C 12 )alkyl, heteroaryl (C 1 -C 12 )alkyl, or (C 3 -C 8 )cycloalkyl (C 1 -C 12 )alkyl; wherein any alkyl, aryl, heteroaryl, or cycloalkyl is substituted with one or more amino or hydroxy; R 3 is a direct bond or C═X, wherein X is O or S; R 4 is (C 1 -C 12 )alkyl optionally substituted with one or more NR a R b , wherein R a and R b are each independently hydrogen, (C 1 -C 12 )alkyl, or (C 6 -C 10 )aryl (C 1 -C 12 )alkyl; wherein any alkyl or aryl of R 4 , R a or R b is optionally substituted with one or more amino, guanidinyl, or hydroxy; R 5 is hydroxy, halo, or hydrogen and R 6 is a direct bond; or R 5 is (C 1 -C 12 )alkyl optionally substituted with one or more NR c R d , wherein R c and R d are each independently hydrogen, (C 1 -C 12 )alkyl, or (C 6 -C 10 )aryl (C 1 -C 12 )alkyl, wherein any alkyl or aryl of R 5 , R c or R d is optionally substituted with one or more amino, guanidinyl, or hydroxy; and R 6 is oxy, thio, or C═X, wherein X is O or S; R 7 is hydrogen, halo, or hydroxy; R 8 is hydrogen or hydroxy; and R 9 is hydrogen or hydroxy; wherein any alkyl is optionally interrupted with one or more (e.g., 1, 2, 3, or 4) oxy, thio, sulfinyl, or sulfonyl; and wherein any alkyl, aryl, heteroaryl, or cycloalkyl is optionally substituted on carbon with one or more (e.g., 1, 2, 3, or 4) halo, cyano, nitro, trifluoromethyl, hydroxy, (C 1 -C 6 )alkoxy, mercapto, oxo, thioxo, or NR e R f , wherein R e and R f are each independently hydrogen, (C 1 -C 12 )alkyl, or (C 6 -C 10 )aryl (C 1 -C 12 )alkyl; or a pharmaceutically acceptable salt thereof. The present invention also provides a pharmaceutical composition. The pharmaceutical composition comprises a compound of formula (I) and a diluent or carrier. The pharmaceutical composition can optionally comprise one or more additional antibiotic agents. The present invention also provides a method of preventing or treating a bacterial infection in a mammal (e.g., human). The method comprises administering to the mammal an effective amount of a compound of the present invention. The method can optionally comprise administering to the mammal one or more additional antibiotic agents. The present invention also provides a method of preventing or treating a bacterial infection in a mammal (e.g., human). The method comprises administering to the mammal an effective amount of a pharmaceutical composition of the present invention. The method can optionally comprise administering to the mammal one or more additional antibiotic agents. The present invention also provides a compound of formula (I) for use in medical therapy. The present invention also provides the use of a compound of formula (I) for the manufacture of a medicament for treating or preventing a bacterial infection in a mammal (e.g., human). The present invention also provides intermediates and methods of making (e.g., synthetically preparing) compounds of formula (I). |
Method for the detection of viable microorganisms |
Method for the detection and enumeration of viable microorganisms. A liquid that comprises one or more markers incorporated in a liquid sol-gel precursor, is provided. A transparent slide is coated with a thin uniform layer of the liquid sol-gel precursor composition. The microorganisms are separated from liquid sample to be analyzed by passing the sample through a filter, and then bringing the filter into close contact with the sol-gel coated slide. The filter is co-incubated with the sol-gel coated slide for a period of time and at a temperature suitable to promote uptake of the markers by the microorganisms. The gel-coated slide irradiated with an external energy source, so as to generate detectable signals emitted from the markers uptaken by the microorganisms. Image of the detectable signals emitted from the microorganisms are acquired, and analyzed using a computer system, in order to provide the identification and enumeration of the microorganisms. |
1-14. (canceled) 15. A method for detecting and enumerating viable microorganisms in a sample comprising: providing a smooth transparent porous material containing a marker therein; separating the microorganisms from a sample to be analyzed and contacting the microorganisms with the smooth transparent porous material; incubating the contacted microorganisms and smooth transparent porous material for a time sufficient to promote uptake of the marker by the microorganisms; irradiating the marker containing microorganisms with an energy source to generate detectable signals emitted by the marker, and detecting the signals emitted and analyzing the signals to identify and enumerate the microorganisms. 16. A method according to claim 15 wherein the microorganisms are bacteria. 17. A method according to claim 15 wherein the energy source is selected from the group consisting of visible light, fluorescent light, UV light, infrared light, an electro-magnetic field, sonar, ultrasonic waves, radio waves, and short wave radiation. 18. A method according to claim 15, further comprising isolating the microorganisms from a sample selected from the group consisting of water, milk, food, saliva, urine, throat swab tests, wounds, sputum, stomach content, and feces. 19. The method according to claim 15, wherein the marker is selected from the group consisting of 3-carboxyumbelliferyl β-D-galactopyranoside, 4-chloromethyl-6,8-difluoroumbelliferyl β-D-galactopyranoside, 4-methylumbelliferyl β-D-galactopyranoside, fluorescein di β3-D-galactopyranoside, 6,8-difluoroumbelliferyl β-D-glucuronide, 5-(pentafluorobenzoylamino) fluorescein di-β-D-glucuronide, and β-trifluoromethylumbelliferyl β-D-glucuronide. 20. The method according to claim 15 further comprising attaching antibiotic substances to the marker. 21. The method according to claim 20, wherein the antibiotic substance is selected from the group consisting of Chloramphenicol, Erythromycin, Tetracycline, Streptomycin, Polymyxin, Nalidixic Acid, Novobyocin, Trimethorprin, Rifanapicin and Penicillin. 22. The method according to claim 15, wherein the markers are provided in a form selected from the group consisting of liposomes; films; multilayers; braided; lamellar, helical, tubular, and fiber shapes; solvated rods; solvated coils; and combination thereof. 23. The method according to claim 15, further comprising providing pyridine or K2SO4 in the smooth transparent porous material. 24. The method according to claim 15, further comprising detecting microorganisms present at less than 103 ml−1. 25. The method according to claim 15, wherein separating the microorganisms from a sample comprises filtering the sample to capture microorganisms on a filter media, and placing the filter media in contact with the smooth transparent porous material containing the marker. 26. The method of claim 25 further comprising co-incubating the filter media with the smooth transparent porous material. 27. The method of claim 26 wherein the co-incubating is conducted at 0.5 to 6 hours at a temperature of between 35 and 44° C. 28. A system for identifying and enumerating viable microorganisms in a sample comprising; a smooth transparent porous material containing at least one marker in the pores therein; separation means for separating the microorganisms from a sample to be analyzed; means for incubating the microorganisms with the marker-containing smooth transparent porous material such that the microorganisms ingest the markers; means for irradiating the marker containing microorganisms for generating detectable signals emitted by the marker; means for detecting the signals; and means for analyzing the detected signals to identify and enumerate the microorganisms. 29. The system of claim 28, wherein the irradiating means comprise an energy source selected from the group consisting of visible light, flourescent light, UV light, infrared light, an electrochemical field, sonar, ultrasonic waves, radio waves and short wave radiation. 30. The system of claim 28, wherein the detecting means comprise a frame grabber, a CCD array camera, a microscope, and an autofocus system. 31. The system of claim 28, further comprising a mechanical x-y table. 32. The system of claim 30, wherein the frame grabber has a rate of 30 frames per second. |
<SOH> BACKGROUND OF THE INVENTION <EOH>A major goal of microorganism detection research is to develop inexpensive, fast, reliable, and sensitive detectors. Standard laboratory procedures are currently available for the detection of microorganisms. The vast majority of procedures are based on the use of agar media on which specific microorganisms grow over a period of time. The normal incubation period is between 24 to 48 hours. After the microorganisms multiply their presence can be identified and quantified. The main drawback of the existing tests is the time required for obtaining their results. Bacterial contamination in water sources results in the shutdown of water sources and systems and requires the use of more expensive water supply alternatives. Fast detection of microorganisms is needed to allow for shorter shutdown periods. In the medical sector, bacterial identification and antibiotic sensitivity tests are required in any medical situation in which antibiotics are to be administrated. The time required for obtaining test results is between 72 to 96 hours. Reducing this time period will produce better results and faster patient recovery. In the food and beverage industry, raw materials and manufactured goods are routinely inspected for bacterial contamination. The required incubation period for test results does not allow for immediate process treatment and causes delays both in the manufacturing and supplying of goods. Reducing the taking time period can result in savings in infrastructure and labor. In the last few years several methods were developed in order to identify and enumerate bacteria in 1.5 to 11.0 hours. Methods that are relatively simple require a large amount of bacteria (above 10 4 in 1 ml sample), while methods that can detect small numbers of bacteria are expensive and cannot be used as large scale systems. U.S. Pat. No. 5,811,251 discloses a system for counting the number of viable microorganisms based on a CCD system. However this system cannot differentiate between different types of bacteria and provides only a total number of bacteria. U.S. Pat. Nos. 5,972,641 and 5,518,894 disclose a rapid coliform detection systems using a statistic methods for determining the number of bacteria. Said methods require up to 11 hours for obtaining the results in low number of bacteria. Other patents disclose a method for detection of microorganisms using fluorescence and laser light source (U.S. Pat. Nos. 5,891,394, 5,858,697, 5,763,203, 5,751,839 and U.S. Pat. No. 5,663,057). The disadvantages of said methods is the use of an expensive laser light source and the detection of microorganisms directly from the filter which is not smooth and causes problems during analysis. In addition, these systems are not portable and are relatively expensive. Immunoassay methods are also used for detecting certain types of microorganisms (Lee et al., App. Environ. Microbiol., Vol. 56, pp.1541-1546). In these methods, specific antibodies labeled with a fluorescent or radioactive dye are used to detect the microorganism. However, immunoassay methods are limited in that they require the production of antibodies against each microorganism of interest, which is time-consuming and expensive. “Sol-gel” is the term used to indicate inorganic glass manufactured at room temperatures based on metal oxides. A certain process involving ceramic materials in which the sol (solution) is transformed to a gel phase through hydrolysis, condensation and polymerization. The common starting materials for the sol-gel preparation are ormosils or metal oxides. In recent years sol-gel has been applied to organosilanes to create “glass at room temperature”. Sol-gel type materials comprise pores ranging from tens of angstroms to tens of nanometers, and exhibit a large area to mass ratios e.g., hundreds of square meters per gram. Sol-gel materials are transparent even at UV wavelengths, and are simple to prepare in different shapes, such as powders, monolithic blocks, thin sheets, fibers etc. The use of sol-gel-based materials to entrap various organic molecules in a matrix media was described in the art. (Avnir et al., Supramolecular architecture in two and three dimensions Bein T. (ed.) American Chemical Society Symposium Series XXX, 1992). Using said technology, organic molecules are entrapped at room temperatures within the sol-gel matrix without impairing the structure of the relatively sensitive organic molecule. In addition, the entrapped molecule retains almost all of the original physical and chemical characteristics, and is available to outside reactants as a result of the massive pore system inside the sol-gel. U.S. Pat. No. 6,022,748 discloses a method for the direct detection of analytes using color changes in response to selective binding of analytes to a surface. Said detection occurs in immobilized biopolymeric material encapsulated into metal oxide glass using the sol-gel method. The disadvantages of this method are that only large amounts of bacteria can be detected or enumerated, since only high counts are able to cause a visible color change in the sol-gel. Furthermore, said method cannot differentiate between viable and non-viable microorganisms, since it is based on the binding of the microorganisms to the sol-gel surface, independent whether said microorganisms are viable or not. Armon et al. (J. of Biotechnology 51, 279-285) disclose a method for detecting large quantities of E. coli bacteria by spreading them on sol-gel doped with specific compounds, said compounds being uptaken into the bacteria, which consequently causes the bacteria to glow at specific wavelengths. However, this method does not provide a method suitable to count bacteria present in a given sample. In addition, detection of low number of microorganisms is not possible using said method. The art has so far failed to provide a fast method for the enumeration of microorganisms, which is sensitive enough to provide a reliable count at low microorganism concentrations. It is a purpose of this invention to provide a fast and sensitive method for the detection of viable microorganisms. It is another object of the invention to provide a method and compositions useful in providing an enumeration of microorganisms found in low-count samples. Other objects and advantages of the invention will become apparent as the description proceeds. |
