text
stringlengths 0
1.67M
|
|---|
Hollow fiber membrane for the treatment of waste lubricants and method for its production |
The present invention proposes a new formulation for the making of a cellulose acetate hollow fiber membrane for ultrafiltration with high water permeability, capable of oil and water separation with minimal energy consumption and low fouling tendencies. |
1. A hollow fiber membrane made of a cellulose ester for the separation of oil from water, the membrane exhibiting a Molecular Weight Cut-Off (MWCO) of about 5,000 to 30,000, a COD removal of above 95 percent and a low oil fouling tendency. 2. A hollow fiber membrane according to claim 1 wherein the membrane has a pure water permeability of about 100 to 300 L/m2.h.bar. 3. A hollow fiber membrane according to claim 1 wherein the membrane has a wall thickness of 200 to 500 microns. 4. A hollow fiber membrane according to claim 1 wherein the cellulose ester is cellulose acetate. 5. A process for making cellulose based hollow fibers for the separation of oil from water which comprises the steps of: a. forming a doping solution of about 15-25 weight percent cellulose acetate polymer, about 60-81 weight percent of organic solvent and about 4-15 weight percent non-solvent additive or additives; b. spinning the hollow fibers via the phase inversion technique using a tube in orifice spinneret; and c. leaching hollow fibers of solvent and non-solvent additive(s) by immersing in a water bath. 6. A process according to claim 5 wherein the making of the cellulose based hollow fibers is performed at a temperature of 10° C. to 30° C. 7. A process according to claim 5 wherein said organic solvent comprises: N-methyl-2-pyrrolidone, dimethylacetamide, acetone, dimethylsulfoxide, dimethylformamide and dioxan. 8. A process according to claim 5 wherein said non-solvent additives comprises of: polyvinylpyrrolidone, or inorganic acids, or organic acids, or inorganic salts or a mixture of all or some of the mentioned compounds. 9. A process according to claim 5 wherein said step of spinning the hollow fibers via the phase inversion technique using a tube in orifice spinneret further utilizes an external coagulant of water and an internal coagulant of water or a mixture of water and NMP, where the mixture has a NMP composition of 20-80 wt. % in water. 10. A process according to claim 9 wherein said step of spinning the hollow fibers via the phase inversion technique using a tube in orifice spinneret further exposes the hollow fiber to an air gap of 0-50 cm before it reaches the external coagulant. 11. A doping solution for spinning of cellulose acetate hollow fiber membranes for the separation of oil from water comprising of: 15-25 weight percent of cellulose acetate polymer, 60-81 weight percent of organic solvent and 4-15 weight percent of non-solvent additive or additives. 12. A doping solution according to claim 11 wherein said non-solvent additive or additives comprises of: polyvinylpyrrolidone, or inorganic acids, or organic acids, or inorganic salts or a mixture of all or some of the mentioned compounds. 13. A doping solution according to claim 11 wherein said doping solution is prepared at temperature of 10-30° C. |
<SOH> BACKGROUND OF THE INVENTION <EOH>Lubricant fluids are widely used in machining processes like metal finishing, metal working and also in the electronics industries. They are used for a variety of reasons such as improving equipment life, reducing work piece thermal deformation, improving surface finish and flushing away impurities from the work zone. There are various categories of such lubricants and one of the most popular is the soluble oil fluids. The oil concentrate of such oil fluids consists of mineral oils and some emulsifiers. They are used in a diluted form with water having an oil concentration of about 3-10%. Together they form a stable emulsion when mixed with water. The resulting oil-in-water emulsion typically has a milky white appearance. After extended periods of use, the emulsion usually becomes inefficient through progressive degradation or contamination and requires replacement. The waste lubricant fluid has to be treated to local environmental sewage standards before it can be disposed of properly. Current practices of waste lubrication fluid treatment involves essentially two steps: 1) Solid-liquid separation and then 2) Liquid-liquid separation. Solid-liquid separation is to remove solid contaminants like work piece debris from the waste fluid before going to the second step. Current methods basically involve some form of filtration or centrifugal action to separate the solid contaminants from the liquids. Solid contaminants can also be separated by allowing the solids to settle to the bottom of a container. Liquid-liquid separation is more complex. The oil-in-water emulsion has to be broken into its separate oil and water components before disposal. This is often done using chemicals to break the emulsion. However, this method results in more chemicals being present in the water. The oil layer is then skimmed off to separate the oil from the water. The water has to be further treated before discarding while the recovered oil is often reused as fuels or simply incinerated. Another method used is to subject the liquid to centrifugal action to separate the oil from water. As can be seen, the treatment of such oil-in-water emulsions from waste lubricants is not a simple matter. The equipment, space and costs involved are generally quite high. Merely separating the oil from the water is not enough. The water must meet the environmental standards of local authorities before it can be discharged. Most current methods do not provide a simple solution to separating the oil from the water and treating the water at the same time. In addition, some of the oil droplets formed in such emulsions are so fine that they cannot be easily separated by the above mentioned conventional methods. A known proposed alternative is the use of ultrafiltration membranes to separate the oil from the water in such emulsions. This method also has the distinct advantage of reducing Chemical Oxygen Demand (COD) levels which is a criteria in waste water disposal. However, present use of commercially available tubular or hollow fiber membranes for the treatment of such waste lubricant fluids causes serious fouling problems due to the hydrophobic characteristics of the membranes. Furthermore, the equipment is expensive and consumes large amounts of energy. The life of the membranes could be greatly affected due to the serious fouling problem associated with currently available membranes. The present invention proposes a new formulation for the making of a cellulose acetate hollow fiber membrane with high water permeability, capable of oil and water separation with low fouling tendencies. |
<SOH> SUMMARY OF THE INVENTION <EOH>The objectives of the invention are achieved by producing a hollow fiber membrane from cellulose acetate. The characteristics of the membrane are: a molecular weight cut-off (MWCO) of 5,000 to 30,000, a pure water permeability of 100 to 300 L/m 2 .h.bar and a low fouling tendency by the retentate(oil). The method of manufacture of the hollow fibers has also been made simpler to reduce costs and simplify production. |
Heat-shrinkable polystyrene based resin film roll and method for production thereof, and heat-shrinkable label |
A film roll comprising a heat-shrinkable polystyrene based resin film wound into a roll, characterized in that, each of the samples taken out from the roll exhibits, in a heat shrinkage test under the condition of the immersion in a hot water at 85° C. for 10 sec, a heat shrinkage rate in the main shrinking direction of within ±5% relative to an average rate of the total samples; a heat-shrinkable polystyrene based resin film taken from the roll; a heat-shrinkable label comprising the film; a method for producing the heat-shrinkable polystyrene based resin film roll which comprises using raw material chips having a specific form, or using a hopper having a specific shape for feeding raw material chips to an extruder, or limiting the variation of the surface temperature of a film in a specific production step to a specific range. |
1. A heat-shrinkable polystyrene based resin film roll comprising a heat-shrinkable polystyrene based resin film to be wound thereinto; wherein, in a constant range such that film physical properties are stable with respect to a flow direction in producing the film, making a finishing end of a roll of the film roll into a beginning end, making a starting end of a roll thereof into a terminating end, providing a first cut out part in a 2 m or less inward portion from said beginning end, and further providing another cut out part at every approximately 100 m from the first cut out part, in measuring a heat shrinkage rate of a sample cut out from each of the cut out_parts, which is denoted by a rate of change in length in a main shrinking direction after a treatment of immersing in a hot water at a temperature of 85° C. for 10 seconds with respect to a state before said treatment, said heat-shrinkable polystyrene based resin film exhibits the heat shrinkage rate of each of the samples within ±5% relative to an average value of the heat shrinkage rate of the total samples. 2. A heat-shrinkable polystyrene based resin film roll according to claim 1, wherein, drawing a marked line at an interval of 200 mm in a main shrinking direction on a sample cut out_so as to have a width of 15 mm and a length of 210 mm, said heat-shrinkable polystyrene based resin film exhibits a maximum heat shrinkage rate of 40% or more, which is a maximum value of a rate of change in length in the main shrinking direction of said sample after a treatment of heating at every 10° C. from 100° C. to 150° C. for 1 minute with respect to a length between the marked lines before said treatment. 3. A heat-shrinkable polystyrene based resin film roll according to claim 1, wherein, being mounted on a bottle as a label form of a cylindrical tube-shaped transparent vessel such that a main shrinking direction is made into a cross-sectional direction of a cylinder, said heat-shrinkable polystyrene based resin film exhibits an average value T of a transmittance of near ultraviolet rays represented in the following formula 1, which is 0.5 or less after heat-shrinking in a case of irradiating the vessel from outside to inside thereof with the near ultraviolet rays from a direction perpendicular to a rotational symmetry axis of the vessel. T=A/B formula 1 A: an average value (n=10) of a light energy density transmitting into the film and the vessel in a state of mounting the heat-shrinkable polystyrene based resin film on the transparent vessel B: an average value (n=10) of a light energy density transmitting into the transparent vessel in a state of not mounting the heat-shrinkable polystyrene based resin film on the transparent vessel 4. A heat-shrinkable polystyrene based resin film roll according to claim 1, wherein, drawing a marked line at an interval of 50 mm in a longitudinal direction in a middle of a sample cut out so as to have a width of 5 mm and a length of 100 mm while regarding a main shrinking direction as the longitudinal direction, said heat-shrinkable polystyrene based resin film exhibits a rate of change in length of 0% to 90% in the main shrinking direction of said sample after a treatment of loading a tension of 51.18 gf at a temperature of 110° C. for 1 minute with respect to a length between the marked lines before said treatment. 5. A heat-shrinkable polystyrene based resin film roll according to claim 1, wherein, drawing a marked line at an interval of 200 mm in a main shrinking direction on a sample cut out_so as to have a width of 15 mm and a length of 210 mm, said heat-shrinkable polystyrene based resin film exhibits a heat shrinkage rate of 5% or more, which is denoted by a rate of change in length between the marked lines in the main shrinking direction of said sample after a treatment of immersing in a hot water at a temperature of 65° C. for 10 seconds with respect to a state before said treatment. 6. A heat-shrinkable polystyrene based resin film roll according to claim 1, wherein, in measuring a dynamic viscoelasticity of the film under the conditions of an elastic mode, a frequency of 50 Hz, a temperature range of −20° C. to 250° C. and a heating rate of 2° C./minute, said heat-shrinkable polystyrene based resin film exhibits a dispersion except alpha dispersion, which is measured in a temperature range such that alpha dispersion derived from polystyrene is measured. 7. A heat-shrinkable polystyrene based resin film roll according to claim 1, wherein, in an undrawn sheet before being drawn into said heat-shrinkable polystyrene based resin film, in measuring a dynamic viscoelasticity of the film under the conditions of an elastic mode, a frequency of 50 Hz, a temperature range of −20° C. to 250° C. and a heating rate of 2° C./minute, said heat-shrinkable polystyrene based resin film comprises said undrawn sheet to be drawn exhibiting a dispersion except alpha dispersion, which is measured in a temperature range such that alpha dispersion derived from polystyrene is measured. 8. A heat-shrinkable polystyrene based resin film roll according to claim 1, wherein said heat-shrinkable polystyrene based resin film has a width of 200 mm or more and a length of 300 m or more. 9. A heat-shrinkable polystyrene based resin film roll according to claim 1, said roll containing a polystyrene based resin having a syndiotactic structure. 10. A heat-shrinkable polystyrene based resin film roll according to claim 1, wherein said heat-shrinkable polystyrene based resin film comprises two or more kinds of resins of different compositions. 11. A method for producing a heat-shrinkable polystyrene based resin film roll according to claim 10, comprising the step of mixing and melt-extruding the resins composing the heat-shrinkable polystyrene based resin film; wherein a shape of raw material chips for each of said resins is rendered columnar and/or elliptical; and a major axis and a minor axis of a cross section perpendicular to a longitudinal direction and a length in the longitudinal direction of raw material chips for another resin with respect to raw material chips for a resin mixed in the largest quantity are each within ±50% as a difference in an average value. 12. A method for producing a heat-shrinkable based resin film roll according to claim 10, comprising the step of mixing and melt-extruding the resins composing the heat-shrinkable polystyrene based resin film by using an extruder provided with a funnel-shaped hopper as a feeding portion of raw material chips; wherein a tilt angle as an angle formed by an oblique side and a horizontal line segment in a funnel-shaped part of said hopper is 65° or more. 13. A method for producing a heat-shrinkable polystyrene based resin film roll according to claim 1, comprising the steps of preheating, drawing and heat-treating; wherein a variation of a surface temperature of a film measured at an arbitrary point of time in each of the steps is within ±1° C. relative to an average temperature covering the total length of the film. 14. A heat-shrinkable polystyrene based resin film being taken from a heat-shrinkable polystyrene based resin film roll according to claim 1. 15. A heat-shrinkable label comprising a heat-shrinkable polystyrene based resin film according to claim 14. |
<SOH> BACKGROUND ART <EOH>A heat-shrinkable film has a function of shrink properties and thereby can be integrally laminated on an object through shrinkage force and shaping properties of the film itself without using a fixing means such as an adhesive agent and a catch, thereby having a function of not merely mechanically protecting an object with lamination and coating but also tying, sealing and the like. Further, in the case where a heat-shrinkable film itself has a particular function, which can be retrofitted to an object with lamination. This characteristic has been effectively used in the field of packaging in which a main purpose is to preserve an object, protect it during distribution and allow display and design properties thereto, being utilized for coating, tying, exterior wrapping or sealing of, for example, various vessels such as jars including bottles made of glass and plastics, and cans, and continuous bodies such as pipes, sticks, wood and various rodlike bodies, or sheet-form bodies; specifically, being used for coating a part or the whole of a cap portion, a shoulder portion and a barrel portion of jars for the purpose of displaying, protecting, tying, improving commercial values by functionalization, and the like; further, being used for collecting and packaging every plural pieces of bodies to be packaged such as boxes, jars, plates, sticks and notebooks, and packaging (skin package) bodies to be packaged by a film closely contacted therewith. In the case where molding for display and design is previously allowed to a film, then the film is made into a commercial product, namely a label. Raw materials for a heat-shrinkable film to be used involve polyvinyl chloride, polystyrene, polyester, polyamide, aliphatic polyolefin, a derivative thereof, rubber hydrochloride and the like. Typically, a film comprising these raw materials is molded into a tube shape to cover, for example, jars, and pipes and the like are collected to be thereafter packaged and tied by heat-shrinking the film. Any conventional heat-shrinkable film, however, is poor in heat resistance and thereby is not allowed to resist boiling and retorting at high temperatures, accordingly having a defect such as not to be pasteurized at high temperatures in the case of being applied to uses for food, sanitary fitments and pharmaceuticals. The problem is that, for example, retorting easily damages a conventional film during the treatment. With regard to a conventional heat-shrinkable film, a film comprising polyvinyl chloride based resin is extremely favorable for heat-shrinkable properties but poor in adhesive properties to ink of printing for a label, and further easily produces a gelatinous substance of an additive mixed thereinto on the occasion of filming, thereby easily causing a pin hole on a printing plane. In addition, the problem is that the film is discarded and incinerated with difficulty in view of environment. A film comprising polyester based resin is superior in heat resistance, dimensional stability, solvent resistance and the like; however, a precise control technique of producing conditions is required for achieving desirable heat-shrinkable properties, adhesive properties and the like, leading to the problem of costs and the like. Also, the usefulness of a heat-shrinkable film has been allowing the heat-shrinkable film to be used in the field in which a film and a label except the heat-shrinkable film have been conventionally used. With regard to a label of beverage vessels, particularly, a sticking label comprising a film except paper and a heat-shrinkable film has been frequently replaced with the heat-shrinkable label. In such a case, a special function is required for protecting vessels and contents. For example, preservation by heating, which has been conventionally performed only for beverages filled in glass jars and metal cans, can be performed also for beverages filled in plastic bottles by an improvement in the heat resistance thereof; consequently bottles mounted with a label made of a heat-shrinkable film are put together with canned beverages in a heat insulating case such as a hot warmer at a convenience store and a station stall, and the diversification of a high-temperature environment experienced