<SOH> SUMMARY OF THE INVENTION <EOH>It has now been surprisingly found, and this is an object of the present invention, that viable microorganisms at a concentration lower than 10 3 ml −1 may be detected and enumerated in a 2-hours period, using organic or inorganic substances that are entrapped in porous sol-gel glass (hereinafter referred to as “markers”, for the sake of brevity). The present invention relates to methods and compositions for the detection and enumeration of viable microorganisms using organic or inorganic substances that are incorporated in porous sol-gel glass (markers). The microorganisms metabolize said markers, and thereby emit detectable radiation, electromagnetism or fluorescence. Thus, a fast visualization of viable microorganisms is obtained on the sol-gel glass. The sol-gel surface is extremely smooth and transparent and allows for an almost uniform focal point for high resolution microscopic scanning. According to a preferred embodiment of the invention, the following steps are carried out: a) Providing a liquid composition comprising one or more marker(s) incorporated in a liquid sol-gel precursor; b) Coating a transparent slide, e.g., a glass slide, with a thin uniform layer of said liquid sol-gel precursor composition; c) Separating the microorganisms from a liquid sample to be analyzed by passing said sample through a filter, and then bringing said filter into close contact with the sol-gel-coated slide; d) Co-incubating said filter with said sol-gel-coated slide for a period of time and at a temperature suitable to promote uptake of the marker(s) by the microorganisms, e.g. at 35-44° C. for 0.5 to 6 hours; e) Irradiating said sol-gel-coated slide with an external energy source such as to generate detectable signals emitted from the marker(s) metabolized by the microorganisms; and f) Acquiring images of said detectable signals emitted from the microorganisms, and analyzing said images using a computer system, thereby to provide the identification and enumeration of said microorganisms. The present invention further relates to a method for preparation of a liquid sol-gel mixture containing organic or inorganic substances (markers). Said markers are metabolized by the microorganisms that are to be identified. Coliform bacteria that can be detected according to the present invention are actually a broad group of bacteria that include E. coli, Enterobacter spp., Klebsiella spp. and Citrobacter spp. Coliform bacteria are identified by detecting the activity of an enzyme, β-Galactosidase (E.C. 3.2.1.23), using fluorogenic or chromogenic substances 3-carboxyumbelliferyl β-D-galactopyranoside (CUG) or 4-chloromethyl-6,8-difluoroumbelliferyl β-D-galactopyranoside (CMDi FUG). According to the present invention, E. coli are identified by detecting the activity of an E. coli -specific-enzyme, β-Glucuronidase (GUS or EC 3.2.1.31), using the following fluorogenic or chromogenic substances: 4-methylumbelliferyl β-D-galactopyranoside (MUG), fluorescein di β-D-galactopyranoside (FDG), 6,8-difluoro-4-methylumbelliferyl β-D-glucuronide, lithium salt (DiFMUGGlcU), 2-dodecylresorufin, Elf-97, fluorescein di-β-glucoronide (FDGlcU), 5-(pentafluorobenzoylamino) fluorescein di-β-D-glucoronide (PFB-FDGlcU) and β-trifluoromethylumbelliferyl β-D-glucoronide. According to another preferred embodiment of the invention, an antibiotic material is incorporated into the sol-gel mixture for identifying bacterial antibiotic resistance. It may be appreciated that the emission of fluorescence from bacteria in spite of the presence of a specific antibiotic, indicates that said bacteria is antibiotic-resistant. Partial resistance may be indicated when the presence of the specific antibiotic leads to a partial reduction in the number of fluorescent bacteria. The following antibiotics are added to the sol-gel mixture: Chloramphenicol, Erythromycin, Tetracycline, Streptomycin, Polymyxin, Nalidixic Acid, Novobyocin, Trimethoprin, Rifanapicin and Penicillin. According to the present invention, it is possible to provide the markers as liposomes; films; multilayers; braided, lamellar, helical, tubular, and fiber-like shapes; solvated rods; solvated coils; and combinations thereof. According to the present invention, it is also possible to detect injured or stressed microorganisms by incorporating pyruvate or K 2 SO 4 within the sol-gel. It is known in the art that pyruvate or K 2 SO 4 can be used to resuscitate or improve chlorinated injured coliform bacteria (“enumeration and differentiation of chlorine-stressed total coliform bacteria” Robert A Duncanson—Ph.D. dissertation—University of Rhode Island 1993). According to the present invention it is possible to add polylysine or similar substances at a concentration of between 10 to 100 parts per million to the sol-gel solution to allow for enhancing bacteria absorption. All the above and other characteristics and advantages of the invention will be further understood from the following illustrative and non-limitative examples of preferred embodiments thereof. |
Extension arm for a sheet-processing printing machine |
A sheet delivery mechanism for a sheet-fed printing machine which is adapted to reduce changes in the position of sheet material in a stack during a stack changeover operation and which facilitates the formation of a stack with properly aligned edges. The sheet-delivery mechanism includes at least one length adjustable edge guide 16 supported between a stack support plate 14 and a cross element 15 which can be detachably connected to the frame of the sheet delivery mechanism. |
1-10. (canceled) 11. A sheet delivery mechanism for a sheet-fed printing machine comprising an endless conveyor for transporting printed sheet material to a delivery stack formed by stacking said sheet material, a separating device for separating the delivery stack into an auxiliary stack and a main stack, a stack lifting device including a vertically movable stack support plate for supporting the delivery stack, at least one edge guiding device connected to said support plate and extending in parallel vertical relation adjacent to an edge of the main stack formed by stacking the sheet material, and said edge guide device having a vertical length that varies depending upon the vertical position of said support plate. 12. The sheet delivery mechanism of claim 11 including at least two said edge guiding devices along a common edge of said main stack. 13. The sheet delivery mechanism of claim 11 in which said edge guiding device is connected in vertically extended fashion between said support plate and a frame of said edge guiding device. 14. The sheet delivery mechanism of claim 11 in which said edge guiding device is connected at one end to a crossarm detachably mounted to said frame. 15. The sheet delivery mechanism of claim 11 in which said edge guiding device includes a flexible material vertically positioned adjacent an edge of said main stack and a winding real for winding said flexible material upon itself during raising movement of said support plate. 16. The sheet delivery mechanism of claim 15 in which said flexible material is a band. 17. The sheet deliver system of claim 11 in which said edge guiding device is arranged in parallel adjacent relation to a front edge of the main stack formed by stacking the sheet material. 18. The sheet delivery mechanism of claim 11 in which said edge guiding device is arranged in parallel adjacent relation to a lateral edge of a main stack formed by the sheet material. 19. The sheet delivery mechanism of claim 11 in which said edge guiding device is arranged in parallel adjacent relation to a rear edge of the main stack formed by stacking the sheet material . 20. The sheet delivery mechanism of claim 11 in which said sheet guiding device changes in length as an incident to vertical movement of the support plate. 21. The sheet delivery mechanism of claim 11 in which the vertical length of said edge guiding device is changeable in synchronism with vertical movement of the stack support plate. 22. The sheet delivery mechanism of claim 11 in which said edge guiding device is arranged a predetermined short distance from the edge of the main stack. 23. The sheet delivery mechanism of claim 11 in which said edge guiding device includes a tensioned band material that is wound upon itself to shorten its length upon raising movement of said support plate. 24. The sheet delivery mechanism of claim 11 in which said edge guiding device includes a winding device mounted on the stack for winding the edge guiding device to change its length. 25. The sheet delivery mechanism of claim 24 in which said winding device is removably mounted on said stack support plate. 26. The sheet delivery mechanism of claim 11 in which said main stack of sheet material is supported by said support plate in inclined relation to the horizontal toward an adjacent edge guiding device. |
Arrangement in ventilatory treatment of the lungs |
The invention relates to a valve arrangement in the ventilatory treatment of the lungs of a living creature (2) under a state of anaesthesia, comprising valve equipment (4) devised to carry an insufflation gas and/or an insufflation gas mixture from a lung ventilation unit (3) into the lungs and airways (2a) of the living creature (2) and allow expiration of gas and/or gas mixture held in the airways. The said valve equipment (4) and a combination of sensor units (61, 61A, 62) are arranged in close proximity to one another. They are inter-connected by an end section for a bundle of tubing (30) from the lung ventilation unit (3), and the said sensor units (61, 61a, 62) are located closer to the said living creature (2) than the said valve equipment (4). |
1. A valve arrangement in the ventilatory treatment of the lungs of a living creature under a state of anaesthesia, comprising valve equipment devised to carry an insufflation gas and/or an insufflation gas mixture from a lung ventilation unit into the lungs and airways of the living creature and allow expiration of gas and/or gas mixture held in the airways, a sensor unit in gas-measuring equipment, the sensor unit being devised to sense the velocity-related pressure gradient in measuring the velocity of the insufflation gas and the duration of the insufflation phase, a sensor unit devised to sense the velocity-related pressure gradient in measuring the velocity of expired gas and the duration of the expiration phase, a sensor unit for measuring the pressure of the gas and its variation in pressure over time and/or a sensor unit for diverting part of the gas mixture for measuring the presence of and/or percentage of one or more gas components in the gas mixture, characterized in that valve equipment has a valve housing consisting of at least two parts, and these parts can be conjoined or separated by means of an end-related rotary movement. 2. An arrangement according to claim 1, characterized in that the said rotary movement is arranged around an axis of rotation at the end of a section of tubing intended for e.g. insufflation gas. 3. An arrangement according to claim 1, characterized in that the end of at least one section of tubing has the shape of part of a sphere. 4. An arrangement according to claim 1, characterized in that a ring-shaped gasket is arranged between the parts in one of the parts and has the external shape of part of a sphere. 5. An arrangement according to claim 3, characterized in that part of the sphere formed by the ring-shaped gasket is truncated by two planes located on either side of the centre of the sphere, forming small circles with the same or different diameters. 6. An arrangement according to claim 1, characterized in that one of the said two parts has a system of channels for connection to a means for coupling a plurality of tubes, preferably gathered in a bundle of tubing. 7. An arrangement according to claim 1, characterized in that one of the parts has a lid devised for sealed contact with a membrane in a valve located between the parts. 8. An arrangement according to claim 1, characterized in that one of the parts has a number of channel-closing first coupling means. 9. An arrangement according to claim 8, characterized in that the said first coupling means is devised to enclose the second part's second coupling means. 10. An arrangement according to claim 4, characterized in that the elasticity of the said ring-shaped gasket is such that the first and second coupling means can made to interact axially during relative movement of the first and second part. 11. An arrangement according to claim 1, characterized in that one of the said parts is provided with a locking arrangement for firm locking to the second part when these parts are conjoined. |
<SOH> FIELD OF INVENTION <EOH>The present invention relates to an arrangement for ventilatory treatment of the lungs of a living creature and has been devised primarily for use during a state of anaesthesia caused by intravenous infusion of a liquid anaesthesia-inducing drug. The arrangement in accordance with the present invention comprises valve equipment devised to carry an insufflation gas and/or an insufflation gas mixture from a lung ventilator unit to the lungs and airways of the living creature and allow controlled expiration of the gas and/or gas mixture held in the airways. The arrangement and equipment can additionally comprise one or more sensors belonging to gas measuring equipment. One of these sensors can then be devised to sense a pressure gradient related to gas velocity in measuring the velocity of insufflation gas and the duration of the insufflation phase. Another sensor unit, or the same one as above, can be devised to sense a pressure gradient related to gas velocity in measuring the velocity of expired gas and the duration of the expiratory phase. Yet another sensor can be devised to measure the pressure and/or time-related variations in the pressure of insufflation gas and/or expired gas. Yet another sensor can be devised to divert part of the gas mixture for analysis for measurement of the presence of an/or percentage of one or more gas components in the gas mixture. The invention relates more specifically to a refinement of the arrangement taught and disclosed in the Swedish patent application 99 02051-3, filed on 3 Jun. 1999 and entitled “Arrangemang vid en lungventilatorisk behandling” (Eng. =Arrangement in ventilatory treatment of the lungs.) |