after shrinkage mounting has been demanding an improvement in the heat resistance of a heat-shrinkable film. In such a case, a conventional heat-shrinkable film easily causes a label defect due to softening, embrittlement and the like during and after the preservation by heating of vessels mounted therewith. With regard to a hot warmer, particularly, a hot plate portion for putting vessels thereon is controlled at a temperature of approximately 50° C. to 75° C. in order to make the temperature of beverages into approximately 55° C., however, the temperature inside the hot plate exceeds 120° C. partially and temporarily, whereby the defect of a heat-shrinkable film is occasionally caused. Further, in the case where vessels fall in a hot warmer, a heat-shrinkable film is contacted with pressure on the surface of a hot plate, and thereby the problem is occasionally caused such that the conditions of harsh temperature and pressure render the defect of the film serious and deteriorate heat resistance after shrinkage mounting. Also, a function of protecting bodies to be packaged from rays, particularly, near ultraviolet rays having a great influence has been demanded for vessels, packaging materials and the like accommodating the bodies to be packaged, which are easily deteriorated by the rays, for example, beverages such as green tea, juice and beer, food having synthetic or natural colorant with a low light resistance, cosmetics, sanitary fitments, and pharmaceuticals. In addition, a heat-shrinkable label has been vigorously applied to the field of a label of plastic bottle vessels with reference to the problem of recycling, and various forms and modes of packaging design have been performed. Also, the low-temperature moist heat shrinking process, which is a process used for aseptic fill packaging allowed by a composition of cleaning technique, sterilizing technique, high-speeding technique of packaging and the like, can offer the sterilization of beverages and the like in a short time and thereafter the completion of packaging by a short-time process at relatively low temperatures, so as to intend the prevention of heat deterioration of contents and the improvement of packaging efficiency, thereby requiring the development of a heat-shrinkable film usable for this low-temperature moist heat shrinking process. A heat-shrinkable film usable for the low-temperature moist heat shrinking process needs to be superior in shrink properties in a low-temperature range, and additionally a relatively high shrinkage rate is advantageous thereto in view of the shortening of process time. A heat-shrinkable polyester based resin film has been conventionally used as a film having such properties; however, a bottle and a label made of the film are difficult to separate in the case where it is necessary to separately collect them, while a heat-shrinkable polystyrene based resin film, for which gravity separation is allowed, has been desirably used and has poor low-temperature shrink properties, though; the setting of a low shrinkage temperature easily causes the problem such that natural shrinkage is rendered larger before being packaged and heat resistance is deteriorated after shrinkage mounting. In addition, a heat-shrinkable polystyrene based film for a special use as described above has been in an increasing demand, so that a homogeneous film roll needs to be produced, which can provide a film stably functioning with a favorable repeatability even in any part of the roll. In the case of a film roll having an inhomogeneous quality, for example, for the reason that heating conditions in a tunnel are the same in the heat shrinking process of a label, a large variation of heat shrinkage rate of the above-mentioned each labels causes a label exhibiting an improper heat shrinkage rate, which causes appearance defect such as shrinkage deficiency, shrinkage spot, wrinkling, distortion of patterns and tight ends, and thereby is inappropriate for a final product. The same label for a final product is typically processed from a piece of film roll, so that a large variation of heat shrinkage rate of films composing a piece of film roll increases the fraction defective in the heat shrinking process as described above. In particular, this is a serious problem in uses for a full label for bottles, which covers a large area and requires a high shrinkage rate. Also, close adhesion stress in mounting on vessels varies with a region, thereby occasionally resulting in the occurrence of defect in heat resistance even with the use of a film having a superior heat resistance in a hot warmer. Further, in the case of allowing a film low-temperature shrink properties, then the setting of a low shrinkage temperature causes the problem such that natural shrinkage is rendered larger before being packaged and heat resistance is deteriorated after shrinkage mounting. The present invention is intended for providing a heat-shrinkable polystyrene based resin film which has a sufficiently high heat shrinkage rate, causes no shrinkage unevenness thereon in heat-shrinking, has a beautiful appearance, additionally maintains the appearance stably even under the conditions of high temperatures after shrinking, and particularly is the most appropriate for the preservation by heating such as a hot warmer; also, offers an extremely high covering properties even in mounting on vessels having a complicated shape, and is the most appropriate for packaging products to which the prevention of deterioration by rays is necessary; further, a heat-shrinkable polystyrene based film roll which can stably provide the heat-shrinkable polystyrene based resin film having a sufficiently high heat shrinkage rate in the low-temperature shrinking process, and can reduce the occurrence of defect, such as shrinkage defect, shrinkage spot, wrinkling, distortion and tight end in the after-processing step, caused by the variation of heat shrinkage rate in the film roll; and a method for production thereof and a heat-shrinkable label. |
Use of annellated pyrrole compounds in the treatment of articular cartilage or subchondral bone degenaration |
Treating or preventing degeneration or destruction of articular cartilage and/or subchondral bone in the affected joint of a mammal is accomplished by administering a compound of formula (I), wherein the variables have the meanings given in the present description. A preferred compound of formula (I) is formula (II). This treatment ameliorates, diminishes, actively treats, reverses or prevents any injury, damage or loss of articular cartilage or subchondral bone subsequent to said early stage of said degeneration. |
1-14. (Canceled). 15: A method of treating or preventing degeneration or destruction of articular cartilage and/or subchondral bone in one or more joints of a mammal in need of such treatment, comprising administering to said mammal an amount therapeutically effective for treating or preventing degeneration or destruction of articular cartilage and/or subchondral bone, of one or more than one compound of Formula (I): wherein X represents CR8R9, S, O, NR12 or C(O); A represents CR10R11 or a bond between X and the atom carrying radicals R6 and R7; the first of radicals R1, R2, R3 represents aryl, optionally substituted with one or more than one substituents independently selected among the group consisting of halogen, alkyl, halogenoalkyl, alkoxy, aryloxy, halogenoalkoxy, alkylthio, hydroxy, nitro, alkylsulfinyl, alkylsulfonyl, sulfamoyl, N-alkylsulfamoyl, N,N-di-alkylsulfamoyl, alkylsulfonamido and alkylsulfon-N-alkylamido; or an aromatic or non-aromatic, mono- or bicyclic, optionally benzoannellated, heterocyclic group having 1, 2 or 3 heteroatoms independently selected from N, O and S and optionally being substituted with one or more than one substituents independently selected among the group consisting of halogen, alkyl, halogenoalkyl, alkoxy, aryloxy, halogenoalkoxy, alkylthio, hydroxy, nitro, alkylsulfinyl, alkylsulfonyl, sulfamoyl, N-alkylsulfamoyl, N,N-di-alkylsulfamoyl, alkylsulfonamido and alkylsulfon-N-alkylamido; the second of radicals R1, R2, R3 represents alkyl, optionally substituted with one or more than one substituents independently selected among the group consisting of halogen, cycloalkyl, alkoxy, trifluormethoxy, hydroxy and trifluormethyl; cycloalkyl, optionally substituted with one or more than one substituents independently selected among the group consisting of halogen, alkyl, halogenoalkyl, cycloalkyl, alkoxy, halogenalkoxy and hydroxy; aryl, optionally substituted with one or more than one substituents independently selected among the group consisting of halogen, alkyl, halogenoalkyl, alkoxy, aryloxy, halogenoalkoxy, alkylthio, hydroxy, nitro, alkylsulfinyl, alkylsulfonyl, sulfamoyl, N-alkylsulfamoyl, N,N-di-alkylsulfamoyl, alkylsulfonamido and alkylsulfon-N-alkylamido; or an aromatic or non-aromatic, mono- or bicyclic, optionally benzoannellated, heterocyclic group having 1, 2 or 3, heteroatoms independently selected from N, O and S and optionally being substituted with one or more than one substituents independently selected among the group consisting of halogen, alkyl, halogenoalkyl, alkoxy, aryloxy, halogenoalkoxy, alkylthio, hydroxy, nitro, alkylsulfinyl, alkylsulfonyl, sulfamoyl, N-alkylsulfamoyl, N,N-di-alkylsulfamoyl, alkylsulfonamido and alkylsulfon-N-alkylamido; the third of radicals R1, R2, R3 represents H, alkyl, halogenoalkyl, hydroxyalkyl, —CHO, —COOH, halogen, cyano, alkylsulfonyl, sulfamoyl or B—Y, wherein B represents alkylene or alkenylene, optionally substituted with hydroxy or alkoxy; Y represents —COOH, SO3H, OPO(OH)2, OP(OH)2, —CHO or tetrazolyl; or the second and the third of radicals R1, R2, R3 represent, together with the atom they are attached to, saturated or unsaturated cycloalkyl; R4-R11, which may be the same or different, represent hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, hydroxy, COOH or acyloxy, where vicinal radicals may also represent bonds or geminal radicals, together with the C atom they are attached to, may also represent carbonyl or cycloalkyl; R12 represents hydrogen, alkyl or phenyl, and optical isomers, physiologically acceptable salts and derivatives thereof. 16: The method according to claim 15, wherein the first and the second of radicals R1, R2, R3 independently represent an optionally substituted aryl or aromatic heterocyclic residue. 17: The method according to claim 15, wherein the third of radicals R1, R2, R3 represents COOH or B—Y, wherein Y is COOH and B represents alkylene. 18: The method according to claim 16, wherein the third of radicals R1, R2, R3 represents COOH or B—Y, wherein Y is COOH and B represents alkylene. 19: The method according to claim 15 wherein said compound of formula (I) is [6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizine-5-yl]-acetic acid of the formula (la) a physiologically acceptable salt or a physiologically hydrolysable ester thereof. 20: The method according to claim 15, wherein the degeneration or destruction of articular cartilage and/or subchondral bone comprises injury, damage or loss of articular cartilage and/or subchondral bone. 21: The method according to claim 15, wherein said degeneration or destruction is at an early stage. 22: The method according to claim 15, wherein the status of said mammal is presently or prospectively in a condition of said degeneration or destruction. 23: The method according to claim 22, wherein said status of said mammal as presently or prospectively being in said condition is determined by one or more of the following: (A) positive results from the clinical examination and evaluation of the joints of said mammal, including measurement of hip dysphasia progression; (B) performance of any invasive surgical procedure on one or more joints of said mammal; (C) positive results from an examination of one or more joints of said mammal using noninvasive procedures including radiographic and magnetic resonance imaging (MRI); and (D) positive results from any biochemical test performed on body fluids or joint tissue of said mammal with respect to one or more of the following substances: (1) increased interleukin-1 beta (IL-β); (2) increased tumor necrosis factor alpha (TNFα); (3) increased ratio of IL-1β to IL-1 receptor antagonist protein (IL-1 Ra); (4) increased expression of p55 TNF receptors (p55 TNF-R); (5) increased interleukin-6 (IL-6); increased leukemia inhibitory factor (LIF); (6) unchanged or decreased insulin-like growth factor-1 (IGF-1); (7) decreased transforming growth factor beta (TGFβ); unchanged or decreased platelet-derived growth factor (PDGF); (8) unchanged or decreased basic fibroblast growth factor (b-FGF); (9) increased keratin sulfate; (10) increased matrix metalloproteases (MMPs) including stromelysin; (11) increased ratio of matrix metalloproteases (MMPs) including stromelysin, to tissue inhibitor of metalloproteases (TIMP); (12) increased osteocalcin; (13) increased alkaline phosphatase; (14) increased cAMP responsive to hormone challenge; (15) increased urokinase plasminogen activator (uPA); (16) increased cartilage oligomeric matrix protein; (17) presence of type-II specific collagen neoepitopes and (18) increased collagenase. 24: The method according to claim 15, wherein said treatment or prevention comprises administering said compound in an amount of about 1-10 mg/kg/day. 25: The method according to claim 15, wherein said treatment or prevention includes administering in addition to one or more than one compound of Formula (I) one or more members selected from the group consisting essentially of polysulfated glycosaminoglycan (PSGAG), glucosamine, chondroitin sulfate (CS), hyaluronic acid (HA), pentosan polysulfate (PPS), doxycycline, and minocycline. 26: A pharmaceutical composition, comprising: (A) one or more than one compound of Formula (I) as defined in claim 15; and (B) one or more members selected from the group consisting essentially of (1) polysulfated glycosaminoglycan (PSGAG), glucosamine, chondroitin sulfate (CS), hyaluronic acid (HA), pentosan polysulfate (PPS), doxycycline, and minocycline. 27: A pharmaceutical composition according to claim 26, wherein said compound of formula (I) is [6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizine-5-yl]-acetic acid of the formula (la) a physiologically acceptable salt or a physiologically hydrolysable ester thereof. |
<SOH> BACKGROUND OF THE INVENTION <EOH>Nonsteroidal antiphlogistika (NSAIDs), such as acetylsalicylic acid (ASA), diclofenac, indomethacin, ibuprofen and naproxen, are widely used in the clinic. From a pharmacological point of view they act as inhibitors of the cyclooxygenase (COX). Pyrrolizines which pharmacologically act similar, are known from numerous publications. For instance, antiphlogistically active pyrrolizines are described in Arch. Pharm. 319, 65-69 (1986); 319, 231-234 (1986); 318, 661-663 (1985); 318, 663-664 (1985); 319, 500-505 (1986); 319, 749-755 (1986); 327, 509-514 (1994); 330, 307-312 (1997) as well as in J. Med. Chem. 1987, 30, 820-823 and 1994, 37, 1894-1897. Further pyrrolizines can be taken from U.S. Pat. No. 5,260,451 (corresponding to EP 0397175) as well as from WO 95/32970; WO 95/32971; and WO 95/32972. These compounds are represented by the structural formula and share an annellated diarylpyrrol moiety as well as a third acidic residue R3. The compounds are characterized by a high lipophilicity, good bioavailability and half-lifes in the medium range, s. Drugs of the Future, 1995, 20 (10):1007-1009. Further pyrrolizines of similar constitution are described in DE 198 45 446.6 and WO 01/05792. Moreover, alkylsulfinylbenzoyl and alkylsulfonylbenzoyl substituted pyrrolizines, according to U.S. Pat. No. 4,232,038, are said to have anti-inflammatory, analgetic and antipyretic properties. According to DE 196 24 290.8 and DE 196 24 289.4 certain compounds of this type have a lipid-reducing action. ML3000 ([2,2-dimethyl-6-(4-chlorophenyl)-7-phenyl-2,3-dihydro-1H-pyrrolizine-5yl]-acetic acid) of the Formula (Ia) is a non-antioxidant balanced dual inhibitor of COX and 5-Lipoxygenases (5-LO) (3). The drug is a nonselective inhibitor of COX, inhibiting both COX-1 and COX-2. This drug has analgetic, antipyretic and anti-inflammatory activity, and has been demonstrated to have potent anti-inflammatory action in a number of animal models including carrageenan-induced paw edema in the rat, and rat adjuvant arthritis (4). Osteoarthritis (OA) is the most common of musculosceletal diseases. It mainly affects the weight-bearing diarthrodial joints such as the hip and knee, but also affects other joints such as interphalangual joints and the spine. The structural changes of this disease include the progressive erosion of the articular cartilage, the formation of osteophytes and, at the clinical stage of the disease, a variable degree of synovial inflammation. Also associated with these changes is a significant remodeling of the subchondral bone, which, according to several studies, is believed to be predominantly an excessive bone resorption in the early stage of the disease, followed by excessive bone formation leading to bone sclerosis and an increased thickening of the subchondral bone. The mechanisms leading to the development and progression of structural changes seen in osteoarthritis (OA) are multiple and complex, and remain largely unknown. They involve not only cartilage, where a number of morphological changes are observed, but also the synovial membrane which is the site of an inflammatory reaction of variable degree and severity (1). There are a number of pathways believed to be responsible for the catabolism of cartilage matrix including the upregulation of soluble factors, e.g., interleukin-1 (IL-1), tumor necrosis factor-α (TNF-α), and prostaglandins, which can induce loss of articular cartilage. Direct injury to chondrocytes also stimulates matrix metalloprotease (MMP) activity, e.g., collagenases, stromelysins and gelatinases, and the production of various inflammatory mediators (2). It has to be considered that metabolic processes continuously occur in any given joint that are necessary for its repair and normalization subsequent to it being subjected to an insult such as a traumatic injury. Accordingly, in order for a compound to be an acceptable chondroprotective agent it must first of all be capable of sustaining such chondrocyte metabolic activity, i.e., of not inhibiting or interfering with the cellular replication and biosynthesis of matrix components which are part of the healing process. In this regard, the skilled artisan will recognize that many NSAIDs display a marked inhibitory action on the biosynthesis of the principal components of the extracellular matrix. At the same time an acceptable chondroprotective agent must be capable of counteracting the degradative action of mediators such as various cytokines, prostaglandins and proteinases on the cartilage. Accordingly, it has been accepted in the art that potential chondroprotective drugs should be evaluated both as to their positive effects on anabolic pathways as well as to their ability to inhibit catabolic processes. Catabolic events which have typically been monitored include, inter alia, the release and inhibition of matrix degrading enzymes, effects on prostaglandin and leukotriene biosynthesis, and the ability of the drug to inhibit IL-1 mediated degradation of articular cartilage. A number of drugs like NSAIDs, with activity directed at inhibiting COX enzymes, have been in use for many years. Although they may effectively reduce the symptoms of the osteoarthritis such as pain, they have shown limited ability in reducing the in vivo progression of experimental OA (8,9). While treatment with Tenidap and Carprofen, two NSAIDs with both cyclooxygenase-1 (COX-1) and COX-2 inhibitory activity, were shown to exhibit anti-OA effects (8,9) other NSAIDs, such as diclofenac or ASA, were ineffective (10) or even demonstrated to accelerate cartilage damage in the experimental dog model of OA (11). Similarly, in humans, a recent study in knee OA patients has demonstrated that, based on X-ray criteria, treatment with tiaprofenic acid, a further NSAID, over a 5-year period could not retard the progression of cartilage damage and that indomethacin even accelerated its progression (15). Surprisingly, it has been found that certain annellated pyrrole compounds, such as ML3000, significantly reduce the development of lesions in experimental dog OA. The protective effect of these compounds was particularly evident in the reduction in the development of cartilage lesions. This phenomenon was associated not only with a significant inhibition of both PGE 2 and LTB 4 production, but also with an in situ reduction in two major catabolic factors involved in cartilage degradation, namely IL-1β and collagenase-1. |
<SOH> SUMMARY OF THE INVENTION <EOH>Thus, the present invention relates to the use of annellated pyrrole compounds represented by the general formula (I): wherein X represents CR8R9, S, O, NR12 or C(O); A represents CR10R11 or a bond between X and the atom carrying radicals R6 and R7; the first of radicals R1, R2, R3 represents aryl, optionally substituted with one or more than one substituents independently selected among the group consisting of halogen, alkyl, halogenoalkyl, alkoxy, aryloxy, halogenoalkoxy, alkylthio, hydroxy, nitro, alkylsulfinyl, alkylsulfonyl, sulfamoyl, N-alkylsulfamoyl, N,N-di-alkylsulfamoyl, alkylsulfonamido and alkylsulfon-N-alkylamido; or an aromatic or non-aromatic, mono- or bicyclic, optionally benzoannellated, heterocyclic group having 1, 2 or 3 heteroatoms independently selected from N, O and S and optionally being substituted with one or more than one substituents independently selected among the group consisting of halogen, alkyl, halogenoalkyl, alkoxy, aryloxy, halogenoalkoxy, alkylthio, hydroxy, nitro, alkylsulfinyl, alkylsulfonyl, sulfamoyl, N-alkylsulfamoyl, N,N-di-alkylsulfamoyl, alkylsulfonamido and alkylsulfon-N-alkylamido; the second of radicals R1, R2, R3 represents alkyl, optionally substituted with one or more than one substituents independently selected among the group consisting of halogen, cycloalkyl, alkoxy, trifluormethoxy, hydroxy and trifluormethyl; cycloalkyl, optionally substituted with one or more than one substituents independently selected among the group consisting of halogen, alkyl, halogenoalkyl, cycloalkyl, alkoxy, halogenalkoxy and hydroxy; aryl, optionally substituted with one or more than one substituents independently selected among the group consisting of halogen, alkyl, halogenoalkyl, alkoxy, aryloxy, halogenoalkoxy, alkylthio, hydroxy, nitro, alkylsulfinyl, alkylsulfonyl, sulfamoyl, N-alkylsulfamoyl, N,N-di-alkylsulfamoyl, alkylsulfonamido and alkylsulfon-N-alkylamido; or an aromatic or non-aromatic, mono- or bicyclic, optionally benzoannellated, heterocyclic group having 1, 2 or 3, heteroatoms independently selected from N, O and S and optionally being substituted with one or more than one substituents independently selected among the group consisting of halogen, alkyl, halogenoalkyl, alkoxy, aryloxy, halogenoalkoxy, alkylthio, hydroxy, nitro, alkylsulfinyl, alkylsulfonyl, sulfamoyl, N-alkylsulfamoyl, N,N-di-alkylsulfamoyl, alkylsulfonamido and alkylsulfon-N-alkylamido; the third of radicals R1, R2, R3 represents H, alkyl, halogenoalkyl, hydroxyalkyl, —CHO, —COOH, halogen, cyano, alkylsulfonyl, sulfamoyl or B—Y, wherein B represents alkylene or alkenylene, optionally substituted with hydroxy or alkoxy; Y represents —COOH, SO 3 H, OPO(OH) 2 , OP(OH) 2 , —CHO or tetrazolyl; or the second and the third of radicals R1, R2, R3 represent, together with the atom they are attached to, saturated or unsaturated cycloalkyl; R4-R11, which may be the same or different, represent hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, hydroxy, COOH or acyloxy, where vicinal radicals may also represent bonds or geminal radicals, together with the C atom they are attached to, may also represent carbonyl or cycloalkyl; R12 represents hydrogen, alkyl or phenyl, and optical isomers, physiologically acceptable salts and derivatives thereof, for treating or preventing degeneration or destruction of articular cartilage and/or subchondral bone. The term “alkyl, alkoxy etc.” includes linear or branched alkyl groups, such as CH 3 , C 2 H 5 , n-propyl, CH(CH 3 ) 2 , n-butyl, CH(CH 3 )—C 2 H 5 , isobutyl, C(CH 3 ) 3 , n-pentyl or n-hexyl, in particular CH 3 , C 2 H 5 or CH(CH 3 ) 2 , preferably having—unless otherwise stated—1 to 8, in particular 1 to 6 and more preferably 1 to 4 carbon atoms; as a substituent of a radical R1 to R12 “alkyl, alkoxy etc.” preferably comprises 1 to 4 carbon atoms. Substituted “alkyl, alkoxy etc.” includes in particular: halogenoalkyl, i.e., alkyl, which is partially or completely substituted with fluoro, chloro, bromo and/or iodo, e.g. CH 2 F, CHF 2 , CF 3 , CH 2 Cl, 2-fluoroethyl, 2-chloroethyl or 2,2,2-trifluoroethyl; as a substituent of a radical R1 to R12 halogenoalkyl preferably means CHF 2 and especially CF 3 ; halogenoalkoxy, i.e., alkoxy, which is partially or completely substituted with fluoro, chloro, bromo and/or iodo, e.g. halogenoalkoxy residues corresponding to the afore-mentioned halogenoalkyl residues; as a substituent of a radical R1 to R12 halogenoalkoxy preferably means OCHF 2 and especially OCF 3 ; alkoxyalkyl, i.e., alkyl substituted by alkoxy, e.g. —CH 2 —OCH 3 or 2-Methoxyethyl; hydroxyalkyl, i.e., alkyl which is—preferably mono—substituted by hydroxy, e.g., hydroxymethyl or 2-hydroxyethyl; trifluoromethylalkyl, i.e. alkyl, which is—preferably mono—substituted by trifluoromethyl, e.g., the residues as described in respect of hydroxyalkyl which are substituted with trifluormethyl instead of hydroxy; trifluoromethoxyalkyl, i.e. alkyl, which is—preferably mono—substituted by trifluoromethoxy, e.g., the residues as described in respect of hydroxyalkyl which are substituted with trifluormethxy instead of hydroxy; cycloalkylalkyl, i.e., alkyl, which is—preferably mono—substituted by cycloalkyl, e.g. the residues as described in respect of hydroxyalkyl which are substituted with cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl instead of hydroxy. The term “cycloalkyl” includes mono- or bicyclic alkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc., preferably having—unless otherwise stated—3 to 9, in particular 3 to 7 and more preferably 5 or 6 carbon atoms. The term “alkylene” includes linear or branched alkylene groups, such as methylene and ethylene, preferably having—unless otherwise stated—1 to 8, in particular 1 to 6 and more preferably 1 to 4 carbon atoms. If alkylene is substituted with hydroxyl or alkoxy, monosubstitution is preferred. The term “alkenylene” includes linear or branched, mono- or polyunsaturated alkylene groups, such as ethenylene, preferably having—unless otherwise stated—2 to 8, in particular 2 to 6 and more preferably 2 to 4 carbon atoms. If alkenylene is substituted with hydroxyl or alkoxy, monosubstitution is preferred. Acyloxy means —OCOR, wherein R represents alkyl or aryl. Preferred examples are acetyloxy and benzoyloxy. —COOAlkyl means alkoxycarbonyl, such as CO—OCH 3 , CO—OC 2 H 5 , CO—OCH 2 —C 2 H 5 , CO—OCH(CH 3 ) 2 , n-butoxycarbonyl, CO—OCH(CH 3 )—C 2 H 5 , CO—OCH 2 —CH(CH 3 ) 2 , CO—OC(CH 3 ) 3 , in particular CO—OCH 3 , CO—OC 2 H 5 , CO—OCH(CH 3 ) 2 or CO—OCH 2 —CH(CH 3 ) 2 . —COOAlkPhenyl means an alkoxycarbonyl group which is substituted on the alkyl moiety with phenyl, such as benzyloxycarbonyl. Alkylthio means —S-Alkyl and is also referred to as alkylsulfanyl or alkylmercapto, such as SCH 3 , SC 2 H 5 , SCH 2 —C 2 H 5 , SCH(CH 3 ) 2 , n-butylthio, 1-methylpropylthio, 2-methylpropylthio, SC(CH 3 ) 3 . Methylthio is preferred. Alkylsulfinyl means —S(O)-Alkyl and is also referred to as alkylsulfoxo, such as SO—CH 3 , SO—C 2 H 5 , n-propylsulfinyl, 1-methylethylsulfinyl, n-butylsulfinyl, 1-methylpropylsulfinyl, 2-methylpropylsulfinyl, 1,1-dimethylethylsulfinyl. Methylsulfinyl is preferred. Alkylsulfonyl means —S(O) 2 -Alkyl and is also referred to as alkylsulfone, such as SO 2 —CH 3 , SO 2 —C 2 H 5 , n-propylsulfonyl, SO 2 —CH(CH 3 ) 2 , n-butylsulfonyl, 1-methylpropylsulfonyl, 2-methylpropylsulfonyl, SO 2 —C(CH 3 ) 3 . Methylsulfonyl is preferred. Sulfamoyl means —S(O) 2 NH 2 and is also referred to as amidosulfonyl or sulfonic acid amid. N-Alkylsulfamoyl means mono-substituted sulfamoyl —S(O) 2 NH-Alkyl, e.g. —S(O) 2 NH—CH 3 . N,N-Dialkylsulfamoyl means di-substituted sulfamoyl —S(O) 2 N-(Alkyl) 2 , wherein the N-bounded alkyl residues may be the same or different, e.g. —S(O) 2 N(CH 3 ) 2 . Alkylsulfonamido means —NHS(O) 2 -Alkyl, such as NHSO 2 —CH 3 , NHSO 2 —C 2 H 5 , n-propylsulfonamido, NHSO 2 —CH(CH 3 ) 2 , n-butylsulfonamido, 1-methylpropylsulfonamido, 2-methylpropylsulfonamido, NHSO 2 —C(CH 3 ) 3 . Methylsulfonamido is preferred. Alkylsulfon-N-alkylamido means —N(Alkyl)S(O) 2 -Alkyl, wherein the N- and the S-bounded alkyl residues may be the same or different, e.g. N(CH 3 )SO 2 —CH 3 . Carbonyl, CHO, —COOH, —SO 3 H means C═O, formyl, carboxy, carboxycarbonyl and sulfo, respectively. “Aryl” preferably means naphthyl and in particular phenyl. The term “halogen” includes a fluoro, chloro, bromo or iodo atom. Usually fluoro and chloro, and in some cases also bromo are preferred. “Heterocyclic residues” include in particular 5- or 6-membered heterocyclic residues which may be aromatic or non-aromatic, mono- or bicyclic, and/or benzoannellated. Examples are nitrogen-containing heterocyclic residues, such as pyrrolyl, imidazolyl, pyrazolyl, pyridazinyl, pyrazinyl, indolyl, chinolinyl, especially pyridyl, pyrimidyl and isochinolinyl. The aromatic residues also include heterocyclic residues which contain an oxygen or a sulfur atom, such as thienyl, benzothienyl, furanyl and especially benzofuranyl. Also included are heterocyclic residues which contain 2 or more than 2 different heteroatoms, such as thiazolyl, isothiazolyl, thiadiazolyl, isoxazolyl and oxazolyl. Thienyl, pyridyl and thiazolyl are preferred aromatic heterocyclic residues. Non-aromatic residues include nitrogen-containing heterocyclic residues, such as pyrrolidinyl, piperidinyl and piperazinyl. This also includes heterocyclic residues which contain 2 or more than 2 different heteroatoms, such as morpholinyl. Substituted residues, in particular alkyl, cycloalkyl, aryl and heteroaryl, are preferably mono-, di- or tri-substituted. The [α]-annelland may be 6- or especially 5-membered, heterocyclic or especially alicyclic, if alicyclic, then unsaturated or especially saturated, and/or substituted or unsubstituted. The [α]-annellated pyrrole compounds of Formula (I) include in particular those wherein X represents CR8R9 and A represents a bond between X and the atom carrying radicals R6 and R7 (pyrrolizines); X represents CR8R9 and A represents CR10R11 (indolizines); X represents NR12 and A represents a bond between X and the atom carrying radicals R6 und R7 (pyrrolo[1,2-a]imidazoles); X represents S and A represents a bond between X and the atom carrying radicals R6 and R7 (pyrrolo[2,1-b]thiazoles); X represents S and A represents CR10R11 (pyrrolo[2,1-b]1,3-thiazines); X represents O and A represents CR10R11 (pyrrolo[2,1-b]1,3-oxazines); X represents O and A represents a bond between X and the atom carrying radicals R6 and R7 (pyrrolo[2,1-b]oxazoles), residues not mentioned having the meanings given above. If the [α]-annelland is a 5-membered unsaturated residue, especially R4 and R6 represent a bond, such as, e.g., in pyrrolizine, pyrrolo[2,1-b]imidazole and pyrrolo[2,1-b]thiazole. If the [α]-annelland is a 6-membered unsaturated residue, especially R4 and R6, such as, e.g., in pyrrolo[2,1-b]1,3-thiazine, pyrrolo[2,1-b]1,3-oxazine or 5,6-dihydroindolizine, and optionally also R8 and R10, such as, e.g., in indolizine, represent a bond. Without being bound to a specific [α]-annelland, according to a particular embodiment of the invention, R4-R7 which may be the same or different represent hydrogen or alkyl. According to a further particular embodiment of the invention, at least one of radicals R4, R5, R6 and R7 represents hydroxyalkyl, in particular hydroxymethyl, and the remaining radicals among R4, R5, R6 and R7 independently represent H or alkyl. According to this embodiment it is preferred that R4 is hydroxyalkyl, in particular hydroxymethyl, and R5 is H or alkyl, and R6, R7 independently are H or alkyl. According to a further particular embodiment of the invention, one of radicals R8 and R9 represents H, alkyl, hydroxyalkyl or alkoxyalkyl and the other represents hydroxyl, alkoxy, carboxyl or acyloxy, or R8 and R9 together with the C atom they are attached to, represent a carbonyl group. 6,7-Dihydro-5H-pyrrolizines are especially useful, i.e. compunds of Formula (I), wherein X represents CR8R9, A represents a bond between X and the atom carrying radicals R6 und R7, and R4, R5, R6, R7, R8, R9 which may be the same or different, have the meanings as given above and preferably represent hydrogen or alkyl. 6,7-Dihydro-5H-pyrrolizines wherein R4 to R9 are hydrogen or at least one or two of radicals R4 to R9, for instance R6 und/oder R7, represent alkyl, in particular methyl, are especially preferred. According to an important aspect of the present invention, compounds of Formula (I), wherein the first and the second of radicals R1, R2, R3, preferably R1 and R2, independently represent an II-electron-rich system selected from aryl and aromatic heterocyclic residues, in particular phenyl, optionally substituted with one or more than one substituents that in particular are independently selected among the group consisting of halogen, alkyl and halogenoalkyl, in particular CF3, R1 being preferably unsubstituted phenyl and R2 being preferably 4-substituted phenyl, are especially useful. According to a further important aspect of the invention, compounds of Formula (I), wherein the third of radicals R1, R2, R3, preferably R3, represents an acidic residue such as COOH or B—Y, wherein Y is COOH and B preferably represents alkylene, or represents a precursor of an acidic residue such as B—Y, wherein Y is tetrazolyl, are especially useful. The use of [6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizine-5-yl]-acetic acid (ML3000) represented by Formula (Ia): its physiologically acceptable salts and derivatives, e.g., physiologically hydrolysable esters, is especially preferred. Physiologically acceptable salts include acid or base addition salts. Acid addition salts are, for instance, salts of compounds of Formula (I) with inorganic acids, such as hydrochloric acid, sulfuric acid, nitric acid or phosphoric acid, or with organic acids, in particular carboxylic acids, e.g. acetic acid, tartaric acid, lactic acid, citric acid, malic acid, amygdalic acid, ascorbic acid, maleic acid, fumaric acid, gluconic acid or sulfonic acid, e.g. methanosulfonic acid, phenylsulfonic acid and toluenesulfonic acid, and the like. Base addition salts are, for instance, salts of compounds of Formula (I) with inorganic bases, such as sodium or potassium hydroxide or with organic bases, such as mono-, di- or triethanolamine, and the like. Physiologically acceptable derivatives include in particular prodrugs of the compounds of formula (I) which are reconverted in vivo to the compounds of formula (I) or an active form thereof (metabolite). Examples are hydrolysable esters of the compounds of formula (I) wherein the third of radicals R1, R2, R3 represents an acidic residue, e.g. alkyl (the third of radicals R1, R2, R3 comprising the functionality COOAlkyl), aralkyl (the third of radicals R1, R2, R3 comprising the functionality COOAlkaryl, e.g., COOAlkPhenyl), pivaloyloxymethyl, acetoxymethyl, phthalidyl, indanyl and methoxymethyl esters thereof. According to a particular aspect, the present invention relates to the use of chondroprotective agents which are selected among the compounds of Formula (I). The term “chondroprotective agent” as used herein will be understood to refer to those compounds whose chief site of action is the cartilage. It will also be appreciated that such chondroprotective agents may also possess anti-inflammatory action with regard to the synovium, may positively impact the biosynthesis of cells in subchondral bone and other connective tissues such as synovial fibroblasts, and may mediate inflammatory cell migration so as to impede the inflammatory process. The present invention provides methods of treatment, and pharmaceutical compositions useful therein as well as suitable packaging therefor, which are applicable to mammals which suffer from or in the future may suffer from injury, damage or loss of articular cartilage and/or subchondral bone in one or more joints of such a mammal. Using the compounds of Formula (I) has particular advantages over other NSAIDs, especially those more established in use, which may actually exacerbate the progress of osteoarthritis, especially when long-term application is indicated. It is surprising that the compounds of Formula (I) are useful in treating or preventing such articular cartilage damage while simultaneously having no adverse impact on the course of inflammation in the mammal joint involved. The ability of the compounds of formula (I) to reverse the disease process which ultimately leads to articular cartilage and/or subchondral bone destruction and loss has far-reaching implications for the safe and effective treatment of mammals, especially those which are in the early stages of articular cartilage and/or subchondral bone degeneration or destruction. As used herein, the term “mammal(s)” denotes any mammal, preferably humans, cat, dog or horse, of which there are a large number of different breeds. In accordance with the present invention, treating or preventing the degeneration or destruction of articular cartilage and/or subchondral bone in one or more joints of a mammal in need of such treatment, comprises administering to said mammal an amount therapeutically effective for treating or preventing said degeneration or destruction of articular cartilage and/or subchondral bone, of one or more than one compound of Formula (I). Said treatment or prevention especially comprises ameliorating, diminishing, actively treating, reversing or preventing any degeneration or destruction, e.g. injury, damage or loss, of articular cartilage and/or subchondral bone, especially subsequent to said early stages of said degeneration or destruction. The expression “treating or preventing” as used herein with reference to the administration of the chondroprotective compounds of the present invention, is intended to refer to both the therapeutic objective of said administration as well as the therapeutic results actually achieved by said administration. As above-discussed, the extent of therapy accomplished by administration of said compounds may range from an amelioration to a significant diminishing of the course of the disease, and beyond to active treatment of the disease, including a reversal of the disease process. The higher degrees of therapeutic effectiveness result in the prevention of any injury, damage or loss of articular cartilage and/or subchondral bone subsequent to the early stages of degeneration in said articular cartilage and/or subchondral bone. The expression “the early stages of degeneration in articular cartilage and/or subchondral bone” is intended to mean the very beginning of the initial pathologic