<SOH> SUMMARY OF THE PRESENT INVENTION <EOH>Technical Problems When the technical deliberations that a person skilled in this particular art must make in order to provide a solution to one or more technical problems she/he encounters are taken into consideration, it will be seen that it is initially necessary to realise the measures and/or sequence or measures that must be undertaken to this end and to realise which means is/are required. On this basis, the technical problems listed below should be relevant to development of the present invention. When the prior art, as described above, is considered, it will be seen that a technical problem resides, in the ventilatory treatment of the lungs of a living creature under a state of anaesthesia created by intravenous infusion of a liquid anaesthesia-inducing drug, in disclosing a valve arrangement consisting of control-lable valve equipment, combined with a plurality of sensor units which can be located very close to the creature. It will also be seen that a technical problem resides in the provision of conditions, with simple means, enabling the arrangement and the valve equipment to offer less dead space in relation to known equipment for this application. It will also be seen that a technical problem resides in realising the significance of and the advantages for a patient under a state of deep anaesthesia, induced by an intravenous infusion of a liquid drug, of being able to offer utilisation of only one insufflation tube, devised with one cross-section for being able to carry an insufflation gas or gas mixture from the lung ventilator to the patient and, additionally, a plurality of tubes with a much smaller cross-section for determining in the lung ventilator different criteria for the gas or gas mixture and for controlling a valve in the valve equipment from the lung ventilator via a lung ventilator valve. It will also be seen that a technical problem resides in realising the importance of and the advantages afforded by development of a valve arrangement made from a few simple parts, the parts being devised for easy cleaning, rinsing and/or replacement. It will also be seen that a technical problem resides in realising the importance of and advantages afforded by having the valve equipment comprise a valve housing, enclosing sensor units, which can be made in two parts that attach to one another with a rotary movement. These parts can be conjoined or separated by means of this rotary movement. It will be seen that a technical problem resides in realising the importance of and advantages afforded by arranging the said rotary movement around an end-oriented valve housing's axis of rotation. It will be seen that a technical problem resides in realising the importance of and advantages afforded by devising the area around the end-oriented axis of rotation with a passage for gas and an elastic ring-shaped gasket. It will be seen that a technical problem resides in realising the importance of and advantages afforded by having the said elastic gasket absorb the relative, axial movement between the said two parts forming the valve housing in order to provide a tight seal between the respective connector means for each part for sensor unit channel tubes sections when the parts are conjoined. It will be seen that a technical problem resides in realising the importance of and advantages afforded by using an elastic ring-shaped gasket between the parts. The gasket can be mounted on one of the parts and have the shape of part of a sphere. It will be seen that a technical problem resides in realising the importance of and advantages afforded by truncating the part of the sphere with two planes, located on either side of a sphere's centre, forming small circles with the same or different diameters. It will be seen that a technical problem resides in realising the importance of and advantages afforded by having one of the said two parts contain a system of channels for interconnection to a coupling means for a plurality of tubes, preferably arranged in a single tubing bundle. It will also be seen that a technical problem resides in realising the importance of and advantages afforded by orienting the system of channels so as to connect openings in the coupling means with the openings in one, the first, of the said two parts. It will be seen that a technical problem resides in realising the importance of and advantages afforded by equipping one of the parts with a lid, devised to seal against a peripheral area of a valve membrane. It will be seen that a technical problem resides in realising the importance of and advantages afforded by devising one of the parts with a number of channel system first coupling means, arranged in a row, in a two-part coupling arrangement, preferably with an intermediate gasket. It will be seen that a technical problem resides in realising the importance of and advantages afforded by devising the said first coupling means on one part to enclose a second coupling means on the second part in the same coupling arrangement. It will be seen that a technical problem resides in realising the importance of and advantages afforded by using a said ring-shaped elastic gasket with an elasticity allowing the first and second coupling means, in a coupling arrangement, to interconnect during cam-guided relative movement between the first section and the second section. It will be seen that a technical problem resides in realising the importance of and advantages afforded by providing one of the said two parts with a locking means, such as one or two clamps, so the first part locks firmly to the second part. Solution With the intention of solving one or more of the aforesaid technical problems, the present invention takes as its starting point a valve arrangement in ventilatory treatment of the lungs of a living creature under a state of anaesthesia. It comprises valve equipment devised for passing an insufflation gas and/or an insufflation gas mixture from a lung ventilation unit into the creature's lungs and airways and allowing expiration of gas and/or gas mixture held in the airways, and one or more sensor units in gas measuring equipment, one of the sensor units being devised for sensing the velocity-related pressure gradient in measurement of the velocity of the insufflation gas and the duration of the insufflation phase. One, another or the same sensor unit is devised for sensing the velocity related pressure gradient in measuring the velocity of expired gas and the duration of the expiratory phase. A second sensor is devised for measuring gas pressure and/or variations in pressure over time. One sensor can be devised to divert part of the gas mixture for gas analysis in measuring the presence of and/or percentage of one or more gas components in the gas mixture. With the intention of solving one or more of the aforesaid technical problems, the present invention proposes that the said valve equipment comprise a valve housing, which can consist of two parts. These parts can be conjoined or separated by means of an end-related rotary movement. As proposed embodiments that lie within the scope of the inventive concept, it is also proposed that the said rotary movement be arranged around an axis of rotation at the end of a section of tubing for e.g. insufflation gas. It is further proposed that the end of the section of tubing be in the shape of part of a sphere. A ring-shaped gasket is arranged on one of the parts and has an external shape corresponding to part of a sphere. It is further proposed that the part of the sphere be truncated by two planes on either side of a sphere's centre, forming small circles with the same or different diameters. It is further proposed that one of the said two parts comprise a system of channels for interaction with a coupling means for a plurality of tubes, preferably arranged in a single bundle of tubing. It is further proposed than one part be equipped with a lid, devised for sealed interaction with a membrane in a valve. One part has a number of channel-closing and channel-coupling first coupling means, said first coupling means being devised to enclose a coupling means on the second part, thereby jointly forming a coupling arrangement. The invention also teaches the use of a ring-shaped elastic gasket with an elasticity allowing the first and second coupling means to interconnect during cam-guided relative, axial movement between the first part and the second part. The invention also teaches that at least one of the said parts is provided with an arrangement, such as clamps, for locking the two parts together and achieving firm locking to the second part. Advantages Those advantages primarily obtained for an arrangement, in accordance with the present invention, for ventilatory treatment of the lungs reside in the provision of features making possible effective co-ordination of valve equipment and an array of sensor units, so they can be placed near the living creature, preferably with the aid of a connector part. They also make possible the utilisation of only one tube for ventilatory gas between a lung ventilator unit and the living creature or patient being treated by intravenous administration of a liquid anaesthesia-inducing drug, thereby allowing expired gas from the creature to pass via the valve equipment into atmosphere in the immediate vicinity of the creature without contaminating of the lung ventilator with expired gas. Specially shaped coupling means and a coupling arrangement that eliminate the risk of erroneous coupling are also provided. The interacting parts are also devised for easy cleaning, and a valve membrane for the parts is easily removed. The primary characteristic features of a valve arrangement in accordance with the present invention are set forth in the characterising clause of the following claim 1 . |
Diamido alkoxides as polymerisation initiators |
The present invention relates to a complex having the formula (I) wherein M is selected from Sn(II), Sn(IV), Al(III) and Mg(II); each of R1 and R2 is independently hydrocarbyl; R3 is H or hydrocarbyl; and X is a linker group. A further aspect of invention relates to the use of said complex as a polymerisation initiator, particularly in the polymerisation of lactides. |
1. A complex having the formula I wherein M is selected from Sn(II), Sn(IV), Al(III) and Mg(II); each of R1 and R2 is independently hydrocarbyl; R3 is H or hydrocarbyl; and X is a linker group: 2. A complex according to claim 1 wherein linker group X comprises a C1-4 carbon backbone, or a heteroatom-containing C1-4 carbon backbone. 3. A complex according to claim 1 or claim 2 wherein each of R1 and R2 is independently selected from alkyl, cycloalkyl, haloalkyl, aryl, haloaryl or heteroaryl; R3 is H, alkyl, cycloalkyl, haloalkyl, aryl or haloaryl. 4. A complex according to any preceding claim wherein X comprises a vinylene or an arylene group. 5. A complex according to any preceding claim, having the formula II, wherein each of R4, R5 and R6 is independently selected from hydrogen, alky, cycloalkyl, haloalkyl, aryl, haloaryl and heteroaryl, and R1-3 and M are as defined in claim 1. 6. A complex according to claim 5 wherein each of R4, R5 and R6 is independently selected from H, methyl, t-butyl, phenyl and trifluoromethyl. 7. A complex according to any preceding claim wherein M is Sn(II). 8. A complex according to any one of claims 1 to 7 having the formula III wherein Ar is o-diisopropylphenyl. 9. A complex according to any one of claims 1 to 6 wherein M is Mg(II). 10. A complex according to any one of claim 9 having the formula IV wherein Ar is o-diisopropylphenyl. 11. A complex according to any one of claims 1 to 8 having the formula V wherein R1-3 and M are as defined in claim 1, and wherein each of R7 and R8 is independently selected from H, alkyl, cycloalkyl, haloalkyl, aryl, haloaryl and heteroaryl. 12. A complex according to claim 11 wherein R7 is H and R8 is methyl. 13. A complex according to claim 11 or claim 12 having the formula VI wherein Ar is o-diisopropylphenyl. 14. A complex comprising a dimer of a complex according to any preceding claim. 15. A dimer according to claim of formula VII 16. A dimer according to claim 15 of formula VIII wherein Ar is o-diisopropylphenyl. 17. Use of a complex according to any one of claims 1 to 16 as a polymerisation initiator. 18. Use according to claim 17 in the polymerisation of lactide. 19. Use according to claim 18 wherein the lactide is rac-lactide. 20. A process for the polymerisation of lactide, said process comprising contacting an initiating amount of a complex according to any one of claims 1 to 16 with a lactide monomer in the presence of a suitable solvent. 21. A process according to claim 20 wherein the ratio of lactide monomer to the complex is between 100:1 and 20000:1. 22. An article prepared by a process according to 20 or claim 21. 23. An article according to claim 22 wherein said article is a medical article. 24. A composition comprising lactide monomer and a complex according to any one of claims 1 to 16. 25. A composition comprising poly(lactide) and a complex according to any one of claims 1 to 16. 26. A composition comprising poly(lactide) and a complex according to any one of claims 1 to 16, wherein said complex is deactivated, for example, by the addition of methanol. 27. A process for preparing a complex of formula I, said process comprising the steps of: (i) reacting a compound of formula IX, wherein each of Z′ and Z″ is independently H (where —NR1 and/or —NR2 is an amino group) or absent (where —NR1 and/or —NR2 is an imino group), with nBuLi to form a compound of formula X; (ii) reacting said compound of formula X with MCln to form a compound of formula XI, wherein M is selected from Sn(II), Mg(II), Al(Ill) and Sn(IV) and n is 2, 2, 3 or 4 respectively; (ii) reacting said compound of formula XI with LiOR3 to form a complex of formula I; wherein X and R1-3 are as defined in claim 1. 28. A process for preparing a complex of formula XIII, said process comprising the steps of: (i) reacting a compound of formula IX, wherein each of Z′ and Z″ is independently H (where —NR1 and/or —NR2 is an amino group) or absent (where —NR1 and/or —NR2 is an imino group), with MgMe2 to form a compound of formula XII; (ii) reacting said compound of formula XII with R3OH to form a compound of formula XIII; wherein X and R1-3 are as defined in claim 1. 29. A process for preparing a complex of formula XIII, said process comprising the steps of: (i) reacting a compound of formula IX, wherein each of Z′ and Z″ is independently H (where —NR1 and/or —NR2 is an amino group) or absent (where —NR1 and/or —NR2 is an imino group), with (a) nBuLi and (b) R3MgCl to form a compound of formula XIV; (ii) reacting said compound of formula XIV with O2 to form a complex of formula XIII; wherein X and R1-3 are as defined in claim 1. |
System, process and software arrangement for recognizing handwritten characters |
A process and system are provided for determining a most likely combination of characters. In particular, character data which includes information indicative of at least one handwritten character is obtained. The character data includes at least one set of segmentation points for the handwritten character. Then, a score can be provided for each particular character of a set of previously stored characters based on a comparison between the character data and the previously stored particular character. In addition, it is possible to compare visual aspects of the handwritten character to visual aspects of each of the previously stored characters for determining likely characters. Also, a Fisher Matching procedure can be used on the character data to ascertain the likely characters. A plurality of handwritten characters can include a first character that is connected to a second character of the handwritten characters via a ligature. A further score of the ligature can be determined based on a starting point of the ligature and an ending point of the ligature. Furthermore, the first character can be connected to the second character via a transition. A particular score of the transition can be ascertained based on a difference in length of the first character and the second character. This particular score can be combined with a score corresponding to the particular handwritten characters. |
1. A process for determining a most likely combination of characters, comprising the steps of: a) obtaining character data which includes information indicative of at least one handwritten character, the character data including at least one set of segmentation points for the at least one handwritten character; and b) providing a score for each particular character of a set of previously stored characters based on a comparison between the character data and the respective stored particular character. 2. The process according to claim 1, further comprising the step of: c) prior to steps (a) and (b), generating the character data after a user completes entering handwritten characters on an input device. 3. The process according to claim 2, wherein the character data corresponds to a handwritten word. 4. The process according to claim 1, wherein the score is provided for each of the previously stored characters by analyzing a predetermined number of the segmentation points of the character data. 5. The process according to claim 2, wherein the character data is generated when the user disconnects a writing instrument from the input device. 6. The process according to claim 1, wherein the character data includes cursive data corresponding to at least one handwritten cursive character and script data corresponding to at least one handwritten script character. 7. The process according to claim 1, wherein the score for each of the previously stored characters is recorded at predetermined time intervals. 8. The process according to claim 1, wherein the score for a current previously stored character is based on previous scores of a word path associated with a current previously stored character. 9. The process according to claim 8, wherein the score is the average of total scores for the previously stored characters corresponding to the word path. 10. The process according to claim 8, further comprising the step of: d) removing the word path from being considered as the most likely combination of characters, the word path corresponding to a characters sequence. 11. The process according to claim 10, wherein step (d) includes the substep of determining whether the character sequence is to be filtered out based on the score associated with the word path of the character sequence. 12. The process according to claim 11, wherein the determining substep is performed based on a total number of the character sequences. 13. The process according to claim 1, further comprising the step of: e) normalizing the score, and recording the normalized score in a storage arrangement. 14. The process according to claim 13, wherein step (e) is performed for each of the previously stored characters. 15. The process according to claim 1, wherein the character data corresponds to a sequence of handwritten characters, and further comprising the step of: f) determining if the sequence exists in a dictionary. 16. The process according to claim 15, wherein step (f) is performed for each of sequences of a plurality of handwritten characters at predetermined time intervals. 17. The process according to claim 15, wherein the dictionary has a tree-type structure, and wherein step (f) is performed by evaluating whether every character of the sequence is provided at a particular node of the tree-type structure of the dictionary. 18. The process according to claim 15, further comprising the step of: g) if the sequence is not in the dictionary, removing the sequence from being considered as the most likely combination of characters. 19. The process according to claim 15, further comprising the step of: h) if the sequence is not in the dictionary, arranging the score for the sequence to be at least one of lowered or unchanged. 20. The process according to claim 1, wherein the at least one handwritten character includes a plurality of handwritten characters, wherein a first character of the handwritten characters is connected to a second character of the handwritten characters via a ligature, and further comprising the step of: i) determining a further score of the ligature based on a starting point of the ligature and an ending point of the ligature. 21. The process according to claim 20, wherein the further score is combined with the score corresponding to the previously stored characters to form a combined score. 22. The process according to claim 1, further comprising the steps of: j) assigning a vector corresponding to each of the handwritten characters; and k) comparing each of the vectors to recorded vectors which correspond to the previously stored characters. 23. The process according to claim 22, wherein step (k) is performed by applying a Fisher technique to the vectors corresponding to the handwritten characters. 24. The process according to claim 23, further comprising the step of: l) comparing the vectors corresponding to the handwritten characters to a cluster of vectors corresponding to the previously stored characters. 25. The process according to claim 24, wherein step (l) is performed by measuring a Euclidean distance from the vector corresponding to the handwritten characters to each of the clusters. 26. The process according to claim 25, wherein the Euclidean distance is determined from a center of each of the clusters. 27. The process according to claim 1, wherein the at least one handwritten character includes a plurality of handwritten characters, wherein a first character of the handwritten characters is connected to a second character of the handwritten characters via a transition, and further comprising the steps of: m) determining a further score of the transition based on a difference in length of the first character and the second character; and n) combining the further score with the score corresponding to the particular characters to form a combined score. 28. The process according to claim 27, wherein step (m) is determined based on a height difference ratio (MH), a top difference ratio (MT) and a bottom difference ratio (MB) of the first character and the second character. 29. The process according to claim 28, wherein each of the previously stored handwritten characters are assigned to at least one of three classes of characters based on vertical extension dimensions thereof. 30. The process according to claim 29, wherein a first class of the three classes includes first characters which extend beyond a predetermined top position, wherein a second class of the three class includes second characters which extend below a predetermined bottom position, and wherein a third class of the three classes includes third characters which do not extend above the predetermined top position or below the predetermined bottom position. 31. The process according to claim 28, wherein the further score (VBScore) is determined according to the following: VBScore(<c1, c2>)=kH·MH(<c1, c2>)+kT·MT(<c1, c2>)+kB·MB(<c1, c2>), where c1 is the first character, c2 is the second character, kH is a height position coefficient, kT is a top position coefficient, and kB is a bottom position coefficient. 32. The process according to claim 31, wherein the height, top and bottom position coefficients are estimated. 33. The process according to claim 31, wherein the height, top and bottom position coefficients are the same for each pair of the three classes. 34. The process according to claim 31, further comprising the steps of: o) generating a histogram for each pair of the three classes; and p) estimating at least one of the height, top and bottom position coefficients based on the histograms. 35. The process according to claim 1, further comprising the step of: q) prior to steps (a) and (b), segmenting the at least one handwritten character to produce a plurality of segmentation points for the character data. 36. The process according to claim 35, further comprising the step of: r) adding a further segmentation point between two neighboring segmentation points of the plurality of segmentation points if a Euclidean distance between the two neighboring segmentation points if the Euclidean distance is greater than a predetermined threshold. 37. The process according to claim 35, further comprising the steps of: s) establishing a segment between two neighboring segmentation points of each pair of the plurality of segmentation points; and t) assigning a predetermined code to each of the segments using a previously stored list of codes. 38. The process according to claim 37, wherein the predetermined code is assigned to each respective segment based on a similarity of a curvature of the respective segment and a list of previously stored extensions. 39. The process according to claim 38, wherein each respective segment is normalized to be comparable with the previously stored extensions. 40. A process for ascertaining one or more particular characters from character data associated with a handwriting, comprising the steps of: a) obtaining the character data which includes information indicative of at least one handwritten character; and b) comparing visual aspects of the at least one handwritten character to visual aspects of each of previously stored characters to ascertain the one or more particular characters. 41. The process according to claim 40, wherein the at least one handwritten character includes a plurality of handwritten characters, and wherein step (b) includes comparing at least one of a respective angle and a position of two neighboring characters of the handwritten characters. 42. The process according to claim 40, further comprising the step of: c) prior to steps (a) and (b), segmenting the at least one handwritten character to produce a plurality of segmentation points for the character data. 43. The process according to claim 42, further comprising the step of: d) providing a score for each of previously stored characters based on a comparison between the character data and the respective previously stored particular character. 44. The process according to claim 42, further comprising the steps of: e) establishing a segment between two neighboring segmentation points of each pair of the plurality of segmentation points; and f) assigning a predetermined code to each of the segments using a previously stored list of codes. 44. The process according to claim 44, wherein the predetermined code is assigned to each respective segment based on a similarity of a curvature of the respective segment and a list of previously stored extensions. 45. The process according to claim 43, wherein the score is provided for each of the previously stored characters by analyzing the a predetermined number of the segmentation points of the character data. 46. The process according to claim 45 wherein the character data is generated when the user disconnects a writing instruments from the input device. 47. The process according to claim 43, wherein the score for each previously stored character is recorded at a predetermined time intervals. 48. The process according to claim 43, wherein the score for a current previously stored character is based on previous scores of a word path associated with a current previously stored character. 49. The process according to claim 48, wherein the score is an average of total scores for the previously stored characters corresponding to the word path. 50. The process according to claim 40, wherein the character data includes cursive data corresponding to at least one handwritten cursive character and script data corresponding to at least one handwritten script character. 51. The process according to claim 40, further comprising the steps of: g) assigning a vector corresponding to each of the handwritten characters; and h) comparing each of the vectors to recorded vectors which correspond to the previously stored characters. 52. The process according to claim 51, further comprising the step of: i) comparing the vectors corresponding to the handwritten characters to a cluster of vectors corresponding to the previously stored characters. 53. The process according to claim 52, wherein step (i) is performed by measuring a Euclidean distance from the vector corresponding to the handwritten characters to each of the clusters. 54. The process according to claim 53, wherein the Euclidean distance is determined from a center of each of the clusters. 55. The process according to claim 43, wherein the at least one handwritten character includes a plurality of handwritten characters, wherein a first character of the handwritten characters is connected to a second character of the handwritten characters via a transition, and further comprising the steps of: j) determining a further score of the transition based on a difference in length of the first character and the second character; and k) combining the further score with the score corresponding to the previously stored characters to form a combined score. 56. The process according to claim 55, wherein step (k) is determined based on a height difference ratio (MH), a top difference ratio (MT) and a bottom difference ratio (MB) of the first character and the second character. 57. The process according to claim 56, wherein each of the previously stored handwritten characters are assigned to at least one of three classes of characters based on vertical extension dimensions thereof. 58. The process according to claim 57, wherein a first class of the three classes includes first characters which extend beyond a predetermined top position, wherein a second class of the three class includes second characters which extend below a predetermined bottom position, and wherein a third class of the three classes includes third characters which do not extend above the predetermined top position or below the predetermined bottom position. 59. The process according to claim 56, wherein the further score (VBScore) is determined according to the following: VBScore(<c1, c2>)=kH·MH(<c1, c2>)+kT·MT(<c1, c2>)+kB·MB(<c1, c2>), where c1 is the first character, c2 is the second character, kH is a height position coefficient, kT is a top position coefficient, and kB is a bottom position coefficient. 60. The process according to claim 61, wherein the height, top and bottom position coefficients are estimated. 61. The process according to claim 61, wherein the height, top and bottom position coefficients are the same for each pair of the three classes. 62. The process according to claim 61, further comprising the steps of: l) generating a histogram for each pair of the three classes; and m) estimating at least one of the height, top and bottom position coefficients based on the histograms. 63. The process according to claim 40, further comprising the step of: n) prior to steps (a) and (b), segmenting the at least one handwritten character to produce a plurality of segmentation points for the character data. 64. The process according to claim 63, further comprising the step of: o) adding a further segmentation point between two neighboring segmentation points of the plurality of segmentation points if a Euclidean distance between the two neighboring segmentation points is greater than a predetermined threshold. 