changes in the articular cartilage and/or subchondral bone which define and are the result of a disease process. Cartilage is a fibrous connective tissue existing in several forms, e.g., hyaline cartilage, elastic cartilage, and fibrocartilage. It is a connective tissue comprising water, collagen and proteoglycans which together create a unique fiber-reinforced water gel which is stiff but resilient and has considerable shock-absorbing capacity. Articular cartilage is cartilage to be found in the joints of mammals. It comprises living cells (chondrocytes) which generate and are surrounded by the interstitial material generally referred to as the extracellular matrix. Chondrocytes producing the extracellular matrix of the cartilage are highly active, and the integrity of this matrix is maintained by an equilibrium between the actions of the catabolic cytokines IL-1α, β and TNFα and the anabolic cytokines IGF and TGFβ. IL-1α, β and TNFα act by inducing the production of specific matrix degrading metalloproteases, while IGF and TGFβ act as growth factors by inducing the production of the macromolecular building blocks of cartilage, collagen and the proteoglycans. Other cytokines and their inhibitors, as well as tissue inhibitors of metalloprotease (TIMP), also influence this equilibrium, referred to as matrix homeostasis. The term “metalloprotease” as used herein is intended to refer to the matrix metalloproteases (MMPs), especially including those in this family of enzymes which usually exhibit elevated concentrations during articular cartilage degeneration, i.e., the stromelysins, the collagenases, and the gelatinases. Collagenase is generally responsible for the degradation of native collagen; stromelysin is generally responsible for the degradation of the proteoglycans; and gelatinase is generally responsible for the degradation of denatured collagen. An enzyme with MMP properties, aggrecanase, is also included within this term, since it is responsible for the proteolysis of cartilage proteoglycan aggregates which are present during the early stages of cartilage degeneration. The three collagenases present in articular cartilage during the early stages of degeneration are collagenase-1 (MMP-1), collagenase-2 (MMP-8), and collagenase-3 (MMP-13). Of the three stromelysins, stromelysin-1 (MMP-3), stromelysin-2 (MMP-10), and stromelysin-3 (MMP-11), only stromelysin-1 appears in articular cartilage during the early stages of its degeneration. Since osteoarthritis is defined as the failure of the diarthrodial (movable, synovial-lined) joint, it follows that in such a joint there will always be found at least two movable bony surfaces that would meet but for the fact that they are surrounded by the synovial membrane, which secretes synovial fluid, a transparent alkaline viscid fluid which fills the joint cavity, and articular cartilage, which is interposed between the articulating bony surfaces, usually in place of the synovial membrane at that point. The earliest gross pathologic finding in osteoarthrits is softening of the articular cartilage in habitually loaded areas of the joint surface, which in the case of the knee joint of the mammal, especially in models of osteoarthritis involving transection of the cruciate ligament in the knee joint, consists of the femoral condyle and the tibial plateau. With progression of osteoarthritis the integrity of the cartilage surface is lost and the articular cartilage thins, with vertical clefts extending into the depth of the cartilage in a process called fibrillation. Joint motion may cause fibrillated cartilage to shed segments that expose the bone underneath (subchondral), which then undergoes sclerosis. Subchondral cysts also develop which may be filled with synovial fluid. At the joint margins osteophytes (bone spurs) form. Changes in the subchondral bone also play a role in the pathology of cartilage degeneration and destruction. Studies of the joints of mammals, especially dogs, which have undergone anterior cruciate ligament transection reveals subchondral sclerosis and osteopenia, i.e., bone loss in the subchondral trabeculae. Subsequent to these changes, there is a thickening of the subchondral plate. The loss of subchondral bone increases the mechanical strain on the overlying articular cartilage, leading to its degeneration. The subsequent thickening of the subchondral plate negatively affects intrinsic repair mechanisms and thereby contributes to the progression of cartilage breakdown. The breakdown of the extracellular matrix of the cartilage is accompanied by mitotic division of the chondrocytes which then form in clusters. There is a reduction in the glycosaminoglycan components of the cartilage and patchy proteoglycan depletion. In many areas fibrocartilage, characterized by an extracellular matrix of thick, compact parallel collagenous bundles, replaces hyaline cartilage. However, it should be noted that these and the above-described pathologic changes in the articular cartilage are characteristic of later stages of osteoarthritis, and that hypertrophy, i.e., thickening of the articular cartilage occurs first, as shown by the cruciate-deficient mammal, especially dog knee joint model. Cartilage thickening results from increased water content, an increase in proteoglycan synthesis, and an Increase in both the content and concentration of proteoglycans in the articular cartilage. This stage of hypertrophic repair of the articular cartilage may persist for some time, but the repair cartilage tissue which is formed lacks the resiliency and resistance to mechanical stress possessed by normal hyaline cartilage. Eventually, proteoglycan production subsides and the chondrocytes are no longer able to maintain their extracellular matrix. This end stage results in full-thickness loss of articular cartilage. The early stages of the pathologic changes leading to cartilage injury and loss involve attempted repair through increased synthesis of matrix macromolecules. The makeup of the repair cartilage is deficient however, due to altered composition and distribution of the glycosaminoglycan component and a change in its capacity to aggregate with the hyaluronic acid component. Particles released during these pathologic changes may also lead to inflammatory changes in the synovial membrane. However, despite this ongoing pathology, the initial stages of cartilage injury and loss may be asymptomatic with relatively little pain. Accordingly, an appropriate objective is to identify those extracellular matrix components and cytokines for which measurable changes may be identified which profile a mammal subject in the early stages of cartilage injury and loss before focal cartilage loss can be identified radiographically. Meeting this objective will permit diagnostic classification of mammals which are candidates for early pharmacological intervention before significant cartilage degeneration occurs. Said pathologic changes in the articular cartilage include changes in the composition, form and density of the articular cartilage from that present before the onset of said disease process, which result in a degradation of the beneficial properties of said articular cartilage including strength, resilience, elasticity, conformational integrity and stability, viability, and the ability to successfully resist various kinds of mechanical stress, especially the ability to absorb mechanical shocks. These pathologic changes in composition especially include changes in the type and amount of glycosaminoglycans and collagen fibers present in the articular cartilage. Pathologic changes in the subchondral bone include sclerosis thereof, increasing density with decreasing resilience and elasticity thereof, and a diminishing ability to successfully resist various kinds of mechanical stress, especially the ability to absorb mechanical shocks. These pathologic changes especially include improper repair of trabecular microfractures with trabecular thickening, and pathogenic changes in osteoblastic metabolite production and differentiated phenotype. Synovitis, i.e., inflammation of the synovium, the synovial membrane, can contribute to the pathology of cartilage injury and loss. Synovial inflammation is characterized by extensive infiltration of the synovial fluid by mono-nuclear cells, by synovial membrane cell hyperplasia, and by lymphoid aggregates. Synovitis contributes significantly to cartilage injury in rheumatoid and other inflammatory arthropathles. The role of synovial inflammation in the early stages of OA are less well understood, however synovitis is present at the clinical stage of OA. According to one aspect of the present invention, the use of compounds of Formula (I) is directed to treating or preventing the degeneration or destruction of articular cartilage and/or subchondral bone, wherein said degeneration or destruction is associated with osteoarthritis. In particular, said use is directed to treating or preventing the pathologic changes invloved therewith. Thus, the present invention also relates to the treatment of osteoarthritis, wherein said treatment is accompanied by a therapeutically useful impact on articular cartilage and/or subchondral bone. Treating or preventing the degeneration or destruction of articular cartilage and/or subchondral bone may also comprise administering in addition to one or more than one compound of Formula (I), one or more members selected from the group consisting essentially of polysulfated glycosaminoglycan (PSGAG), glucosamine, chondroitin sulfate (CS), hyaluronic acid (HA), pentosan polysulfate (PPS), doxycycline, and minocycline. Further, the compounds of Formula (I) of the present invention may also be combined with other therapeutically active ingredients which would be readily apparent to the skilled artisan in this field, and which will usually be determined by the circumstances under which the therapeutic agent of the present invention is administered. For instance, where a joint has become seriously infected at the same time by microorganisms, e.g., bacteria, fungi, protozoa, virus and the like, the active ingredient of the present invention will desirably be administered in combination with one or more antibiotic, antifungal, antiprotozoal, antiviral or similar therapeutic agents. Also, the active ingredient of the present invention may be administered in combination with NSAIDs as well with inhibitors of other mediators of inflammation. Additional dasses of such inhibitors and examples thereof include, e.g., H 1 -receptor antagonists; kinin-B 1 - and B 2 -receptor antagonists; prostaglandin inhibitors such as PGD-, PGF-PGI 2 -, and PGE-receptor antagonists; thromboxane A 2 (TXA2)-inhibitors; PAF-receptor antagonists; gold in the form of an aurothio group together with various hydrophilic groups; immunosuppressive agents, e.g., cyclosporine, azathioprine, and methotrexate; anti-inflammatory glucocorticoids, e.g., dexamethasone; broad-spectrum antiparasitic antibiotics, e.g., the avermectins and the milbemycins; penicillamine; hydroxychloroquine; anti-gout agents, e.g., coichicine, xanthine oxidase inhibitors, e.g., allopurinol, and uricosuric agents, e.g., probenecid, sulfinpyrazone, and benzbromarone. Because the early stages of articular cartilage degeneration are prevalent among geriatric mammals, it will be appreciated by those skilled in the art that the compounds of Formula (I) may also be administered in combination with therapeutic agents intended for the treatment of disease conditions, syndromes and symptoms which are also found in abundance in older mammals. Such therapeutic agents and the conditions which they are used to treat include, e.g., cognitive therapeutics to counteract memory loss and impairment; and antidyskinetic/antiparkinsonian agents, e.g., selegeline. Another large class of such therapeutic agents includes anti-hypertensives and other cardiovascular drugs intended to offset hypertension, myocardial ischemia including angina, congestive heart failure, and myocardial infarction, e.g., diuretics, vasodilators such as hydralazine, β-adrenergic receptor antagonists such as propranolol, angiotensin-II converting enzyme inhibitors (ACE-inhibitors) such as enalapril used to treat geriatric mammals with mitral insufficiency, and enalapril alone and in combination with neutral endopeptidase inhibitors, angiotensin II receptor antagonists such as losartan, renin inhibitors, calcium channel blockers such as nifedipine, sympatholytic agents such as methyldopa, α 2 -adrenergic agonist such as clonidine, α-adrenergic receptor antagonists such as prazosin, and HMG-CoA-reductase inhibitors (anti-hypercholesterolemics) such as lovastatin or atorvastatin. Still other classes of such therapeutic agents include antineoplastic agents, especially antimitotic drugs including the vinca alkaloids such as vinblastine and vincristine, for treating various cancers; therapeutic agents for treating renal failure; anti-obesity drugs for treating excess weight problems in mammals; anti-parasitic drugs for treating both endo- and ecto-parasites which commonly afflict mammals; and anti-pruritic drugs for treating various types of pruritis in mammals. Other types of drugs which can be used in combination with the anti-inflammatory agents of the present invention include growth hormone secretagogues; strong analgesics; local and systemic anesthetics; and H 2 -receptor antagonists and other gastroprotective agents. It will be recognized by those of ordinary skill in this art that some of the above combinations of therapeutic agents will be used most frequently to treat various acute conditions in mammals, e.g., bacterial infections occurring simultaneously with degenerative joint disease. However, there would be an equal if not greater interest on the part of such skilled persons in treating chronic conditions in mammals. In accordance with a regimen which would be used for this purpose, it is contemplated that the compounds of Formula (I) would be administered in combination with other medications used on a regularly scheduled basis for treating chronic conditions such as hyperlipidemia. It is also envisioned that administration in combinations could assume a number of different forms and still be within the scope of the present invention. For example, the compounds of Formula (I) might simply be formulated with one or more of the other therapeutic agents which are to form the intended combination, into a convenient dosage form, such as an oral tablet, containing all of the drugs forming the combination. Varying half-lives for the different drugs could be accommodated by the person skilled in preparing formulations by creating controlled-release forms of said drugs with different release times so that relatively uniform dosing was achieved. A medicated feed used as the dosage form could also be prepared in accordance with well known principles in the art of formulation, in which the drugs used in the combination were simply present together in admixture in the feed composition. The present invention also contemplates co-administration in which the combination of drugs is achieved by the simultaneous administration of the drugs to be given in combination. Such co-administration could even be by means of different dosage forms and routes of administration. The present invention further contemplates the use of such combinations in accordance with different but regular and continuous dosing schedules whereby desired plasma levels of the drugs involved were maintained in the mammal being treated, even though the individual drugs making up the combination were not being administered to said mammal simultaneously. All such combinations would be well within the skill of the art to devise and administer. When the compounds of Formula (I) are to be used as active ingredients in the methods and compositions of the present invention, they can be incorporated into standard pharmaceutical dosage forms. Thus, the present invention also relates to pharmaceutical compositions comprising a pharmaceutically acceptable carrier and an amount therapeutically effective for treating or preventing said degeneration or destruction of articular cartilage and/or subchondral bone, of a compound of Formula (I) as above-defined. For example, they are useful when administered in systemic or local, oral or parenteral applications and for this purpose are combined with the usual pharmaceutical excipients, diluents and adjuvants, e.g., organic and inorganic inert carrier materials such as water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, gums, polyalkyleneglycols, etc. These pharmaceutical preparations can be employed in a solid form, e.g., as tablets, capsules, and especially in combination with or for admixture with a palatable food item suitable for mammals; or they can be administered in liquid form, e.g., as solutions and elibdrs. Pharmaceutical excipients and adjuvants which can be added include preservatives, antioxidants, antimicrobial agents and other stabilizers; wetting, emulsifying, and suspending agents, and anticaking compounds; fragrance and coloring additives; compositions for improving compressibility, or to create a delayed-, sustained-, or controlled-release of the active ingredient; and various salts to change the osmotic pressure of the pharmaceutical preparation or to act as buffers. Particular dosage forms which have been used with success include a 5% mixed-micelle solution of ML3000 for intravenous injection, a 3% palatable paste, and oral tablets. The therapeutically effective amount of a compound of Formula (I) as defined may be administered systemically to said mammal, wherein said systemic administration comprises: (1) injection or infusion into suitable body tissues or cavities of a pharmaceutical composition containing said compound in suitable liquid form such as aqueous solutions, emulsions or suspensions for intraarterial, intra- or transdermal (including subcutaneous), or intraspinal especially intrathecal and most commonly intramuscular or intravenous delivery thereof; or for serving as a depot for delivery thereof; (2) instillation into suitable body tissues or cavities of a pharmaceutical composition containing said compound in suitable solid form, e.g., comprising a matrix of bio-compatible and bio-erodible materials in which particles of a solid chondroprotective compound of Formula (I) are dispersed, or in which, possibly, globules or isolated cells of a liquid chondroprotective compound of Formula (I) are entrapped, for serving as a solid implant composition for delayed-, sustained-, and/or controlled-release delivery thereof; or (3) ingestion or administration of a pharmaceutical composition containing said compound in suitable solid or liquid form for transdermal delivery thereof, for instance a transdermal patch or a subepidermal (subcuticular) implant, for peroral delivery thereof. A substantial number of the dosage forms described herein may be formulated so as to provide controlled-, sustained-, and/or delayed release of the active ingredient from said dosage form. A useful controlled release dosage form of ML3000 in accordance with the present invention is one which maintains a ML3000 plasma level greater than 100 ng/mL for most of the day after a single oral dose at 5 mg/kg. Preferred oral controlled release dosage forms of ML3000 in accordance with the present invention are ones which maintain a plasma ML3000 concentration greater than 100 ng/mL for a period of time greater than that for which an immediate release dosage form of ML3000 maintains a comparable plasma level, when said immediate release dosage form and controlled release dosage form are administered at the same dose. Immediate release ML3000 dosage forms containing doses