65. The process according to claim 63, further comprising the steps of: p) establishing a segment between two neighboring segmentation points of each pair of the plurality of segmentation points; and q) assigning a predetermined code to each of the segments using a previously stored list of codes. 66. The process according to claim 65, wherein the predetermined code is assigned to each respective segment based on a similarity of a curvature of the respective segment and a list of previously stored extensions. 67. The process according to claim 66, wherein each respective segment is normalized to be comparable with the previously stored extensions. 68. The process according to claim 40, further comprising the step of: r) performing a training procedure to obtain at least two variations of the same character. 69. The process according to claim 68, wherein step (r) is performed using a Fisher technique. 70. A process for ascertaining one or more particular characters from character data associated with a handwriting, comprising the steps of: a) obtaining the character data which includes information indicative of at least one handwritten character; and b) applying a Fisher Matching procedure on the character data to as certain the one or more particular characters. 71. A process for ascertaining at least one particular character from character data associated with a handwriting, comprising the steps of: a) obtaining the character data associated with handwritten characters, a first character of the handwritten characters being connected to a second character of the handwritten characters via a ligature; and b) determining a further score of the ligature based on a start point of the ligature and an end point of the ligature. 72. The process according to claim 71, further comprising the steps of: c) assigning a vector corresponding to each of the handwritten characters; and d) comparing each of the vectors to recorded vectors which correspond to previously stored characters. 73. The process according to claim 72, wherein step (d) is performed by applying a Fisher technique to the vectors corresponding to the handwritten characters. 74. The process according to claim 73, further comprising the step of: e) comparing the vectors corresponding to the handwritten characters to a cluster of vectors corresponding to the previously stored characters. 75. The process according to claim 74, wherein step (e) is performed by measuring a Euclidean distance from the vector corresponding to the handwritten characters to each of the clusters. 76. The process according to claim 75, wherein the Euclidean distance is determined from a center of each of the clusters. 77. A process for ascertaining at least one particular handwritten character from character data associated with handwritten characters, comprising the steps of: a) obtaining the character data, wherein a first character of the handwritten characters is connected to a second character of the handwritten characters via a transition; b) determining a particular score of the transition based on a difference in length of the first character and the second character; and c) combining the particular score with a score corresponding to the handwritten characters to form a combined score. 78. The process according to claim 77, wherein step (b) is determined based on a height difference ratio (MH), a top difference ratio (MT) and a bottom difference ratio (MB) of the first character and the second character. 79. The process according to claim 78, further comprising the step of: d) assigning each of previously stored handwritten characters to at least one of three classes of characters based on vertical extension dimensions thereof. 80. The process according to claim 79, wherein a first class of the three classes includes first characters which extend beyond a predetermined top position, wherein a second class of the three class includes second characters which extend below a predetermined bottom position, and wherein a third class of the three classes includes third characters which do not extend above the predetermined top position or below the predetermined bottom position. 81. The process according to claim 78, wherein the particular score (VBScore) is determined according to the following: VBScore(<c1, c2>)=kH·MH(<c1, c2>)+kT·MT(<c1, c2>)+kB·MB(<c1, c2>), where c1 is the first character, c2 is the second character, kH is a height position coefficient, kT is a top position coefficient, and kB is a bottom position coefficient. 82. The process according to claim 81, wherein the height, top and bottom position coefficients are estimated. 83. The process according to claim 81, wherein the height, top and bottom position coefficients are the same for each pair of the three classes. 84. The process according to claim 81, further comprising the steps of: e) generating a histogram for each pair of the three classes; and f) estimating at least one of the height, top and bottom position coefficients based on the histograms. 85. A software system which, when executed on a processing device, configures the processing device to determine a most likely combination of characters, the software system comprising: a processing subsystem which, when executed on the processing device, configures the processing device to perform the following: a) obtain character data which includes information indicative of at least one handwritten character, the character data including at least one set of segmentation points for the at least one handwritten character, and b) provide a score for each particular character of a set of previously stored characters based on a comparison between the character data and the respective previously stored particular character. 86. The software system according to claim 85, wherein, when executed on the processing device, the processing subsystem is capable of generating the character data after a user completes entering handwritten characters on an input device. 87. The software system according to claim 86, wherein the character data corresponds to a handwritten word. 88. The software system according to claim 86, wherein the score is provided for each of the previously stored characters by analyzing a predetermined number of the segmentation points of the character data. 89. The software system according to claim 86, wherein the character data is generated when the user disconnects a writing instrument from the input device. 90. The software system according to claim 85, wherein the character data includes cursive data corresponding to at least one handwritten cursive character and script data corresponding to at least one handwritten script character. 91. The software system according to claim 85, wherein the score for each of the previously stored characters is recorded at predetermined time intervals. 92. The software system according to claim 85, wherein the score for a current previously stored character is based on previous scores of a word path associated with a current previously stored character. 93. The software system according to claim 92, wherein the score is the average of total scores for the previously stored characters corresponding to the word path. 94. The software system according to claim 92, wherein, when in operation, the processing subsystem is configured to remove the word path from being considered as the most likely combination of characters, the word path corresponding to a characters sequence. 95. The software system according to claim 94, wherein, when in operation, the processing subsystem is configured to determines whether the character sequence is to be filtered out based on the score associated with the word path of the character sequence. 96. The software system according to claim 95, wherein, when in operation, the processing subsystem is configured to make the determination regarding the character sequences based on a total number of the character sequences. 97. The software system according to claim 85, wherein, when in operation, the processing subsystem is configured to normalize the score, and record the normalized score in a storage arrangement. 98. The software system according to claim 85, wherein the character data corresponds to a sequence of handwritten characters, and wherein, when in operation, the processing subsystem is configured to determine if the sequence exists in a dictionary. 99. The software system according to claim 98, wherein the determination regarding the existence of the sequence is performed for each of sequences of a plurality of handwritten characters at predetermined time intervals. 100. The software system according to claim 98, wherein the dictionary has a tree-type structure, and wherein the determination regarding the existence of the sequence is performed by evaluating whether every character of the sequence is provided at a particular node of the tree-type structure of the dictionary. 101. The software system according to claim 98, wherein, when in operation, the processing subsystem is configured to remove the sequence from being considered as the most likely combination of characters if the sequence is not in the dictionary. 102. The software system according to claim 98, wherein, when in operation, the processing subsystem is configured to arrange the score for the sequence to be at least one of lowered or unchanged if the sequence is not in the dictionary. 103. The software system according to claim 85, wherein the at least one handwritten character includes a plurality of handwritten characters, wherein a first character of the handwritten characters is connected to a second character of the handwritten characters via a ligature, and wherein, when in operation, the processing subsystem is configured to determine a further score of the ligature based on a starting point of the ligature and an ending point of the ligature. 104. The software system according to claim 102, wherein the further score is combined with the score corresponding to the previously stored characters to form a combined score. 105. The software system according to claim 85, wherein, when in operation, the processing subsystem is configured to: c) assign a vector corresponding to each of handwritten characters, and d) compare each of the vectors to recorded vectors which correspond to the previously stored characters. 106. The software system according to claim 105, wherein the comparison is performed by applying a Fisher technique to the vectors corresponding to the handwritten characters. 107. The software system according to claim 106, wherein, when in operation, the processing subsystem is configured to compare the vectors corresponding to the handwritten characters to a cluster of vectors corresponding to the previously stored characters. 108. The software system according to claim 107, wherein the comparison of the vectors is performed by measuring a Euclidean distance from the vector corresponding to the handwritten characters to each of the clusters. 109. The software system according to claim 108, wherein the Euclidean distance is determined from a center of each of the clusters. 110. The software system according to claim 85, wherein the at least one handwritten character includes a plurality of handwritten characters, wherein a first character of the handwritten characters is connected to a second character of the handwritten characters via a transition, and wherein, when in operation, the processing subsystem is configured to: e) determine a further score of the transition based on a difference in length of the first character and the second character, and f) combine the further score with the score corresponding to the particular characters to form a combined score. 111. The software system according to claim 110, wherein the further score is determined based on a height difference ratio (MH), a top difference ratio (MT) and a bottom difference ratio (MB) of the first character and the second character. 112. The software system according to claim 111, wherein each of the previously stored handwritten characters are assigned to at least one of three classes of characters based on vertical extension dimensions thereof. 113. The software system according to claim 112, wherein a first class of the three classes includes first characters which extend beyond a predetermined top position, wherein a second class of the three class includes second characters which extend below a predetermined bottom position, and wherein a third class of the three classes includes third characters which do not extend above the predetermined top position or below the predetermined bottom position. 114. The software system according to claim 111, wherein the further score (VBScore) is determined according to the following: VBScore(<c1, c2>)=kH·MH(<c1, c2>)+kT·MT(<c1, c2>)+kB·MB(<c1, c2>), where c1 is the first character, c2 is the second character, kH is a height position coefficient, kT is a top position coefficient, and kB is a bottom position coefficient. 115. The software system according to claim 114, wherein the height, top and bottom position coefficients are estimated. 116. The software system according to claim 114, wherein the height, top and bottom position coefficients are the same for each pair of the three classes. 117. The software system according to claim 114, wherein, when in operation, the processing subsystem is configured to: g) generate a histogram for each pair of the three classes, and h) estimate at least one of the height, top and bottom position coefficients based on the histograms. 118. The software system according to claim 85, wherein, when in operation, the processing subsystem is configured to segment the at least one particular character to produce a plurality of segmentation points for the character data. 119. The software system according to claim 118, wherein, when in operation, the processing subsystem is configured to add a further segmentation point between two neighboring segmentation points of the plurality of segmentation points if a Euclidean distance between the two neighboring segmentation points is greater than a predetermined threshold. 120. The software system according to claim 11 8, wherein, when in operation, the processing subsystem is configured to: i) establish a segment between two neighboring segmentation points of each pair of the plurality of segmentation points and j) assign a predetermined code to each of the segments using a previously stored list of codes. 121. The software system according to claim 120, wherein the predetermined code is assigned to each respective segment based on a similarity of a curvature of the respective segment and a list of previously stored extensions. 122. The software system according to claim 121, wherein each respective segment is normalized to be comparable with the previously stored extensions. 