of 2.5 and 5 mg/kg maintain a plasma ML3000 concentration above 100 and 200 ng/mL for 8 hours, respectively. Preferred peroral dosage forms for systemic administration are solids, e.g., palatable oral compositions such as fast dissolving palatable wafers, tablets, capsules, caplets, etc., and liquids, e.g., solutions, suspensions, emulsions, etc. Pharmaceutical compositions of special types suitable for oral administration to mammals may be used, and include, but are not limited to such items as an oral paste to be delivered to the back of the tongue of the mammal being treated, a granular form to be delivered through incorporation in the mammal's food, and a chewable form wherein the active ingredient is consumed along with the palatable chew, or a chewable form which may deliver the active ingredient by leaching from the body of the chew which is not consumed, during mastication by the mammal being treated. Said therapeutically effective amount of a compound of Formula (I) as defined may also be administered locally to said mammal, wherein said local administration comprises: (1) injection or infusion into a local site of degeneration or destruction of articular cartilage and/or subchondral bone of a pharmaceutical composition containing said compound of formula (I) in suitable liquid form for delivery thereof, including components which provide delayed-release, controlled-release, and/or sustained-release of said compound into said local site; or for serving as a depot for delivery thereof wherein said composition provides storage of said compound and thereafter delayed-, sustained-, and/or controlled-release thereof; or (2) instillation of a pharmaceutical composition containing said compound in suitable solid form for serving as a solid implant for delivery thereof, said composition optionally providing delayed-, sustained-, and/or controlled-release of said compound to said local site. Local administration is focused on suitable articular tissues into which the chondroprotective compound of Formula (I) may be injected, infused, implanted, deposited, inserted, or instilled. Such administration may include, but is not limited to, that which is intraarticular, intrachondrial, intracostal, intraligamentous, intramedulary, intramuscular, intraosteal, intrapelvic, intraspinal, intrasternal, intrasynovial, intratarsal, intrathecal, or intravenous. Pharmaceutical compositions in liquid form containing the chondroprotective compound of Formula (I) offer the advantage of permitting injections of the liquid into or in close proximity to the articular site. By injection of the compound of Formula (I) directly into the joint, it is possible to achieve a high concentration of said compound in a short period of time, thus not only substantially enhancing access of said compound to the joint tissues, and thus the therapeutic activity of the compound of Formula (I), but also at the same time minimizing the occurrence of untoward adverse reactions that might otherwise occur. The result is a high local concentration of the compound of Formula (I) with a correspondingly low systemic carryover concentration. Injections may also be made of pharmaceutical compositions containing the chondroprotective compound of Formula (I), where the pharmaceutical composition is in delayed-release, controlled-release, or sustained-release form. These formulations of recognized composition may be a solids, semi-solids, gels or other liquid/solid combinations in which an erodible matrix or series of coatings is used to provide a continuous release of the compound of Formula (I) at a predetermined rate or at variable rates if desired. The terms “extended-release” and “long-acting” as well as others are used to describe these formulations. All of these employ various combinations of bioerodible polymers, e.g., various cellulosic polymers, and natural materials, e.g., cornstarch and magnesium stearate, to obtain slow and/or uniform dispensing of the compound of Formula (I) contained within the matrix. These pharmaceutical compositions may be injected into the articular site if suitably liquid or suspendable, or may be delivered by other means if more solid in nature. The therapeutically effective amount for treating or preventing articular cartilage and/or subchondral bone degeneration or destruction, of the compound of Formula (I), is administered to a mammal being treated in an amount expressed as milligrams per kilogram of body weight of said mammal, per day: “mg/kg/day”. The expression “per day” as used herein should not be interpreted as necessarily requiring that any particular dosage form be administered on a daily basis to the mammal being treated. The expression “per day” is merely an indication of the smallest convenient but arbitrary segment of time which is being used as part of the overall unit for measuring the dose of chondroprotective compound being administered. The dose, i.e., the therapeutically effective amount of a compound of Formula (I) for treating or preventing articular cartilage and/or subchondral bone degeneration or destruction will usually range from about 0.1 mg/kg/day to about 20.0 mg/kg/day, preferably from about 0.1 mg/kg/day to about 12.0 mg/kg/day, more preferably from about 0.5 mg/kg/day to about 10.0 mg/kg/day, and most preferably from about 0.5 mg/kg/day to about 8.0 mg/kg/day. Typical dosage forms and amounts for ML3000 would include oral administration of ML3000 at a dose rate of 2.5-5.0 mg/kg/day of body weight. It is necessary for the skilled artisan, not only to determine the preferred route of administration and the corresponding dosage form and amount, but said artisan must also determine the dosing regimen, i.e., the frequency of dosing. In general terms it is most likely that the choice will be between once-a-day (s.i.d.) dosing and twice-a-day (b.i.d.) dosing, and that the former will provide more rapid and profound therapy, while the latter will provide less profound but more sustained therapy. However, this generalization does not take into account such important variables as the specific type of articular cartilage or subchondral bone degeneration or destruction involved, the specific therapeutic agent involved and its pharmacokinetics, and the specific patient (mammal) involved. For an approved product in the marketplace, much of this information is already provided by the results of clinical studies carried out to obtain such approval. In other cases, such information may be obtained in a straightforward manner in accordance with the teachings and guidelines contained in the instant specification taken in light of the knowledge and skill of the artisan. The results which are obtained can also be correlated with data from corresponding evaluations of an approved product in the same assays. It is also contemplated that in accordance with the present invention there will also be provided a package suitable for use in commerce for treating or preventing the degeneration or destruction of articular cartilage and/or subchondral bone in one or more joints of a mammal in need of such treatment, comprising a suitable outer carton and an inner container removably housed therein; enclosed in said container a suitable dosage form of a compound of Formula (I) as described hereinabove; and associated with said carton or container printed instructional and informational material, which may be attached to said carton or to said container enclosed in said carton, or displayed as an integral part of said carton or container, said instructional and informational material stating in words which convey to a reader thereof that said active ingredient, when administered to a mammal in a condition of degeneration or destruction of articular cartilage and/or subchondral bone in one or more joints thereof, will ameliorate, diminish, actively treat, reverse or prevent any injury, damage or loss of articular cartilage or subchondral bone. In a preferred embodiment said package comprising carton and container as above-described will conform to all regulatory requirements relating to the sale and use of drugs for the treatment of animals, including especially said instructional and informational material. It is also contemplated that in accordance with the present invention there will further be provided a package of the type described immediately above, comprising a suitable container as described; enclosed in said container an oral dosage form of a compound of Formula (I); and associated with said container printed instructional and informational material as above-described. The method of the present invention can be further defined to comprise two basic steps: (I) establishing the status of a candidate mammal as presently or prospectively being in a condition of degeneration or destruction of articular cartilage and/or subchondral bone in one or more joints of said mammal, thereby confirming that said mammal is in need of such treatment; and thereupon (II) treating or preventing said condition by administering to said mammal an amount therapeutically effective for treating or preventing said degeneration or destruction of articular cartilage and/or subchondral bone, of a chondroprotective compound of Formula (I). The various aspects of Step (II) have already been discussed above in detail. Accordingly, the aspects of Step (I) will now be discussed in detail. As far as diagnosis is concerned, it is expedient to establish the status of a mammal which is a candidate for treatment in accordance with the present invention as to whether or not the mammal is presently or prospectively in a condition of degeneration or destruction of articular cartilage and/or subchondral bone in one or more joints of said mammal. The expression “presently or prospectively” as used herein is intended to mean that in accordance with the below-discussed methods of making that determination, it is possible to identify a candidate mammal as either being presently in need of such treatment, or as very likely or expected to be in need of such treatment in the short term future. Prospective need of treatment may be established by those determinations of positive factors which from the experience of the artisan lead directly to the condition of articular cartilage and/or subchondral bone degeneration or destruction. For example, the artisan may establish from clinical examination of a mammal that it has incipient hip dysplasia, and may confirm this conclusion with radiographic evidence from which it may be determined in accordance with established methods of measurement that the mammal will develop hip dysplasia within the short term future. The status of said mammal as presently or prospectively being in said condition of degeneration or destruction and especially in said early stages, and thus in need of such treatment, is in particular determined by: (A) positive results from the clinical arthroscopic examination and evaluation of the joints of the candidate mammal. The diagnosis of incipient or realized hip dysplasia has already been discussed. Other clinical symptomology and signs would include those gained from direct examination of the joints of the candidate mammal; (B) performance of any invasive surgical procedure on one or more joints of the candidate mammal which would be under most circumstances be sufficient reason by itself to conclude that treatment was needed. This follows from the fact that invasive surgery on the joint of a mammal inevitably degrades the ability of that joint to bear its accustomed load as efficiently as before surgery. The increased mechanical stress on the joint would, in the experience of the skilled artisan, lead directly to the early stages of articular cartilage and/or subchondral bone degeneration. Such surgery on the joint would also produce an effusion of blood and other fluids containing cytokines and other factors which are causative agents of inflammation, and would thereby permit their migration and absorption into the solid tissues of the joint, including the cartilage and/or subchondral bone. The artisan would appreciate that this would also lead directly to the early stages of articular cartilage and/or subchondral bone degeneration; (C) positive results from an examination of one or more joints of said mammal using noninvasive procedures including radiographic and magnetic resonance imaging (MRI). The latter technique is better for evaluating soft tissues than is the former. MRI is a technique for multiplanar body imaging that shows increased soft tissue contrast resolution. Since MRI can visualize soft tissue changes, it is suitable for imaging the pathology of the early changes in articular cartilage and subchondral bone degeneration; (D) positive results from any biochemical test performed on body fluids or joint tissue of the candidate mammal with respect to one or more of the following substances: increased interleukin-1 beta (IL-1β); increased tumor necrosis factor alpha (TNFα); increased ratio of IL-1β to IL-1 receptor antagonist protein (IL-1Ra); increased expression of p55 TNF receptors (p55 TNF-R); increased interleukin-6 (IL-6); increased leukemia inhibitory factor (LIF); unchanged or decreased insulin-like growth factor-1 (IGF-1); decreased transforming growth factor beta (TGFβ); unchanged or decreased platelet-derived growth factor (PDGF); unchanged or decreased basic fibroblast growth factor (b-FGF); increased keratan sulfate; increased stromelysin; increased ratio of stromelysin to tissue inhibitor of metalloproteases (TIMP); increased osteocalcin; increased alkaline phosphatase; increased cAMP responsive to hormone challenge; increased urokinase plasminogen activator (uPA); increased cartilage oligomeric matrix protein; and increased collagenase. IL-1, which occurs as IL-1α and IL-1β, is a catabolic cytokine which mediates articular cartilage injury and loss in mammal joints. It acts by suppressing the synthesis of type II collagen found in articular cartilage while promoting the synthesis of type I collagen characteristic of fibroblasts; by inducing the production of enzymes involved in matrix degradation; and by suppressing the ability of chondrocytes to synthesize new proteoglycans. The number of IL-1 receptors on the surface of chondrocytes in articular cartilage in the early stages of degeneration which must be occupied in order to elicit catabolic enzyme production is only one-fourth as great as that required normally (1% vs. 4%). IL-1 and its modulator IL-1Ra are produced in an autocrine and paracrine fashion by the same synovial macrophages, and IL-1 Ra production may be increased in the presence of granulocyte macrophage colony-stimulating factor (GM-CSF). However, there is a significant disparity between IL-1 and IL-1Ra potency, with approximately 130-fold more IL-1Ra being required to abolish the effects of IL-1, as measured in chondrocytes and cartilage explants. Any imbalance between IL-1 and IL-1Ra will further exacerbate the degeneration of articular cartilage. Consequently, it is also an appropriate objective to measure levels of IL-1 and IL-1Ra and their ratios in mammals in the early stages of articular cartilage degeneration, and the same values in mammals not so afflicted so that measurable changes may be identified which profile a mammal subject in the early stages of cartilage injury and loss before focal cartilage loss can be identified radiographically. These results provide diagnostic classification of mammals which are candidates for early pharmacological intervention before significant cartilage degeneration occurs. Furthermore, the proportion of IL-1α and IL-1β-secreting macrophages occurring in the synovial fluid and synovial tissue of a joint in the early stages of articular cartilage degeneration can be detected and is significantly greater than the proportion of similar cells isolated from synovial fluid and synovial tissue from normal joints, i.e., joints which are not in the early stages of articular cartilage degeneration. Here again, these results provide diagnostic classification of mammals which are candidates for early pharmacological intervention before significant cartilage degeneration occurs. Further still, changes in subchondral bone occur before gross alterations in the articular cartilage become apparent because cytokines responsible for initiating and maintaining the inflammatory process gain access to the lower layers of cartilage through microcracks across the calcified zone. The metabolism of the chondrocytes involved is adversely affected, and in addition the chondrocytes in the middle zone of the articular cartilage produce many cytokines, including those responsible for initiating and maintaining the inflammatory process. These chondrocytes, acting in an autocrine fashion, thus contribute to the destruction of their own extracellular matrix. The increased water content of the articular cartilage also facilitates this process by increasing diffusion of the inflammatory cytokines throughout the matrix. It is, consequently, an appropriate objective to measure levels of various inflammatory cytokines produced by chondrocytes, synovial cells, and/or subchondral osteocytes in mammals, especially canines during the process of articular cartilage degeneration, and the same values in mammals not so afflicted so that measurable changes may be identified which profile a mammal subject in the early stages of cartilage injury and loss before focal cartilage loss can be identified radiographically. These results provide diagnostic classificaton of mammals which are candidates for early pharmacological intervention before significant cartilage degeneration occurs. Tumor necrosis factor alpha (TNFα) has only one-tenth the potency of IL-1 with regard to the degeneration of articular cartilage, but its concentration in synovial fluid significantly increases in the knee joints of mammals, especially with sectioned cruciate ligaments compared to the opposite, unoperated knee. There is also enhanced expression of p55 TNF receptors (TNF-R) on chondrocytes isolated from articular cartilage present in such knee joints. Accordingly, since TNFα plays a role in the pathologic changes which take place in the early stages of cartilage injury and loss, it is likewise an appropriate objective to measure levels of TNFα and TNF-R in the joints of mammals in the early stages of articular cartilage degeneration, and the same values in mammals not so afflicted so that measurable changes may be identified which profile a mammal subject in the early stages of cartilage injury and loss before focal cartilage loss can be identified radiographically. These results provide diagnostic classification of mammals which are candidates for early pharmacological intervention before significant cartilage degeneration occurs. Interleukin-6 (IL-6) is a multifunctional cytokine, but plays an inflammatory role and is found in elevated levels in joints and synovial fluid from damaged as compared to control limbs. IL-6 is also responsible for enhanced expression of TNF-R on chondrocytes and increased proteoglycan production by chondrocytes, as well as induction of glycosaminoglycan release. Measurement of IL-6 levels in joints, synovial fluid and chondrocytes of mammal joints in the early stages of articular cartilage injury and loss, compared to control, can be used as a diagnostic tool for identifying mammals that are appropriate candidates for pharmacological treatment, before any focal cartilage loss is evident from radiographic examination. Leukemia inhibitory factor (LIF) is produced by monocytes, granulocytes, T cells, fibroblasts, and other cell types associated with inflammatory conditions. Synoviocytes and chondrocytes synthesize and secrete LIF in the presence of IL-1β and TNFα. Thus, measurement of comparative increases in levels of LIF can be used diagnostically to select mammal candidates for pharmacologic treatment of the early stages of articular cartilage injury and loss. The degeneration, injury and loss of articular cartilage in mammals is caused by an imbalance between the cytokines that drive the above-described catabolic processes and those cytokines which are responsible for maintaining the synthetic and proliferative responses of the chondrocytes in the cartilage. Insulin-like growth factor (IGF-1), transforming growth factor beta (TGFβ), platelet-derived growth factor (PDGF), and fibroblast growth factor, e.g., basic fibroblast growth factor (bFGF), are all mitogenic with respect to the chondrocytes and stimulate matrix synthesis in articular cartilage. Insulin-like growth factor (IGF) exists as types I and II, and IGF-I is a potent mediator of cartilage synthesis. Furthermore, it reduces degradation and promotes synthesis of proteoglycans even in the presence of IL-1β and TNFα. Serum levels of IGF-1 are maintained by high-affinity binding proteins (IGF-BPs) and IGF-1 is important in both bone and cartilage turnover. Levels of IGF-1 compared to control permit diagnostic evaluation of mammal candidates for early pharmacologic treatment of articular cartilage degeneration. Transforming growth factor (TGFβ) is produced by chondrocytes and is a powerful mitogen for the turnover of both cartilage and bone. Further, it stimulates the synthesis of matrix and has anti-inflammatory activity. It also inhibits the degradation of the matrix by stimulating protease inhibitor production, and blocking collagenase and metalloprotease release. Further still, it promotes cartilage repair by stimulating production of collagen, fibronectin, inhibitors of plasminogen activators, and tissue inhibitors of metalloproteases (TIMP) by various cells in the mammal joint. Synovial fluid levels of TGFβ are low in the joints of mammals in the early stages of articular cartilage injury and loss. Consequently, levels of TGFβ compared to control permit diagnostic evaluation of mammal candidates for early pharmacologic treatment of articular cartilage degeneration. With the progressive degeneration, i.e., catabolism of the articular cartilage in the mammal joint, a number of metabolites are produced which are useful as markers of the cartilage degeneration, both as to its occurrence and as to its advance. For example, degradation of cartilage by IL-1α and IL-1β or TNFα releases glycosaminoglycans (GAGS), which can be measured in the synovial fluid of a mammal being tested. Furthermore, GAG levels change after treatment so that it is possible to monitor the course of pharmacologic intervention, using synovial fluid GAG levels as a marker of articular cartilage turnover. Since the degradation of articular cartilage involves collagen as well as the other cartilage components, several collagen products serve as markers of cartilage degradation in mammal, especially canine articular cartilage injury and loss. Type-II specific collagen breakdown products, e.g., 20-30 amino acid neoepitopes, can be identified in body fluids such as synovial fluid, plasma, serum or urine. The presence of neoepitopes in these body fluids may be used as indicators of OA onset and progression. Keratan sulfate is a particular GAG which has an epitope, 5D4, whose levels in synovial fluid can be used as a marker of early articular cartilage injury and loss. Conversely, levels of chondroitin sulfate, another particular GAG, expressed as a number of epitopes, is associated with anabolic events in the articular cartilage of mammals in the early stages of cartilage injury and loss. Levels of these epitopes in synovial fluid, particularly 3B3, 7D4 and 846, can be determined by specific monoclonal antibodies which recognize them. The 3B3 epitope is expressed on chondroitin sulfate chains of cartilage during repair and the remodeling of the extracellular matrix, and consequently its levels in synovial fluid correlate inversely with those of the above-mentioned 5D4. The expression of 3B3 in newly synthesized PGs in the superficial and upper middle layer of the articular cartilage mean that 3B3 is associated with early changes in the articular cartilage of mammals in the early stages of cartilage degeneration. Accordingly, the determination of 3B3 levels in the synovial fluid of test mammals and comparison of these levels with control values permits the creation of a diagnostic profile of a mammal that is an appropriate candidate for early pharmacologic treatment. Further markers of cartilage anabolic activity are the propeptides of type II procollagen (PIIP). Type II is the major collagen of articular cartilage and it is produced by the chondrocytes as procollagen. During the process of collagen fibril formation, the noncollagenous aminopropeptide and carboxypropeptide are cleaved and released into body fluids, where they can be measured as reflection of anabolic activity in the articular cartilage. Levels of carboxy-PIIP will be raised and its synovial fluid levels correlate with radiographic evidence of changes in the cartilage. Accordingly, measurement of carboxy-PIIP levels in synovial fluid and comparison with controls permits identification of mammal candidates for early pharmacologic treatment. An imbalance in the stromelysin/TIMP ratio in the articular cartilage and joint fluids of mammals in the early stages of articular cartilage degeneration is also useful in identifying such mammals. Altered joint loading following injury causes the production of excess stromelysin, an enzyme produced by chondrocytes and synoviocytes under the influence of IL-1. The concentrations of stromelysin are also higher in fibrillated cartilage than they are in cartilage more distal from the lesion involved. The increased levels of stromelysin may occur for only a fairly short period of time, but where the damage to the joint transcends the tidemark zone of the articular cartilage, and reaches into the subchondral bone, there is a substantial likelihood of subsequent articular cartilage degeneration, usually preceded by a stiffening of the subchondral bone. Further, in the cruciate-deficient mammal model used in detecting the early stages of articular cartilage degeneration, there is an increased number of cells involved in the synthesis of stromelysin, IL-1α, IL-1β, and three oncogene proteins, c-MYC, c-FOS, and c-JUN. In the synovium these are found mainly in the superficial synovial lining cells, while in the cartilage the cells are the chondrocytes on the superficial and middle layers and the cells in the fibrillated areas of the tibial plateau. Further, stromelysin and IL-1 diffuse into the cartilage matrix of the tibial plateau. Stromelysin, which degrades components of connective tissue including proteoglycans and type IX collagen, is actively synthesized in the synovium of mammals in the early stages of articular cartilage degeneration, and is the primary proteolytic enzyme involved in the cartilage destruction. Increased levels of stromelysin mRNA are detectable in the synovia of such mammals, as are increased levels of collagenase mRNA. Increased levels of both isoforms of IL-1, but especially IL-1β, stimulate the increased synthesis of stromelysin by enhancing synovial fibroblast induction of stromelysin and collagenase gene expression. At the same time, IL-1 does not induce mRNA of tissue inhibitor of metalloprotease (TIMP) and the levels of this inhibitor remain unchanged while the detectable levels of metalloproteases in the synovium are dramatically increased. The metalloproteases are secreted by chondrocytes as proenzymes which must be activated before degradation of extracellular matrix macromolecules can take place. Activation involves an enzymatic cascade in which serine proteases including the plasminogen activator/plasmin system play a key role. The integrity of the articular cartilage in a mammal joint depends upon the adequacy of the support which it receives from the bony bed which it covers, i.e., the structural properties of the underlying subchondral bone. Alterations in this bony bed precede degradative changes in the articular cartilage. These alterations include increased stiffening of the subchondral bone, accompanied by loss of shock-absorbing capacity. These subchondral bone changes are caused by inappropriate repair of trabecular microfractures which result, in turn, from excessive loading of the joint. Trabecular thickening of the subchondral bone is part of a bone alteration leading to increased bone mineral density and/or volume in affected joints, which in turn is caused by a bone cell defect in the osteoblasts, resulting in altered phenotypic characteristics in these osteoblast-like cells of the subchondral bone. These alterations in subchondral bone density are not only evidence of an imbalance in the bone remodeling process, but also are a key ingredient in eventual focal cartilage loss. Bone sclerosis is also due to dysregulation of this bone remodeling process. Further, site-related differences in osteoblast metabolism occur which lead to the production of different cartilage-degrading molecules. These changes in osteoblast metabolites in turn lead to corresponding changes in chondrocyte metabolism, rendering them more susceptible to cytokine-induced activity of the types above-described. This osteoblastic anomaly and differentiated phenotype is characterized by divergent production levels of osteocalcin, alkaline phosphatase, cAMP responsive to hormone challenge, urokinase plasminogen activator (uPA), and insulin-like growth factor 1 (IGF-1). Further evidence of subchondral bone activity involvement in eventual articular cartilage degeneration is joint space narrowing which may be measured by bone scintigraphy. These changes in subchondral bone activity are accompanied by corresponding changes in specific bone cell metabolites, e.g., osteocalcin. Osteocalcin is a vitamin K-dependent, calcium binding bone protein which is the most abundant noncollagen protein in bone. Increased levels of osteocalcin are a marker of bone turnover in various disease states, including particularly the early stages of articular cartilage degeneration. Body fluid, especially synovial fluid levels of osteocalcin directly correlate to subchondral bone changes as measured by scintigraphy. In addition to markers of subchondral bone activity as indicators of the early stages of articular cartilage degeneration in mammals, metabolites from cartilage and synovium activity are also useful as markers which indicate the early stages of such cartilage degeneration. For example, detection of increased serum levels of cartilage oligomeric matrix protein serves as a marker of cartilage turnover. Similarly, detection of high levels of hyaluronate in body fluids, especially serum serves as a marker of synovial inflammation. In both cases, the increased body fluid, especially serum levels of these metabolite markers indicate the early stages of articular cartilage degeneration. The expression “body fluid” as used herein is intended to include all of those accessible body fluids usable as clinical specimens which may contain a compound being tested for in sufficient concentration in said fluid to be within the limits of detection of the test device or assay being used. Body fluids will thus include whole blood, serum, plasma, urine, cerebrospinal fluid, synovial fluid, and interstitial and other extracellular fluids. Accordingly, the afore-described measurements usually are conducted in vitro on a specimen (sample) that has been obtained from the candidate mammal. |
Water-based screen printing ink |
The invention relates to a water-based screen, flexo or gravure printing ink composition, to a method of manufacturing said ink composition, to the use of said ink composition for screen, flexo or gravure printing, and to value documents printed with said ink composition. |
1-17. (Cancelled) 18. A water-based screen printing ink composition having (a) an acrylic or urethane-acrylic copolymer emulsion; and (b) a crosslinker; wherein said crosslinker comprises at least two different chemical functionalities within the same molecule, wherein a first of said functionalities is chosen such as to form a covalent link with said polymer prior to printing and a second of said functionalities is selected to effect crosslinking of said polymer to cure the printed ink and that the acrylic or urethane-acrylic copolymer emulsion is selected from the group consisting of those copolymer emulsions having self-crosslinking properties. 19. A water-based screen printing ink composition according to claim 18 wherein the acrylic or urethane-acrylic copolymer emulsion is alkali soluble. 20. A water-based screen printing ink composition according to claim 18 wherein the acrylic or urethane-acrylic copolymer has a Tg value in the temperature range between −10° and 50° C. 21. A water-based screen printing ink composition according to claim 18 wherein the acrylic or urethane-acrylic copolymer emulsion has an acid number between 10 and 90 mg KOH/g. 22. A water-based screen printing ink composition according to claim 18 wherein the acrylic or urethane-acrylic copolymer emulsion has an acid number between 15 and 75 mg KOH/g. 23. A water-based screen printing ink composition according to claim 18 wherein the acrylic or urethane-acrylic copolymer emulsion has a solid content of 35% to 55% by weight of the emulsion. 24. A water-based screen printing ink composition according to claim 18 wherein the said crosslinker is chosen from the group consisting of substituted alkoxy silanes (R1)y(R2O)zSi, wherein R1, R2 are different substituents, and y+z=4. 25. A water-based screen printing ink composition according to claim 18 wherein the said crosslinker is chosen from the group consisting of monosubstituted trialkoxy silanes (R1)y(R2O)zSi, wherein y=1 and z=3. 26. A water-based screen printing ink composition according to claim 18 wherein the said crosslinker is chosen from the group consisting of monosubstituted triethoxysilanes. 27. A water-based screen printing ink composition according to claim 18 wherein the said crosslinker is chosen from the group consisting of epoxy-cycloaliphatic triethoxysilanes and glycidyl-triethoxysilanes. 28. A water-based screen printing ink composition according to claim 18, further comprising an imidazole catalyst. 29. A water-based screen printing ink composition according to claim 18 comprising between 30% and 70% by weight of self-crosslinking acrylic or urethane acrylic copolymer emulsion with respect to the total weight of the composition. 30. A water-based screen printing ink composition according to claim 18 comprising between 35% and 60% by weight of self-crosslinking acrylic or urethane acrylic copolymer emulsion with respect to the total weight of the composition. 31. A water-based screen printing ink composition according to claim 18 comprising between 40% and 55% by weight of self-crosslinking acrylic or urethane acrylic copolymer emulsion with respect to the total weight of the composition. 32. A water-based screen printing ink composition according to claim 18 comprising between 0.25% and 3% by weight of said crosslinker, with respect to the total weight of the composition. 33. A water-based screen printing ink composition according to claim 18 comprising between 0.5% and 2% by weight of said crosslinker, with respect to the total weight of the composition. 34. A water-based screen printing ink composition according to claim 18 comprising between 1% and 2% by weight of said crosslinker, with respect to the total weight of the composition. 35. A water-based screen printing ink composition according to claim 18 further comprising a catalyst 36. A water-based screen printing ink composition according to claim 35 wherein the catalyst constitutes between 0.05% and 0.6% of the total weight of the composition. 37. A water-based screen printing ink composition according to claim 35 wherein the catalyst constitutes between 0.1% and 0.4% of the total weight of the composition. 38. A water-based screen printing ink composition according to claim 35 wherein the catalyst constitutes between 0.2% and 0.4% of the total weight of the composition. 39. A water-based screen printing ink composition according to claim 18 wherein the composition has a pH value between 7.0 and 8.5 40. A water-based screen printing ink composition according to claim 39, wherein said pH value is between 7.5 and 8.3. 41. A water-based screen printing ink composition according to claim 39, wherein said pH value is between 7.5 and 8.0. 42. A water-based screen printing ink composition according to claim 18, further comprising pigments making up between 10% to 25% of the total weight of the composition. 43. A water-based screen printing ink composition according to claim 18, further comprising pigments making up between 12% and 20% of the total weight of the composition. 44. A water-based screen printing ink composition according to claim 18, further comprising pigments making up between 15% and 18% of the total weight of the composition. 45. A water-based screen printing ink composition according to claim 18, further comprising a pigment selected from the group consisting of luminescent pigments, magnetic pigments, optical effect pigments and optically variable pigments, and mixtures thereof. 46. A water-based screen printing ink composition according to claim 18, further comprising a flake pigment having first and second parallel planar surfaces and an aspect ratio greater than two. 47. A water-based screen printing ink composition according to claim 18, further comprising a flake pigment having first and second parallel planar surfaces and an aspect ratio greater than five. 48. A method of manufacturing a water-based screen printing ink composition according to claim 18, comprising the steps of (a) providing an acrylic or urethane-acrylic copolymer emulsion; (b) providing a crosslinker which is capable of forming a covalent link under first conditions with the polymer provided in (a), and crosslinking the resulting polymer under second conditions; and (c) intimately mixing the components provided in (a) and (b) and allowing the polymer provided in (a) to react with the crosslinker provided in (b) under said first conditions. 49. A method of using a water-based ink composition comprising acrylic or urethane-acrylic copolymer emulsions and a crosslinker, wherein said crosslinker is covalently linked with said acrylic or urethane-acrylic copolymer and wherein said acrylic or urethane-acrylic copolymer emulsion is selected from the group consisting of copolymer emulsions having self-crosslinking properties, as a screen, flexo or gravure printing ink, comprising the steps of providing a water-based ink composition comprising the above ingredients, and performing a screen, flexo or gravure printing process with said water-based ink composition. 50. Value document carrying indicia printed by using a water-based screen, flexo or gravure printing ink composition according to claim 18. |
Automatically response system using a schedule and method thereof |
The present invention relates to a communication terminal, and more particularly, to an automatically response method which controls a call requests of sender using the registered schedule in advance. The automatically response method includes registering at least one schedule inputted from recipient, retrieving a schedule information for schedule notice based on at least one schedule, displaying the retrieved schedule information to the recipient, and performing an automatically response to a call requests of sender. Therefore, the invention intercepts a call requests which be telephoned in public place or private time. Also, the invention prevents a misunderstanding between sender and recipient and allows sender to be a call standby effectively, informing sender of the reason why a call is impossible and the available time of calling. |