123. A software system which, when executed on a processing device, configures the processing device to ascertain one or more particular characters from character data associated with a handwriting, the software system comprising: a processing subsystem which, when executed on the processing device, configures the processing device to perform the following steps: a) obtaining the character data which includes information indicative of at least one handwritten character, and b) comparing visual aspects of the at least one handwritten character to visual aspects of each of previously stored characters to ascertain the one or more particular characters. 124. A software system which, when executed on a processing device, configures the processing device to ascertain one or more particular characters from character data associated with a handwriting, the software system comprising: a processing subsystem which, when executed on the processing device, configures the processing device to perform the following steps: a) obtaining the character data which includes information indicative of at least one handwritten character, and b) applying a Fisher Matching procedure on the character data to ascertain the one or more particular characters. 125. A software system which, when executed on a processing device, configures the processing device to ascertain at least one particular character from character data associated with handwritten characters, the software system comprising: a processing subsystem which, when executed on the processing device, configures the processing device to perform the following steps: a) obtaining the character data associated with handwritten characters, a first character of the handwritten characters being connected to a second character of the handwritten characters via a ligature, and b) determining a further score of the ligature based on a starting point of the ligature and an ending point of the ligature. 126. A software system which, when executed on a processing device, configures the processing device to ascertain at least one particular handwritten character from character data associated with handwritten characters, the software system comprising: a processing subsystem which, when executed on the processing device, configures the processing device to perform the following steps: a) obtaining the character data, wherein a first character of the handwritten characters is connected to a second character of the handwritten characters via a transition, b) determining a particular score of the transition based on a difference in length of the first character and the second character, and c) combining the particular score with a score corresponding to the particular handwritten characters to form a combined score. |
<SOH> BACKGROUND INFORMATION <EOH>Currently, technologies such as microcomputers, word processors, fax machines and electronic mails utilize electronic handwriting recording and recognition techniques to enable a useful and versatile communication between such devices. In particular, conventional computer-based handwriting analysis methods include a recognition and interpretation of characters, as well as a verification of the handwritten data. The known electronic handwriting recognition procedures generally transcribe a message, represented in a spatial form of graphical marks, into a computer text, e.g., into a sequence of 8-bit ASCII characters. These handwriting interpretation techniques generally determine the most likely meaning of a particular handwritten text, e.g., a mailing address written on an envelope. The handwriting verification techniques are used to determine whether the handwritten text belongs to a particular individual, and can be used in, e.g., the forensic investigations. The handwriting recognition techniques can be considered as being in two separate categories—on-line recognition and off-line recognition. The on-line handwriting recognition techniques are generally used with a transducer/input device is connected to a computer which is available to the user. One such arrangement is shown in FIG. 1 , which illustrates an on-line handwriting recognition system 5 that can also be used with conventional techniques and techniques according to the present invention. The transducer/input device converts the user's writing motion into a sequence of signals, and sends this signal information to a computer 50 . The computer 50 generally includes a handwriting recognition system. An exemplary transducer can be a tablet digitizer 10 . This tablet digitizer 10 generally includes a plastic or electronic pen 15 and a pressure or electrostatic-sensitive writing surface 20 on which the user provides the handwritten information using the pen 15 . By sampling or tracking the movement of a tip of the pen 15 on the writing surface 20 , the tablet digitizer 10 is able to detect certain information when the pen 15 is in contact with the writing surface 20 e.g., the x and y coordinates of a sampled point on the writing surface 20 , providing information indicative of whether the pen 15 touches the writing surface 20 (“pen-down state” or has been removed therefrom—“pen-up state”, etc.). The information is transmitted to the connected computer 50 for recognition processing by the handwriting recognition system. A “stroke” in the data in the “on-line” recognition system can be defined as a sequence of sampled points from the pen-down state to the pen-up state of the pen 15 . Thus, the completed writing of a word would likely consist of a sequence of one or more strokes. The tablet digitizer 10 then captures the temporal (dynamic) data of the word when it samples the points on the contours that the user is forming. The off-line handwriting recognition techniques are generally related to the field of Optical Character Recognition (“OCR”). In contrast to the on-line handwriting recognition techniques, these off-line techniques are not interactive. In the exemplary OCR system, a machine-printed material is scanned into a computer file in two-dimensional image representation using a scanner. Then, the off-line handwriting recognition technique of this conventional OCR system attempts to recognize the scanned handwritten data. One of the benefits of the on-line handwriting recognition techniques which set them apart from the off-line handwriting OCR or other image recognition techniques is their ability to utilize the temporal and dynamic input sequence information which is provided directly by the user in real-time. This dynamic information obtained by the on-line handwriting recognition techniques provides a vivid separation of the foreground from the background, and thus can bypass the pre-processing procedures that are required to be performed by the off-line handwriting recognition techniques. Also, the obtained on-line dynamic information is generally more compact than the off-line information because of the different dimensionalities in representation. The difference in the data size also leads to the difference in the processing time. Another advantage of the on-line handwriting recognition techniques is their use of the sequence information of the data received thereby which allows the character boundary segmentation easier to be performed. After the preprocessing stage, most handwriting recognition systems and methods attempt to separate their received data into intervals/segments (which correspond to hypothetical characters), and apply an evaluation process to such intervals/segments. The recognition performance of such system and process is substantially dependent on the quality and robustness of the character segmentation. Due to the cues available from the temporal ordering of its input data, the on-line handwriting recognizer may generate the segmentations in a reliable and efficient manner. For example, when the two neighboring characters overlap in the respective occupying regions, it is significantly more difficult for an off-line recognition system and method to segment such characters correctly. This is because any simple geometric separation would likely contain a portion of at least one of the characters. Using the on-line handwriting recognition system, it would be easier to handle the above-described scenario. As known to those having ordinary skill in the art, the handwriting recognition systems (whether on-line or off-line) are designed to support three different styles, i.e., a printed style, a cursive style and a mixed style. Recognizing the printed style of handwriting is, most likely, simpler than recognizing other handwriting styles. This is because each character of such style has clearer boundaries with its neighboring characters. For example, the characters in the printed style are usually separated by the “pen-up” signal in the on-line handwriting recognition system. In recognizing the cursive handwritten script, however, most of the component characters are connected to their neighbors by a sub-stroke (i.e., a “ligature”) which is not a part of any character or letter, but only a connecting pattern between two characters/letters. In this situation, it is more difficult to hypothesize about the character segmentation since there is less information regarding the likely segmentation boundaries of each character. Handwritings having a printed style can be regarded as a subset of the cursive mode recognition, and the mixed mode can be obtained as a by-product of obtaining both printed and cursive modes support. Therefore, one having ordinary skill in the art would understand that it is the hardest task to recognize characters in the cursive mode. Conventional handwriting recognition systems and methods can be writer-independent or writer-dependent. For example, writer-independent systems can handle the idiosyncrasies of user's writing styles, and writer-dependent systems are trained to recognize a single user's writing style. It is possible to have the same character (or a class of character) written in different ways, e.g., so that they are in different subclasses or allographs. Therefore, each character class usually consists of one or more subclasses. Correctly identifying a good set of allographs is a challenging task which requires a recording of a huge number of samples, which usually cannot be done by the conventional systems and methods. Also, a larger number of subclasses/allographs would require additional time for processing for such conventional systems which would not be preferable, especially when using an on-line character recognition system or method. |
<SOH> SUMMARY OF THE INVENTION <EOH>Various embodiments of a process and system according to the present invention overcome the above-described deficiencies of the conventional systems and methods. In particular, a process and system are provided which determine the most likely combination of characters. In particular, character data which includes information indicative of at least one handwritten character is obtained, which is preferably on-line data or real-time data. The character data includes at least one set of segmentation points for the handwritten character. Then, a score can be determined for each particular character of a set of previously stored characters based on a comparison between the character data and the respective particular character. In addition, it is possible to generate the character data after a user completes entering handwritten characters on an input device. The character data may correspond to a handwritten word. Also, the score can be provided for each of the previously stored characters by analyzing a predetermined number of the segmentation points of the character data. The character data may be generated when the user disconnects a writing instrument from the input device. The character data can also include cursive data corresponding to at least one handwritten cursive character, and script data corresponding to at least one handwritten script character. According to another embodiment of the present invention, the score for each of the previously stored characters can be recorded at predetermined time intervals. The score for a current previously stored character may be based on previous scores of a word path associated with the current previously stored character. This score can preferably be the average of the total scores for the previously stored characters corresponding to the word path which includes the score for the current previously-stored character. The word path can be removed from being considered to be the most likely combination of characters. Also, the word path preferably corresponds to a characters sequence of the certain characters. A determination can also be made as to whether the character sequence is to be filtered out based on the score associated with the word path of the character sequence. This determination is preferably made based on a total number of the character sequences. In yet another embodiment of the present invention, the score can be normalized, and the normalized score may be stored in a storage arrangement. The character data may also correspond to a sequence of handwritten characters, and it is possible to determine whether the sequence exists in a dictionary. This determination regarding the existence of the sequence may be performed for each of the sequences of a plurality of handwritten characters at predetermined time intervals. Also, the dictionary may have a tree-type structure, and the determination regarding the existence of the sequence can be performed by evaluating whether every character of the sequence is provided at a particular node of this tree-type structure of the dictionary. The sequence can be removed from consideration as being the most likely combination of characters if the sequence is not in the dictionary. In addition, the score for the sequence can be lowered and/or unchanged if the sequence is not in the dictionary. In still another embodiment of the present invention, a first character of the handwritten characters is connected to a second character of the handwritten characters via a ligature, and a further score of the ligature is determined based on a starting and ending points of the ligature. This further score may be combined with the score corresponding to the previously stored characters so as to form a combined score. According to another embodiment of the present invention, a vector corresponding to each of the handwritten characters can be assigned, and a comparison of each of the vectors can be made to vectors corresponding to the previously-stored characters. This comparison can be performed by applying a Fisher technique to the vectors corresponding to the handwritten characters. The vectors corresponding to the handwritten characters can preferably be compared to a cluster of vectors corresponding to the previously stored characters. This comparison of the vectors may be performed by measuring a Euclidean distance from the vector corresponding to the handwritten characters to each of the clusters. The Euclidean distance can be measured from a center of each of the clusters. According to still another embodiment of the present invention, a first character of the handwritten characters may be connected to a second character of the handwritten characters via a transition. A