1. A call responding method based on schedules, comprising: registering at least one or more schedules input by receiver; searching schedule information based on at least one said schedule; displaying to said receiver said searched schedule information; and automatically responding to a caller's call request. 2. The call responding method according to claim 1, wherein at least one or more schedules is a monthly schedule, a weekly schedule, a special time schedule. 3. The call responding method according to claim 1, said step for registering a receiver-input of one or more schedules comprises the steps of: providing a corresponding input screen for the receiver's selected schedule menu; recognizing schedule information input through said input screen; and registering said schedule information to a corresponding database. 4. The call responding method according to claim 1, said step for searching schedule information based on at least one said schedule comprises the steps of: searching one or more schedule registers at every preset searching cycle; checking whether schedule type is ‘0’ and the status of Do-Not-Disturb time; deleting schedule information from corresponding schedule register if said schedule type is ‘0’ or if said Do-Not-Disturb time is past; searching in order of special time schedule, weekly schedule, and monthly schedule after said step of searching one or more schedule register is completed; and storing search-resulted schedule information into one or more schedule registers. 5. The call responding method according to claim 4, wherein said Do-Not-Disturb time is calculated from current time and a finish time. 6. The call responding method according to claim 4, further comprising the step of: maintaining said schedule register's schedule information in a case that said Do-Not-Disturb time is not past. 7. The call responding method according to claim 1, said step for displaying to said receiver said searched schedule information comprises the steps of: confirming schedule type by checking number 1 schedule register; checking said Do-Not-Disturb schedule register is empty in a case that said schedule type is not ‘0’; storing schedule register's schedule information in a case that said Do-Not-Disturb schedule register is empty; repeating above steps for each schedule register to the last schedule register; and displaying computed result corresponding to said schedule type. 8. The call responding method according to claim 7, further comprising the step of: comparing schedule register's start time against Do-Not-Disturb schedule register's start time in a case that said Do-Not-Disturb schedule register is not empty, while repeating above said steps. 9. The call responding method according to claim 7, wherein said searched result is at least one of schedule notify, Do-Not-Disturb state signal, or schedule notify & Do-Not-Disturb state signal. 10. The call responding method according to claim 1, the step for automatically responding to a caller's connect request comprises the steps of: checking Do-Not-Disturb schedule register to compare current time against Do-Not-Disturb start time, in a case that there is a caller request for a call; communicating Do-Not-Disturb status and possible receive time to said caller, in a case that said current time is within said Do-Not-Disturb time; and producing emergency call signal ring, in a case that said caller makes an emergency call request while in a Do-Not-Disturb state. 11. The call responding method according to claim 10 wherein said emergency call request is executed with a password input. 12. A communication terminal, comprising: means for registering a receiver-input of at least one or more schedules; means for searching schedule information based on at least one said schedule; means for displaying to said receiver said searched schedule information; means for denying connection to a caller's call request, based on current time's schedule information; and means for storing and register at least one said schedule. 13. The terminal according to claim 12, further comprising: means for temporarily memorizing schedule information resulted from said means to search. 14. The terminal according to claim 12, the means for storing includes Do-Not-Disturb list database, monthly schedule database, weekly schedule database, and special time schedule database. 15. The terminal according to claim 12, further comprising: means for producing an emergency call signal ring during a Do-Not-Disturb state, if said caller makes an emergency call request. 16. The terminal according to claim 15, wherein the emergency call request is executed with a password input. 17. The terminal according to claim 12, wherein said means to register includes a means to set a Do-Not-Disturb time with “one-touch”. |
<SOH> BACKGROUND ART <EOH>In these days, accelerating development of telecommunication technology and convenience of telecommunication has resulted in a rapid increase in number of people using phones and cellular phones. Cellular phone has an advantage that it can be used at anytime and on anywhere; hence, it is owned by almost one per person. Despite the strength that cellular phone can be used irrespective of time and place, cellular phone's bell ringing sound in public places has become a serious pollution problem in our modern times. Especially, in non-allowed public places, such as school, government building, and library, or even in private times when one does not wish to receive a call, such as while sleeping, rest, studying, or driving. phone ringing sound not only bothers cellular receiver but also people around the receiver. In order to resolve these problems, several techniques such as auto-answering Voice message system and connection disabling system have been developed. Auto-answering system originated from usage in regular wired-phones whereby during receiver's absence, pre-recorded message is played and caller can leave a voice message if needed. Connection disabling system is when a receiver changes cellular phone to non-receiving mode in a public places or where telecommunication signals are fundamentally blocked, calls will not get through to cell phones and hence not cause it to make ringing noise. However, when call signals are fundamentally blocked, there will be a problem of caller not being able to connect even emergency calls. Also, when Auto-answering system is employed, receiver can only check message left by a caller and cannot proactively respond to caller's request. On another invention, patent application number 2000-0037072 that is published in Korea, call connection can be controlled depending on a caller's identity. However, this invention has a complexity of requiring each and every caller to be already registered. Furthermore, the above invention cannot handle calls by non-registered callers. And even for registered callers, if their phone numbers change, those callers' call will not be connected unless registered phone number is changed. On the other hand, aside from techniques to respond to noise pollution, when a receiver determines a schedule for a ringing, there is no means to connect other than receiver's scheduled time. |
<SOH> BRIEF DESCRIPTION OF INVENTION <EOH>FIG. 1 shows an outline of the call responding system according to a preferred operation scenario with a caller terminal and receiver terminal and a Communication Service Center. FIG. 2 shows a detailed structure of receiver's Terminal according to the call responding system preferred operation scenario. FIG. 3 shows Do-Not-Disturb list database table according to the call responding system preferred operation scenario. FIG. 4 shows a monthly schedule database table according to the call responding system preferred operation scenario. FIG. 5 shows a weekly schedule database table according to the call responding system preferred operation scenario. FIG. 6 shows a special-time schedule database table according to the call responding system preferred operation scenario. FIG. 7 shows a data structure in schedule register according to the call responding system preferred operation scenario FIG. 8 shows a data structure in Do-Not-Disturb schedule register according to the call responding system preferred operation scenario FIG. 9 shows a process flowchart of inputting schedule information according to the call responding system preferred operation scenario FIG. 10 shows a process flowchart of searching schedule information according to the call responding system preferred operation scenario FIG. 11 shows a process flowchart of displaying schedule information and indicating Do-Not-Disturb state according to the call responding system preferred operation scenario FIG. 12 shows a process flowchart of automatically responding to the Caller corresponding to current Do-Not-Disturb state when a caller makes a call request, according to the call responding system preferred operation scenario detailed-description description="Detailed Description" end="lead"? |
Substances |
The present invention provides a soluble T cell receptor (sTCR), which comprises (i) all for part of a TCR α chain, except the transmembrane domain thereof, and (ii) all or part of a TCR β chain, except the transmembrane domain thereof. (i) and (ii) each comprise a functional variable domain and at least a part of the constant domain of the TCR chain, and are linked by a disulphide bond between constant domain residues which is not present in native TCR. |
1. A soluble T cell receptor (sTCR), which comprises (i) all or part of a TCR α chain, except the transmembrane domain thereof, and (ii) all or part of a TCR β chain, except the transmembrane domain thereof, wherein (i) and (ii) each comprise a functional variable domain and at least a part of the constant domain of the TCR chain, characterised in that (i) and (ii) are linked by a disulphide bond between cysteine residues substituted for: Thr 48 of exon 1 of TRAC*01 and Ser 57 of exon 1 of TRBC1*01 or TRBC2*01; Thr 45 of exon 1 of TRAC*01 and Ser 77 of exon 1 of TRBC1*01 or TRBC2*01; Tyr 10 of exon 1 of TRAC*01 and Ser 17 of exon 1 of TRBC1*01 or TRBC2*01; Thr 45 of exon 1 of TRAC*01 and Asp 59 of exon 1 of TRBC1*01 or TRBC2*01; or Ser 15 of exon 1 of TRAC*01 and Glu 15 of exon 1 of TRBC1*01 or TRBC2*01. 2. A sTCR as claimed in claim 1, wherein one or both of (i) and (ii) comprise all of the extracellular constant Ig domain of the TCR chain. 3. A sTCR as claimed in claim 1, wherein one or both of (i) and (ii) comprise all of the extracellular domain of the TCR chain. 4. A soluble αβ-form T cell receptor (sTCR), wherein a covalent disulphide bond links cysteine residues substituted for Thr 48 of exon 1 of TRAC*01 and Ser 57 of exon 1 of TRBC1*01 or TRBC2*01; Thr 45 of exon 1 of TRAC*01 and Ser 77 of exon 1 of TRBC1*01 or TRBC2*01; Tyr 10 of exon 1 of TRAC*01 and Ser 17 of exon 1 of TRBC1*01 or TRBC2*01; Thr 45 of exon 1 of TRAC*01 and Asp 59 of exon 1 of TRBC1*01 or TRBC2*01; or Ser 15 of exon 1 of TRAC*01 and Glu 15 of exon 1 of TRBC1*01 or TRBC2*01. 5. A soluble T cell receptor (sTCR), which comprises (i) all or part of a TCR α chain, except the transmembrane domain thereof, and (ii) all or part of a TCR β chain, except the transmembrane domain thereof, wherein (i) and (ii) each comprise a functional variable domain and at least a part of the constant domain of the TCR chain, and are linked by a disulphide bond between constant domain residues which is not present in native TCR and wherein an interchain disulphide bond in native TCR is not present. 6. A sTCR as claimed in claim 5, wherein one or both of (i) and (ii) comprise all of the extracellular constant Ig domain of the TCR chain. 7. A sTCR as claimed in claim 5, wherein one or both of (i) and (ii) comprise all of the extracellular domain of the TCR chain. 8. A soluble αβ-form T cell receptor (sTCR), wherein a covalent disulphide bond links a residue of the immunoglobulin region of the constant domain of the α chain to a residue of the immunoglobulin region of the constant domain of the β chain, wherein an interchain disulphide bond in native TCR is not present. 9. A sTCR as claimed in claim 5, wherein the disulphide bond which is not present in native TCR is between cysteine residues substituted for residues whose β carbon atoms are less than 0.6 nm apart in the native TCR structure. 10. A sTCR as claimed in claim 5, wherein the disulphide bond which is not present in native TCR is between cysteine residues substituted for Thr 48 of exon 1 of TRAC*01 and Ser 57 of exon 1 of TRBC1*01 or TRBC2*01. 11. A sTCR as claimed in claim 5, wherein the disulphide bond which is not present in native TCR is between cysteine residues substituted for Thr 45 of exon 1 of TRAC*01 and Ser 77 of exon 1 of TRBC1*01 or TRBC2*01. 12. A sTCR as claimed in claim 5, wherein the disulphide bond which is not present in native TCR is between cysteine residues substituted for Tyr 10 of exon 1 of TRAC*01 and Ser 17 of exon 1 of TRBC1*01 or TRBC2*01. 13. A sTCR as claimed in claim 5, wherein the disulphide bond which is not present in native TCR is between cysteine residues substituted for Thr 45 of exon 1 of TRAC*01 and Asp 59 of exon 1 of TRBC1*01 or TRBC2*01. 14. A sTCR as claimed in claim 5, wherein the disulphide bond which is not present in native TCR is between cysteine residues substituted for Ser 15 of exon 1 of TRAC*01 and Glu 15 of exon 1 of TRBC1*01 or TRBC2*01. 15. A sTCR as claimed in claim 1, wherein an interchain disulphide bond in native TCR is not present. 16. A sTCR as claimed in claim 5, wherein native α and β TCR chains are truncated at the C-terminus such that the cysteine residues which form the native interchain disulphide bond are excluded. 17. A sTCR as claimed in claim 5, wherein cysteine residues which form the native interchain disulphide bond are substituted to another residue. 18. A sTCR as claimed in claim 17, wherein cysteine residues which form the native interchain disulphide bond are substituted to serine or alanine. 19. A sTCR as claimed in claim 1, wherein an unpaired cysteine residue present in native TCR β chain is not present. 20. A sTCR as claimed in any one of claims 1, wherein (i) and (ii) each comprise the functional variable domain of a first TCR fused to all or part of the constant domain of a second TCR, the first and second TCRs being from the same species. 21. A sTCR as claimed in claim 20, wherein the constant domains of the second TCR are truncated N-terminal to the residues which form the non-native interchain disulphide bond. 22. A sTCR as claimed in claim 1, wherein one or both of the chains are derivatised with, or fused to, a moiety at its C or N terminus. 23. A sTCR as claimed in claim 1, wherein one or both of the chains have a cysteine residue at its C and/or N terminus to which a moiety can be fused. 24. A sTCR as claimed in claim 1, further comprising a detectable label. 25. A sTCR as claimed in claim 1 associated with a therapeutic agent. 26. A multivalent T cell receptor (TCR) complex comprising a plurality of sTCRs as claimed in claim 1. 27. A complex as claimed in claim 26, comprising a sTCR multimer. 28. A complex as claimed in claim 27, comprising two or three or four or more T cell receptor molecules associated with one another, preferably via a linker molecule 29. A complex as claimed in claim 26, wherein the sTCRs or sTCR multimers are present in a lipid bilayer or are attached to a particle. 30. A method for detecting MHC-peptide complexes, which comprises: (i) providing a soluble TCR as claimed in claim 1 or a multivalent T cell receptor complex as claimed in claim 26; (ii) contacting the soluble TCR or multivalent TCR complex with the MHC-peptide complexes; and (iii) detecting binding of the soluble TCR or multivalent TCR complex to the MHC-peptide complexes. 31. A pharmaceutical formulation comprising a sTCR as claimed in claim 1, and/or a multivalent TCR complex as claimed in claim 26, together with a pharmaceutically acceptable carrier. 32. A nucleic acid molecule comprising a sequence encoding (i) or (ii) of a sTCR as claimed in claim 1, or a sequence complementary thereto. 33. A vector comprising a nucleic acid molecule as claimed in claim 32. 34. A host cell comprising a vector as claimed in claim 33. 35. A method for obtaining (i) or (ii) as defined in claim 1, which method comprises incubating a host cell as claimed in claim 34 under conditions causing expression of the peptide and then purifying the polypeptide. 36. A method as claimed in claim 35, further comprising mixing (i) and (ii) under suitable refolding conditions. 37. A method for obtaining a soluble T cell receptor (sTCR), which method comprises: incubating a host cell which comprises a vector comprising a nucleic acid molecule encoding (i) all or part of a TCR α chain, except the transmembrane domain thereof, and a host cell which comprises a vector comprising a nucleic acid molecule encoding (ii) all or part of a TCR β chain, except the transmembrane domain thereof under conditions causing expression of (i) and (ii), wherein (i) and (ii) each comprise a functional variable domain and at least a part of the constant domain of the TCR chain; purifying (i) and (ii); and mixing (i) and (ii) under refolding conditions such that they are linked by a disulphide bond between constant domain residues which is not present in native TCR. 38. A method as claimed in claim 37, wherein one or both of (i) and (ii) comprise all of the extracellular constant Ig domain of the TCR chain. 39. A method as claimed in claim 37, wherein one or both of (i) and (ii) comprise all of the extracellular domain of the TCR chain. 40. A method for obtaining a soluble co-form T cell receptor (sTCR), which method comprises: incubating a host cell which comprises a vector comprising a nucleic acid molecule encoding a TCR α chain and a host cell which comprises a vector comprising a nucleic acid molecule encoding a TCR β chain under conditions causing expression of the respective TCR chains; purifying the respective TCR chains; and mixing the respective TCR chains under refolding conditions such that a covalent disulphide bond links a residue of the immunoglobulin region of the constant domain of the α chain to a residue of the immunoglobulin region of the constant domain of the β chain. 41. A method as claimed in claim 37, wherein an interchain disulphide bond in native TCR is not present. 42. A method as claimed in claim 41, wherein native α and β TCR chains are truncated at the C-terminus such that the cysteine residues which form the native interchain disulphide bond are excluded. 43. A method as claimed in claim 41, wherein cysteine residues which form the native interchain disulphide bond are substituted to another residue. 44. A method as claimed in claim 43, wherein cysteine residues which form the native interchain disulphide bond are substituted to serine or alanine. 45. A method as claimed in claim 37, wherein an unpaired cysteine residue present in native TCR β chain is not present. 46. A method as claimed in claim 37, wherein the disulphide bond which is not present in native TCR is between cysteine residues substituted for residues whose β carbon atoms are less than 0.6 nm apart in the native TCR structure. 47. A method as claimed in claim 37, wherein the disulphide bond which is not present in native TCR is between cysteine residues substituted for Thr 48 of exon 1 of TRAC*01 and Ser 57 of exon 1 of TRBC1*01 or TRBC2*01. 48. A method as claimed in claim 37, wherein the disulphide bond which is not present in native TCR is between cysteine residues substituted for Thr 45 of exon 1 of TRAC*01 and Ser 77 of exon 1 of TRBC1*01 or TRBC2*01. 49. A method as claimed in claim 37, wherein the disulphide bond which is not present in native TCR is between cysteine residues substituted for Tyr 10 of exon 1 of TRAC*01 and Ser 17 of exon 1 of TRBC1*01 or TRBC2*01. 50. A method as claimed in claim 37, wherein the disulphide bond which is not present in native TCR is between cysteine residues substituted for Thr 45 of exon 1 of TRAC*01 and Asp 59 of exon 1 of TRBC1*01 or TRBC2*01. 51. A method as claimed in claim 37, wherein the disulphide bond which is not present in native TCR is between cysteine residues substituted for Ser IS of exon 1 of TRAC*01 and Glu 15 of exon 1 of TRBC1*01 or TRBC2*01. 52. A method as claimed in claim 37, wherein (i) and (ii) each comprise the functional variable domain of a first TCR fused to all or part of the constant domain of a second TCR, the first and second TCRs being from the same species. 53. A method as claimed in claim 52, wherein the constant domains of the second TCR are truncated N-terminal to the residues which form the non-native interchain disulphide bond. 54. A method as claimed in claim 37, wherein one or both of the chains are derivatised with, or fused to, a moiety at its C or N terminus. 55. A method as claimed in claim 37, wherein one or both of the chains have a cysteine residue at its C and/or N terminus to which a moiety can be fused. 56. A method as claimed in claim 37, wherein the sTCR further comprises a detectable label. 57. A method as claimed in claim 37, wherein the sTCR is associated with a therapeutic agent. 58. A method as claimed in claim 1, further comprising combining a plurality of sTCRs to form a multivalent T cell receptor (TCR) complex. 59. A method as claimed in claim 58, wherein the sTCRs are combined to form a sTCR multimer. 60. A method as claimed in claim 59, wherein two or three or four or more T cell receptor molecules are associated with one another, preferably via a linker molecule 61. A method as claimed in claim 58, wherein the sTCRs or sTCR multimers are combined in a lipid bilayer or are attached to a particle. 62. A method for detecting MHC-peptide complexes, which comprises: (i) providing a soluble TCR produced by the method of claim 37 or a multivalent T cell receptor complex produced by the method of claim 58; (ii) contacting the soluble TCR or multivalent TCR complex with the MHC-peptide complexes; and (iii) detecting binding of the soluble TCR or multivalent TCR complex to the MHC-peptide complexes. 63. A pharmaceutical formulation comprising a sTCR produced by the method claim 37, and/or a multivalent TCR complex produced by the method of claim 58, together with a pharmaceutically acceptable carrier. |