further score of the transition can also be determined based on a difference in length of the first character and the second character, and the further score combined with the score corresponding to the particular characters to form a combined score. This further score is preferably determined based on a height difference ratio (M H ), a top difference ratio (M T ) and a bottom difference ratio (M B ) of the first and the second characters. Each of the previously stored handwritten characters may be assigned to at least one of three classes of characters based on vertical extension dimensions thereof. A first class of the three classes may include first characters which extend beyond a predetermined top position, a second class of the three class includes second characters which extend below a predetermined bottom position, and a third class of the three classes includes third characters which do not extend above the predetermined top position or below the predetermined bottom position. The above-referenced further score (VBScore) can be determined according to the following equation: in-line-formulae description="In-line Formulae" end="lead"? VB Score(< c 1 , c 2 >)= k H ·M H (< c 1 , c 2 >)+ k T ·M T (< c 1 , c 2 >)+ k B ·M B (< c 1 , c 2 >), in-line-formulae description="In-line Formulae" end="tail"? where c 1 is the first character, c 2 is the second character, k H · is a height position coefficient, k T is a top position coefficient and k B is a bottom position coefficient. The height, top and bottom position coefficients can preferably be estimated, and may be the same for each pair of the three classes. A histogram can be generated for each pair of the three classes, and the height, top and/or bottom position coefficients may be estimated based on such histograms. According to yet another embodiment of the present invention, the particular character can be segmented to produce a plurality of segmentation points for the character data. It is possible to insert a further segmentation point on the respective segment between two neighboring segmentation points if the Euclidean distance between two such neighboring segmentation points is this distance greater than a predetermined threshold. Also, the segment is preferably established between two neighboring segmentation points of each pair of the plurality of segmentation points, and a predetermined code is assigned to each of the segments using a previously stored list of codes. This predetermined code can be assigned to each respective segment based on a similarity of a curvature of the respective segment and a list of previously stored extensions. Furthermore, each respective segment is normalized to be comparable with the previously stored extensions. |
Sucking atomizer for gasoline-oxygen cutting-welding |
A jet-inducing atomizer for gasoline-oxygen cutting-welding comprises a main body, a diffusion tube, a preheating oxygen fine-tube and a gasoline fine-tube. The diffusion tube and the preheating oxygen fine-tube are provided at the center of the main body co-axially, and communicated with each other. The gasoline fine-tube enters the main body from one side of the main body, and is communicated with the diffusion tube. The diffusion tube is a conical tube. The coarse end of the conical tube is coincidence with the end face of the body. The fine end of the conical tube is connected with the preheating oxygen fine-tube. The advantages of the gasoline-oxygen cutting machine are as follows: the operation is easy as the gasoline tank needs not be pressurized; there is no leak of gasoline or jet of gasoline in leaking manner during operation. The atomized mixture of gasoline and oxygen is immediately jetted while the oxygen valve is opened, and gasoline is immediately shut off while the oxygen valve is closed. Therefore, safety of operation is increased and the cost is reduced. |
1. A jet-inducing atomizer for gasoline-oxygen cutting-welding comprising a main body of the atomizer, a diffusion tube, a preheating oxygen fine-tube and a gasoline fine-tube, the diffusion tube and the preheating oxygen fine-tube being provided at the center of the main body co-axially, and communicated with each other, the gasoline fine-tube entering the main body from one side of the main body, and being communicated with the diffusion tube, the diffusion tube being a conical tube, the coarse end of the conical tube being coincident with the end face of the body, the fine end of the conical tube being connected with the preheating oxygen fine-tube, the taper α1 of the conical tube equaling to 5°-10°, the length 10 of the conical tube being 2-5 tines of length 11 of the preheating oxygen fine-tube, i.e. 10=(2-5) 11, the length 11 of the preheating oxygen fine-tube being 3-5 mm, the distance 12 between the intersection point of the gasoline fine-tube with the diffusion tube and the connection point of the diffusion tube and the preheating oxygen tube equaling to 2-8 nun. 2. The atomizer as cited in claim 1, wherein the angle α2 between the gasoline fine-tube and the perpendicular surface of the diffusion tube equals to 0-45°. 3. The atomizer as cited in claim 1, wherein the diameter d1 of the preheating oxygen fine-tube equals to 0.5-2.5 mm. 4. The atomizer as cited in claim 1, wherein the diameter d2 of the small end of the diffusion tube equals to 1.5-3 mm. 5. The atomizer as cited in claim 1, wherein the diameter d3 of the gasoline fine tube equals to 0.5-2 mm. |
<SOH> BACKGROUND OF INVENTION <EOH>At present, a series of gasoline-oxygen cutting machines invented by the present applicant can cut steel materials having various thickness. Said cutting machines consist of a cutting nozzle, a special cutting torch and a pressure-stabilized gasoline supply tank, etc. (c.f. ZL95211651.0, ZL94247487.2 and ZL97250604.7). The cutting machines according to said patents have the following deficiencies: when gasoline passes from the gasoline tank to the torch and nozzle by compressed air, the atomizing of gasoline in the cutting torch is not perfect; gasoline often leaks from the outlet of the nozzle while the operation is not appropriate; and gasoline may leak or jet in leaking manner, thus causing unsafety in case the rubber tube connecting the gasoline tank and the cutting torch breaks. |
<SOH> SUMMARY OF INVENTION <EOH>The object of invention is to provide a jet-inducing atomizer for gasoline -oxygen cutting-welding. Based on the principle of hydrodynamics, the atomizer is mounted in the cutting torch, gasoline is sucked from the gasoline tank by an oxygen jet stream under high speed, and is atomized in the cutting torch and the cutting nozzle, and mixed with oxygen, and the mixture is then jetted from the cutting nozzle for ignition to obtain a cutting flame. A Jet-inducing atomizer for gasoline-oxygen cutting-welding according to the present invention comprises a main body of the atomizer, a diffusion tube, a preheating oxygen fine-tube and a gasoline fine-tube. The diffusion tube and the preheating oxygen fine-tube are provided at the center of the main body co-axially, and communicated with each other. The gasoline fine-tube enters the main body from one side of the main body, and is communicated with the diffusion tube. The diffusion tube is a conical tube. The coarse end of the conical tube is coincident with the end face of the body. The fine end of the conical tube is connected with the preheating oxygen fine-tube. The taper α 1 of the conical tube equals to 5°-10°. The length 1 0 of the conical tube is 2-5 times of the length 1 1 of the preheating oxygen fine-tube, i.e. 1 0 =(2-5) 1. The length 1 1 of the preheating oxygen fine-tube is 3-5 mm. The distance 1 2 between the intersection point of the gasoline fine-tube with the diffusion tube and the connection point of the diffusion tube with the preheating oxygen tube equals to 2-8 mm. In the atomizer as mentioned above, the angle α 2 between the gasoline fine-tube and the perpendicular surface of the diffusion tube equals to 0-450. The diameter d 1 of the preheating oxygen fine-tube equals to 0.5-2.5 mm. The diameter d 2 of the small end of the diffusion tube equals to 1.5-3 mm. The diameter d 3 of the gasoline fine tube equals to 0.5-2 mm. The atomizer of the present invention is fixed at the head of the cutting torch or in the preheating oxygen tube. After the preheating oxygen tube is opened, gasoline is sucked into the cutting torch and atomized to obtain cutting flame which is combusted sufficiently, has concentrated flame and is easy to be adjusted. The obvious advantages of the gasoline-oxygen cutting machine according to the invention are as follows: the operation is easy as the gasoline tank needs not be pressurized; there is no leak of gasoline or jet of gasoline in leaking manner during operation. The atomized compound of gasoline and oxygen is immediately jetted while the oxygen valve is opened, and gasoline is immediately shut off while the oxygen valve is closed. Therefore, safety of operation is increased and the cost is reduced. |
Exoenzyme toxin of aeromonas salmonicida, and uses thereof |
A protein toxin named Aeromonas salmonicida exoenzyme T (AcxT), which belongs to the family of ADP-ribosylating toxins, is disclosed as is a Calcium (or other cation concentration) dependent promoter of A. salmonicida. Also disclosed are diagnostic, preventive, and therapeutic techniques, including the preparation of bacterin vaccines based on AexT for inducing immunity against A. salmonicida infections. |
1-29. (canceled) 30. An isolated polypeptide comprising at least one selected epitope or epitopic region of AexT. 31. An isolated nucleic acid fragment encoding the polypeptide of claim 30. 32. An isolated nucleic acid fragment comprising SEQ ID NO:1, or the complement thereof. 33. A method for reducing the susceptibility of fish to infection by a virulent strain of A. salmonicida comprising the intraperitoneal, intramuscular, intradermal, intracellular, spray, immersion, or oral administration to said fish of a composition comprising an immunogenic amount of at least one epitope or epitopic region of AexT, a natural or genetically modified variant thereof, or an antigenic peptide derived or synthesized thereof. 34. The use of the polypeptide of claim 30 in a vaccine for reducing the susceptibility of fish to infection by a virulent strain of A. Salmonicida. 35. The use of the nucleic acid fragment of claim 31 in a vaccine for reducing the susceptibility of fish to infection by a virulent strain of A. salmonicida. 36. The use of the nucleic acid fragment of claim 32 in a vaccine for reducing the susceptibility of fish to infection by a virulent strain of A. salmonicida. 37. A method for the inducement of AexT production in A. salmonicida comprising the growth of A. salmonicida on Ca2+ or other cation depleted medium. 38. A bacterin vaccine for the immunization of fish comprising killed or inactivated A. salmonicida cells in which expression of the polypeptide of claim 31 had been induced prior to the inactivation, or in which A. salmonicida has been manipulated (using recombinant or other means) to constitutively express said polypeptide prior to inactivation. 39. A method for reducing the susceptibility or a poikilothermic fish to infection by a virulent strain of A. salmonicida comprising the intraperitoneal, intramuscular, intradermal, intracellular, spray, immersion, or oral administration to said fish of an immunogenic amount of a composition comprising the nucleic acid fragment as claimed in claim 31, fragments, synthetic oligonucleotides, or DNA sequence homologues thereof. 40. A method for reducing the susceptibility or a poikilothermic fish to infection by a virulent strain of A. salmonicida comprising the intraperitoneal, intramuscular, intradermal, intracellular, spray, immersion, or oral administration to said fish of an immunogenic amount of a composition comprising the nucleic acid fragment as claimed in claim 32, fragments, synthetic oligonucleotides, or DNA sequence homologues thereof. |
<SOH> BACKGROUND OF THE INVENTION <EOH>The fish disease furunculosis derived its name from the characteristic lesions observed as furuncles formed on the surface of fish as a result of infection with Aeromonas salmonicida . This pathogen causes most severe losses in production farms of salmon and trout, and leads to the use of large amounts of antibiotics in closed and open waters for therapy of fununculosis. In order to develop efficient strategies to prevent A. salmonicida outbreaks, it is essential to know the main mechanisms of pathogenicity of A. salmonicida. Several potential virulence factors of A. salmonicida have been described thus far. They include the surface array-layer protein, the hemolysins ASH1, ASH3, ASH4, H-lysin, salmolysin, the serine protease AspA and the Glycerophospholipid:Cholesterol Acyltransferase (GCAT) complexed with lipopolysaccharide (LPS). While there are many reports on potential virulence factors of A. salmonicida , in particular hemolysins, little is known about their activity and their role in pathogenesis. Many of them seem not to play a primary role in pathogenesis, since deletion mutants of GCAT and aspA genes showed neither of them to be essential for acute A. salmonicida -induced furunculosis. AspA however is essential for pro-GCAT processing in broth cultures and might also be involved in activation of other secreted enzymes or toxins. Various attempts have been made to develop vaccines to prevent A. salmonicida infections mainly on the basis of killed cells (bacterins). Current vaccines achieve some level of protection. However, the nature of the antigens in efficient vaccines is not well defined. Significant differences of protein patterns are seen in cultures of A. salmonicida grown in vivo by an intraperitoneal implant technique in rainbow trout compared to cultures grown in vitro in culture medium. Such differences are thought to be the reasons of variable efficacy of former furunculosis vaccines due to a lack of appropriate antigens in certain vaccine preparations. Several pathogenic bacteria use ADP-ribosylation as a key mechanism to modify properties of host cell proteins, thus to modulate their function and induce disease. Hence ADP-ribosylation of eukaryotic regulatory proteins is the underlying pathogenic mechanism of a heterogeneous family of bacterial protein toxins. ADP-ribosylating toxins are broadly distributed among highly pathogenic bacteria and are the primary cause of various severe human diseases such as diphtheria, cholera and pertussis. Among them, the ADP-ribosyltransferase toxin called exoenzyme S (ExoS) of Pseudomonas aeruginosa is one of the most prominent representatives. It is secreted via a type III-dependent secretion mechanism. Type II secretion systems generally have the potential to recognize receptors on target cells, induce biosynthesis of the corresponding toxins, and finally inject these bacterial toxins directly into the host cells without secretion to the medium. Recently, it was shown that ExoS is a bifunctional toxin containing an N-terminal part resembling the Yersiniae YopE toxin which catalyses rho-dependent actin depolymerisation, and a C-terminal ADP-ribosylating domain. Unique to most bacterial toxins, the ADP-ribosylating toxin ExoS does not have a rigid target protein specificity and ribosylates a number of target proteins including IgG3, apolipoprotein A-I, vimentin and several members of the Ras superfamily. Intracellular expression of the amino-terminal domain of ExoS elicits the disruption of actin, while expression of the carboxyl-terminal domain of ExoS possesses FAS (factor activating exoenzyme S)-dependent ADP-ribosyltransferase activity and is cytotoxic to eukaryotic cells. FAS is a member of the 14-3-3 family of proteins that regulate the activity of several eukaryotic enzymes. Prior to this invention, no analogues to ExoS have been found in bacteria other than P. aeruginosa. |
<SOH> SUMMARY OF THE INVENTION <EOH>A protein toxin named Aeromonas salmonicida exoenzyme T (AexT), which belongs to the family of ADP-ribosylating toxins, was identified and characterized in Aeromonas salmonicida , the etiological agent of furunculosis in fish. This discovery has enabled the development of diagnostic, preventative, and therapeutic techniques, including the preparation of traditional or recombinant vaccines based on AexT for inducing immunity against A. salmonicida infections, and including the identification and characterization by known methods of homologous toxins and promoters in other Aeromonas species or other bacterial genera. Also identified and characterized was the Calcium- (or other cation concentration-) dependent promoter of A. salmonicida . This novel promoter is useful for regulating the expression of proteins in recombinant expression systems. In one embodiment, the invention comprises an isolated nucleic acid segment (SEQ ID NO:1) encoding a 50 kDa exoenzyme of A. salmonicida . In another embodiment, the invention comprises a nucleic acid segment that encodes a protein having the amino acid sequence of SEQ ID NO:2, including variants that retain either biological activity or immunogenicity or both. Due to the degeneracy of the genetic code and the possible presence of flanking nucleic acid fragments outside of the coding region, it will be understood that many different nucleic acid sequences may encode the amino acid sequence of SEQ ID NO:2 and variants, and that all such sequences would be encompassed within the present invention. In a further embodiment, a method of producing, protecting, capturing, or preserving AexT toxin by growing A. salmonicida on Ca 2+ or other cations depleted medium is provided. This provides a means of preparing a vaccine that is much more effective than currently available vaccines against A. salmonicida . In another embodiment, the invention relates to the use of AexT as an immunogen and to the use of AexT in a recombinant or traditional vaccine to reduce the incidence of infection by A. salmonicida. In another embodiment, the invention comprises an improved bacterin vaccine in which the production of AexT has been induced prior to inactivation of the A. salmonicida cells, or in which A. salmonicida has been manipulated (using recombinant or other means) to constitutively express AexT prior to inactivation. In a further embodiment, the invention provides a means of diagnosing A. salmonicida , or other bacteria found to contain AexT homologues, by the detection of the AexT protein or the homologous proteins. Also, the invention provides a toxin that in itself may have therapeutic activity in certain unrelated disease states, or for treatment of certain conditions in man or animals. In a further embodiment, the invention comprises an isolated nucleic acid segment (SEQ ID NO:3) encoding the promoter sequence of the gene encoding the AexT protein. This promoter is regulated by Calcium, and possibly by other cations as well as other undefined sensory signals, and is useful for regulating the expression of proteins in recombinant expression systems. The gene aexT encoding the toxin AexT, was identified by broad range toxin gene probes. It was cloned and characterized by sequence analysis. The cloned gene was expressed, and purified AexT was obtained by recombinant gene technology in E. coli . AexT shows significant sequence similarity to the ExoS and ExoT exotoxins of Pseudomonas aeruginosa and to the YopE cytotoxin of Yersiniae sp. Recombinant AexT possesses enzymatic ADP-ribosyltransferase activity. Monospecific polyclonal antibodies directed against purified recombinant AexT cross-react with ExoS and ExoT of P. aeruginosa . Secretion of AexT from freshly isolated strains of A. salmonicida requires medium depleted of free Ca 2+ ions (or other cations) or necessitates contact with fish cells, as demonstrated with cultivated rainbow trout gonad cells. These cells undergo significant morphological changes upon infection through the toxic activity of AexT. The dependence on fish cells or on Ca 2+ (or other cation) restricted conditions for the expression and secretion of the AexT protein toxin by A. salmonicida indicates that regulation of expression of the aexT gene and secretion of AexT is coupled to a type III secretion system. The induction of AexT biosynthesis in A. salmonicida is regulated through contact with target cells via a sensory process similar to that found in Yersiniae sp. as indicated by the orfX gene flanking the aexT gene. The orfX shows high similarity to the gene for specific Yop chaperon E (sycE) of Yersiniae . SycE serves as a secretion signal and is part of the type III secretion pathway for secretion of YopE. Cultures of the A. salmonicida type strain ATCC 33658 T , which were passaged in vitro for a large number of generations, and which seem to have lost virulence, do not produce significant amounts of AexT and do not affect rainbow trout gonad cells morphologically upon infection in spite of the presence of the aexT gene, in contrast to a fresh field isolate of A. salmonicida . The ADP-ribosylating toxin AexT is a determinative virulence factor of A. salmonicida and is expected to provide new insights in basic mechanisms of virulence of this pathogen, and potentially a protective antigen for vaccination against furunculosis. Sequence Listing The nucleic and amino acid sequences listed in the accompanying sequence listing are shown using standard letter abbreviations for nucleotide bases, and one letter code for amino acids. Only one strand of each nucleotide acid sequence is shown, but the complementary strand is understood as included by any reference to the displayed strand. Aeromonas salmonicida gene for aexT complete coding DNA sequence. ATGCAGA TTCAAGCAAA CACCGTCGGC Seq ID 1 ACACAGGCCG TCGCTCACCA CAGTGATGCC ACGACCGGAG TTGGCCGGAT GGGTCAGATG GAGGCGCGTC AGGTCGCCAC CGGACAAGAT GCGATCCTGC TGGGCAGTCG CAGCGAACCG CAAAAAGGGC AGGGGCTGCT CTCGCGACTG GGGGCCCAGC TGGCCCGCCC GTTCGTGGCC ATCAAAGAGT GGATCAGCAA CCTGCTGGGG ACGGACAAGC GTGCCGCTGC GCCGAAGGCG CAAACCGCCG TTTCCCCCGA GGATCTTCAG CGACTGATGA AGCAGGCTGC ATTTGGTAGC TCGCTGGGTG GCTTCGCCAA GGCGGACGTG TTGAACAACA TCACAGGCGA ACAATTGGGC AAGGATCACG CCAGTCTGGC GACCGGCAAT GGCCCCCTGC GCTCTCTCTG CACCGCGTTG CAGGCCGTTG TCATAGGATC TCAGCAACCG CAACTCCGGG AGTTGGCTAC CGGGCTGCTG GCCCGCCCCA TCGCCGGTAT CCCGCTCCAG CAGTGGGGGT CGGTAGGCGG CAAGGTGACC GAGCTGCTCA CCAGCGCCCC CCCCGAACTG TTGAAGGAGG CTATGAGCCA GCTACACACC GCGATGGGTG AAGTTGCCGA CCTGCAGCGC GCTGTAAAGG CAGAAGTTGC TGGCGAACCG GCGCGAAGCG CGACCACAGC GGCCGCTGTG GCGCCGCTCC AAAGCGGTGA GAGCGAAGTT AACGTTGAGC CTGCCGACAA GGCGCTGGCA GAGGGCTTGC AGGAGCAATT CGGCCTGGAG GCCGAGCAAT ATCTGGGTGA ACAGCCCCAC GGTACTTACA GCGATGCTGA AGTGATGGCG CTTGGGCTCT ACACCAACGG CGAATACCAG CACCTGAATC GCTCGCTGCG TCAGGAAAAG CAGCTGGATG CAGGGCAAGC GTTGATCGAT CAGGGTATGT CCACCGCTTT TGAGAAAAGT ACCCCCACCG AGCAGTTGAT CAAGACCTTC CGCGGTACCC ACGGCGGCGA TGCGTTCAAC GAGGTGGCAG AGGGGCAAGT CGGTCATGAT GTCGCTTATC TTTCCACCTC TCGGGATCCC AAGGTGGCAA CCAACTTTGG TGGTTCAGGC TCCATATCCA CGATATTTGG CCGCTCGGGG ATCGATGTCA GCGACATATC CGTTGAAGGT GACGAGCAGG AGATCCTCTA TAACAAAGAG ACTGATATGC GGGTATTGCT CAGTGCCAAA GATGAACGGG GCGTCACCCG GCGGGTACTG GAAGAGGCCT CGCTGGGGGA ACAAAGCGGC CACAGCAAGG GGCTGCTGGA CGGGCTGGAT CTGGCAAGAG GAGCGGGCGG TGCCGACAAG CCGCAAGAGC AAGATATCCG TCTGAAGATG CGCGGGCTCG ATTTGGCGTG A Aeromonas salmonicida protein sequence for the AexT protein 1 MQIQANTVGT QAVAHHSDAT TGVGRMGQME ARQVATGQDA ILLGSRSEPQ Seq ID 2 51 KGQGLLSRLG AQLARPFVAI KEWISNLLGT DKRAAAPKAQ TAVSPEDLQR 101 LMKQAAFGSS LGGFAKADVL NNITGEQLGK DHASLATGNG PLRSLCTALQ 151 AVVIGSQQPQ LRELATGLLA RPIAGIPLQQ WGSVGGKVTE LLTSAPPELL 201 KEAMSQLHTA MGEVADLQRA VKAEVAGEPA RSATTAAAVA PLQSGESEVN 251 VEPADKALAE GLQEQFGLEA EQYLGEQPHG TYSDAEVMAL GLYTNGEYQH 301 LNRSLRQEKQ LDAGQALIDQ GMSTAFEKST PTEQLIKTFR GTHGGDAFNE 351 VAEGQVGHDV AYLSTSRDPK VATNFGGSGS ISTIFGRSGI DVSDISVEGD 401 EQEILYNKET DMRVLLSAKD ERGVTRRVLE EASLGEQSGH SKGLLDGLDL 451 ARGAGGADKP QEQDIRLKMR GLDLA* Aeromonas salmonicida promoter sequence for the AexT gene TGATG GCTCCAGATT GATGATGGCG Seq ID 3 CCATTAGAGC AGGTCGCCGC CAGCGGCACT GTTAATGGTG GCTCTCATTT TTTAGCTTTT CGGTCAGCAG GATGGCGCGC CGCGCTCAGT ACAAAAATCG CGACCAATCC CGATAGTCCC TGTTGATACC CTCTCCTAGA CTGGCGGCGA AACATCACAA GAAGACAATC ATC Aeromonas salmonicida protein sequence for the OrfX protein 1 MNSLYHAAIH QLFLSLSLPQ PQQEESVTSL QIGELTCHLT EHPADYLLMF Seq ID 4 51 TRLEVASGAQ AAAQNLFSQD PCKPVLGFDP DDLTPVLWSR QPLQQLDRAQ 101 IHHQVEQLVS AADELSRW* Aeromonas salmonicida gene for orfX complete coding DNA sequence TT ACCACCTGCT TAGCTCGTCA GCGGCAGAGA Seq ID 5 CCAGTTGCTC CAGCTGGTGA TGGATCTGGG CGCGATCCAG CTGCTGCAAC GGCTGGCGAC TCCACAACAC CGGCGTCAGA TCGTCGGGGT CAAAACCCAG AACGGGTTTG CAAGGGTCCT GACTAAACAG GTTTTGCGCG GCGGCCTGGG CGCCGCTAGC TACCTCAAGA CGGGTAAACA TCAGCAGATA GTCGGCTGGG TGCTCGGTCA GGTGGCAGGT CAGTTCGCCG ATCTGCAGGC TGGTGACGCT TTCCTCCTGC TGCGGCTGAG GAAGCGAGAG GGAGAGAAAC AGCTGGTGGA TGGCGGCGTG ATAAAGAGAG TTCAT |
Mewthod and device for analysing the surface of a substrate |
The object of the invention is a process for scanning a surface of a substrate (2), which process consists in taking at least one reflected image of at least one test pattern (1) on the said surface and extracting by digital processing local phases in two directions, characterized in that variations in local slopes are calculated by digital processing from the local phases in order to deduce therefrom variations in curvature or variations in altitude of the said surface. |
1-27. (canceled) 28. Process for scanning a surface of a substrate, comprising: taking at least one reflected image of at least one test pattern on the surface; extracting by digital processing local phases in two directions; and calculating variations in local slopes by digital processing from the local phases to deduce therefrom variations in curvature or variations in altitude of the surface. 29. Process for scanning a surface of a substrate according to claim 28, wherein the at least one reflected image is taken after reflected on a reflective surface. 30. Process for scanning a surface of a substrate according claim 28, wherein the digital processing comprises superimposing the at least one reflected image of the at least one test pattern onto a reference test pattern to obtain a moiré from which the extracting of the local phases is realized. 31. Process for scanning a surface of a substrate according to claim 28, wherein the extracting of the local phases is realized by a phase stepping. 32. Process for scanning a surface of a substrate according to claim 28, wherein in the digital processing the extracted local phases are compared to reference phases, phase variations are deduced therefrom, which are converted by a sensitivity factor to form variations in local slopes. 33. Process for scanning a surface of a substrate according to claim 32, wherein the variations in curvature are obtained by the digital processing involving derivation of the variations in local slopes. 34. Process for scanning a surface of a substrate according to claim 32, wherein the variations in altitude are obtained by the digital processing involving integration of the variation in local slopes. 35. Process for scanning a surface of a substrate according to claim 28, further comprising placing the substrate in a position suitable for facilitating the digital processing. 36. Process for scanning a surface of a substrate according to claim 35, wherein the substrate is placed by a mechanical positioning device. 37. Process for scanning a surface of a substrate according to claim 28, wherein the taking of the at least one reflected image is effected in a course of movement of the substrate. 38. Process for scanning a surface of a substrate according to claim 28, wherein the taking of the at least reflected image is effected on a transparent substrate in a course of deformation. 39. Process for scanning a surface of a substrate according to claim 28, wherein the at least one test pattern is reflected over a whole of a surface of the substrate. 40. Process for scanning a surface of a substrate according to claim 28,, wherein the at least one reflected image is taken instantaneously. 41. Process for scanning a surface of a substrate according to claim 28, wherein a design of the test pattern is deformed in at least one direction. 42. Process for scanning a surface of a substrate according to claim 28, wherein the substrate is shaped and transparent. 43. Process for scanning a surface of a substrate according to claim 37, wherein the taking of the at least one reflected image is effected on a passing substrate. 44. Process for scanning a surface of a substrate according to claim 43, wherein the substrate is passed on a conveyor and the substrate is focused in two directions forming a plane of the conveyor. 45. Device for realizing the process according to claim 28, comprising at least one camera, at least one flash-type pulse lighting, at least one test pattern, and digital image-processing means, wherein the processing means are configured to generate a moiré. 46. Device according to claim 45, wherein the digital image-processing means comprises algorithms for phase extraction calculation, for conversion calculation, and for derivation or integration calculation. 47. Device according to claim 45, wherein the camera is positioned above a conveyor. 48. Device according to claim 47, further comprising mechanical means provided for focusing the substrate in two directions forming a plane of the conveyor. 49. Device according to claim 45, wherein the device is positioned within a warm chamber. 50. Device according to claim 45, wherein an optical axis of a lens of the camera is normal to a surface of the substrate at a center of a field of observation when a single test pattern is used. 51. Use of a device according to claim 45 for scanning defects of a window. 52. Use of a device according to claim 45 for measuring a variation in overall three-dimensional shape of a window. 53. Use of a device according to claim 45 for checking inherent flatness of a window. 54. Use of a device according to claim 45, for checking a window intended for realizing a visual display screen. |
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