Pharmaceutical compositions for the treatment of infections of the respiratory system by pathogenic agents |
The present invention relates to pharmaceutical compositions for the treatment of infections by pathogen agents of the respiratory system, for example Staphylococcus aureus, and more particularly it relates to the aforesaid compositions containing N-acetyl-cysteine possibly combined with thiamphenicol. |
1. A process for preparing a pharmaceutical composition containing N-acetyl-cysteine for the preventive or disruptive treatment of biofilms produced by Staphylococcus aureus and by other pathogen agents of the respiratory system. 2. A process for preparing a pharmaceutical composition containing thiamphenicol useful for increasing the activity of N-acetyl-cysteine in inhibiting or disrupting the biofilm produced by Staphylococcus aureus and by other pathogen agents of the respiratory system. 3. A pharmaceutical composition containing N-acetyl-cysteine and thiamphenicol and use thereof in inhibiting or disrupting biofilms produced by Staphylococcus aureus and by other pathogen agents of the respiratory system. 4. A process for preparing a pharmaceutical composition containing thiamphenicol glycinate acetylcysteinate useful for inhibiting or disrupting biofilms produced by Staphylococcus aureus and by other pathogen agents of the respiratory system. |
Use of dmso in the treatment of neurodegenerative diseases caused by prions |
The present invention relates to a pharmaceutical composition for the treatment and/or delaying the onset of clinical symptoms and/or delaying the progress of a neurodegenerative disorder caused by prions. The composition of the invention comprises as an active ingredient DMSO, and optionally further comprising pharmaceutically acceptable additives and/or diluents. The composition of the invention is particularely applicable in the treatment of neurodegenerative disorders associated with enhanced accumulation of PrPSc into amyloid plaques. The invention further relates to methods of treatment of a neurodegenerative disorder caused by prions and to the use of DMSO in the preparation of a pharmaceutical composition for the treatment and/or delay of the onset of clinical symptoms and/or delay of progress of neurodegenerative disorders caused by prions. |
1-25. (canceled) 26. A method comprising utilizing DMSO in the treatment and/or delay of the onset of clinical symptoms and/or delay of the progress of a neurodegenerative disorder caused by prions, said disorder being any one of CJD, vCJD, Kuru, GSS syndrome and FFI, specifically a Creutzfeldt-Jakob disease, wherein in said method said DMSO is administered orally. 27. A method comprising utilizing DMSO in preventing the agregation of PrPSc in the brain and/or facilitating the urinary excretion of PrPSc in patients suffering from a progressive neurodegenerative disorder caused by prions. 28. A method comprising utilizing DMSO in preventing the agregation of PrPSc in the brain and/or facilitating the urinary excretion of PrPSc in patients suffering from a progressive neurodegenerative disorder caused by prions, thereby alleviating or delaying the onset of said disorder. 29. The method of claim 27, wherein said neurodegenerative disorder is any one of Creutzfeldt-Jacob disease (CJD), variant CJD (vCJD), Kuru, Gerstmann-Sträussler-Scheinker syndrome (GSS) and fatal familial insomnia (FFI), specifically a Creutzfeldt-Jakob disease. 30. The method of claim 28, wherein said neurodegenerative disorder is any one of Creutzfeldt-Jacob disease (CJD), variant CJD (vCJD), Kuru, Gerstmann-Sträussler-Scheinker syndrome (GSS) and fatal familial insomnia (FFI), specifically a Creutzfeldt-Jakob disease. 31. A method for preparation of a pharmaceutical composition for the treatment and/or delaying the onset of clinical symptoms and/or delaying the progress of neurodegenerative disorder caused by prions, comprising utilizing as active ingredient DMSO, and optionally further comprising utilizing pharmaceutically acceptable additives and/or diluents, wherein said DMSO is administered orally. 32. The method of claim 31, wherein said neurodegenerative disorder is any one of Creutzfeldt-Jacob disease (CJD), variant CJD (vCJD), Kuru, Gerstmann-Sträussler-Scheinker syndrome (GSS) and fatal familial insomnia (FFI), specifically a Creutzfeldt-Jakob disease. 33. The method of claim 31, wherein said pharmaceutical composition is in the form of an aqueous solution of DMSO. 34. The method of claim 32, wherein said pharmaceutical composition is in the form of an aqueous solution of DMSO. 35. The method of claim 33, wherein the concentration of DMSO in said pharmaceutical composition is from about 1% (w/v) to about 100% (w/v). 36. The method of claim 35, wherein said concentration of DMSO is from about 5% (w/v) to about 50% (w/v). 37. The method of claim 36, wherein said concentration of DMSO is 20% (w/v). 38. The method of claim 31, wherein said pharmaceutical composition is for one to six times per day administration. 39. The method of claim 38, wherein said pharmaceutical composition is for two to four times per day administration. 40. The method of claim 39, wherein said pharmaceutical composition is for three times per day administration. 41. The method of claim 32, wherein the dose of DMSO per patient per day is about 0.2 g/kg. 42. The method of claim 32, wherein the dose of DMSO per patient per day is from about 0.1 g to about 30 g. 43. The method of claim 42, wherein the dose of DMSO per patient per day is from about 1 g to 15 g. 44. A method of treating and/or delaying the onset of clinical symptoms and/or delaying the progress of CJD, comprising orally administering to a CJD patient a therapeutically effective amount of DMSO or of a pharmaceutical composition as defined in claim 31. 45. The method of claim 44, comprising administering to said patient from about 3 g to about 30 g, preferably 15 g per day of DMSO. 46. A method of preventing the agregation of PrPSc in the brain and facilitating the urinary excretion of PrPSc in a patient suffering from a progressive neurodegenerative disorder caused by prions, comprising orally administering to said patient a therapeutically effective amount of DMSO or of a pharmaceutical composition as defined in claim 31. 47. A method of preventing the agregation of PrPSc in the brain and facilitating the urinary excretion of PrPSc in a patient suffering from a progressive neurodegenerative disorder caused by prions, comprising orally administering to said patient a therapeutically effective amount of DMSO or of a pharmaceutical composition as defined in claim 31, thereby alleviating or delaying the onset of said disorder. 48. The method of claim 46, wherein said neurodegenerative disorder is any one of Creutzfeldt-Jacob disease (CJD), variant CJD (vCJD), Kuru, Gerstmann-Sträussler-Scheinker syndrome (GSS) and fatal familial insomnia (FFI), specifically a Creutzfeldt-Jakob disease. 49. The method of claim 47, wherein said neurodegenerative disorder is any one of Creutzfeldt-Jacob disease (CJD), variant CJD (vCJD), Kuru, Gerstmann-Sträussler-Scheinker syndrome (GSS) and fatal familial insomnia (FFI), specifically a Creutzfeldt-Jakob disease. 50. The method of claim 46, wherein said administration is via the oral route. 51. The method of claim 47, wherein said administration is via the oral route. 52. The method of claim 46, comprising administering to said patient from about 3 g to about 30 g, preferably 15 g per day of DMSO. 53. The method of claim 47, comprising administering to said patient from about 3 g to about 30 g, preferably 15 g per day of DMSO. |
<SOH> BACKGROUND OF THE INVENTION <EOH>All publications mentioned throughout this application are fully incorporated herein by reference, including all references cited therein. Prion diseases, also known as TSEs (transmissible spongiform encephalopathies), are a group of fatal neurodegenerative diseases of animals and humans recognized neuropathologically by the classic triad of spongy degeneration (affecting any part of the cerebral grey matter), neuronal loss and the proliferation and hypertrophy of astrocytes [Beck, E. & Daniel, P. M. Postgrad Med J 45(524), 361-70 (1969)]. The disease originates from the conversion of PrP C molecules into protease-resistant and insoluble PrP Sc molecules by a yet not deciphered mechanism in which PrP Sc serves as a template. The hallmark of these diseases is the accumulation of the abnormal isoform of prion protein (PrP Sc ) in the brain, forming amyloid plaques [Prusiner, S. B. & DeArmond, S. J. Lab Invest 56(4), 349-63 (1987)]. Among the animal diseases, the most prevalent is the bovine spongiform encephalopathy (BSE), commonly known as “mad cow” disease. The sporadic form of Creutzfeldt-Jakob disease (CJD) accounts for approximately 85 percent of all cases of prion disease in humans, whereas infectious and inherited prion diseases account for the rest. The common symptoms of CJD are dementia, followed by loss of coordination, although the sequence of these events can be reversed. The inherited form of CJD affects 10-15% of the patients, and three variants have been characterized. Very rarely, the disease can be acquired through infection, as an inadvertent consequence of a medical procedure. In the sporadic cases, the mean age of onset is 60 years old, and the disease lasts for about 8 months. For the inherited disease, these parameters vary according to the allelic variant, and the mean age of onset is between 45 to 55 years old, while it may last from 8 to 50 months. In Europe, the increasing number of patients with a new variant of CJD, called variant CJD (vCJD) has been associated with the consumption of prion-tainted beef products [Will, R. G. et al. Lancet 347, 921-5 (1996)]. The current understanding is that vCJD is contracted by horizontal transmission through beef or lamb products derived from animals contaminated with BSE or scrapie, respectively. Nowadays, CJD constitutes a major health risk, accounting for approximately 85 percent of all cases of human prion disease. The incidence of Creutzfeldt-Jakob disease is approximately one case per 1 million people, but among persons between the ages of 60 and 74 years, the incidence is nearly 5 per 1 million [Prusiner, S. N Engl J Med 344(20), 1516-1526 (2001)]. Other prion diseases in humans include Kuru, Gerstmann-Sträussler-Scheinker syndrome (GSS syndrome) and fatal familial insomnia (FFI). In addition, more than 20 pathogenic mutations in the PrP gene have already been documented [Prusiner, S. B. Philos Trans R Soc Lond B Biol Sci 343, 447-63 (1994)]. PrP Sc is the only identified component of the prion, the proteinaceous agent causing prion disease [Prusiner, S. B. et al. Cell 93(3), 337-48 (1998)]. PrP Sc is a conformational aberrant isoform of PrP C , a widely distributed cell-surface glycoprotein of unknown function. The difference between the two PrP isoforms seems to be conformational rather than chemical. PrP C conformation is mostly α-helix, while PrP Sc contains a considerable amount of β-sheet ( FIG. 1 ). However, both proteins share the same amino acid sequence and have the same apparent MW of 33-35 Kd. The level of PrP C expression seems to play a central role in the accumulation of PrP Sc , since PrP C is the source for PrP Sc production. This has been shown both in tissue culture and in transgenic mice. The conversion of α-helical PrP C molecules into β-sheet enriched PrP Sc has been postulated as the cause for the propagation of prion diseases. The pathway for PrP Sc synthesis either may feature the formation of PrP C -PrP Sc heterodimers only, or may include the formation of seeds of aggregation comprised of mediator molecules as well. Currently, the mechanisms involved in this process remain unclear. The organic solvent dimethyl sulfoxide (DMSO) has demonstrated both in vitro and in vivo effects on amyloidotic diseases (diseases where there is amyloid plaque formation, like in prion diseases). In vitro data, from experiments concerned with the degradation of amyloid proteins, suggest that DMSO blocks the assembly of amyloid fibrils but does not interfere with the disassembly of preexisting fibrils [Kito, S. et al. Ann N Y Acad Sci 411, 52-66 (1983)]. Moreover, DMSO has been shown to block the formation of an Aβ peptide intermediate with a high β-sheet content, which is a controlling step in the process of self assembly into amyloid plaques during Alzheimer's disease [Shen, C. L. & Murphy, R. M. Biophys J 69, 640-651 (1995)]. DMSO treatment of scrapie-infected neuroblastoma cells (ScN2a) interfered with the formation of PrP Sc from newly synthesized PrP C . This result suggested that DMSO could act as a “chemical chaperone” to stabilize the α-helical conformation of PrP C and prevent it from undergoing a conformational change that would produce PrP Sc [Tatzelt, J., Prusiner, S. B. & Welch, W. J EMBO Journal 15, 6363-6373 (1996)]. In contrast, the inventors have shown that DMSO does not affect the conversion process as demonstrated by Tatzelt, but rather it affects the accumulation process from PrP Sc into amyloid plaques, which are sedimented in the brain in a state of disease. Interestingly, treatment of brain homogenates with glycerol, also suggested by Tatzelt et al. as a “chemical chaperone”, showed no detectable effect (Inventor's unpublished results). A murine model for caseic amyloidosis has shown that oral administration of DMSO not only prevented the development of the disease, but also seemed to cause its regression in some cases [Murav'ev, I. O. reumatologia 1, 44-46 (1990)]. DMSO has been available for medical study since 1963. It has FDA approval only for the symptomatic treatment of interstitial cystitis, but has been shown beneficial for the treatment of leukemia and cancer, cerebral ischaemia, head trauma and infection [Regelson, W. & Harkins, S. W. Ann N Y Acad Sci 826, 348-74. (1997)]. When given as a continuous treatment to humans, DMSO has no serious side effects [Ravid. M, S. J., Lang. R. Ann Rheum Dis 41, 587-592 (1982); Brobyn, R. D. Ann NY Acad Sci 243, 497-505 (1975)]. There are a few reports on the clinical use of DMSO in amyloidotic diseases. Following a single dose of DMSO, urine of patients suffering from amyloidotic diseases contains material that can form fibrils that can be stained with Congo Red. This result suggests that DMSO may cause the breakdown of amyloid fibrils into a conformation which is transported from body tissues and eliminated through the kidneys [Ravid, M., Kedar, I. & Sohar, E. Lancet 1, 730-731 (1977)]. In addition, following chronic administration of DMSO to humans suffering from Primary and Familial Amyloidosis (FAP), about 50% of the patients showed clinical improvement. However, the mechanism of action of DMSO is still not clearly understood. In search for a therapeutic treatment of CJD and other prion diseases, the inventors have found that treatment with DMSO improves the condition of the patient. It is therefore an object of the present invention to use DMSO and pharmaceutical compositions containing DMSO in the treatment of prion diseases, particularly in humans and specifically CJDs. This and other objects of the invention will be elaborated on the description proceeds. |
<SOH> SUMMARY OF THE INVENTION <EOH>The object of this invention relates, in one aspect, to a pharmaceutical composition and in a second aspect, to a method for the treatment and/or delay of the onset of clinical symptoms and/or delay of the progress of a neurodegenerative disorder caused by prions, comprising as active ingredient DMSO, and optionally further comprising pharmaceutically acceptable additives and/or diluents. Specific neurodegenerative disorders are those associated with enhanced accumulation of PrP Sc into amyloid plaques, and particularly disorders associated with excess of PrP Sc in the brain. These neurodegenerative disorders are progressive neurodegenerative disorders, exemplified by Creutzfeldt-Jacob disease (CJD), variant CJD (vCJD), Kuru, Gerstmann-Sträussler-Scheinker syndrome (GSS syndrome) and fatal familial insomnia (FFI), specifically a Creutzfeldt-Jakob disease. The pharmaceutical composition is preferably for oral administration, from one to six times per day, preferably two to four times per day, and most preferably three times per day, and it is in the form of an aqueous solution of DMSO, wherein the concentration of DMSO is from about 1% (w/v) to about 100% (w/v), preferably 20% (w/v), comprising a dosage of DMSO of about 0.2 g/kg daily, or from about 0.1 g to about 30 g daily, preferably 5 g daily. The invention relates to a method for treating and/or delaying the onset of clinical symptoms and/or delaying the progress of a prion disease, comprising administering to a CJD patient a therapeutically effective amount of DMSO or of a pharmaceutical composition comprising as active ingredient DMSO and optionally further comprising pharmaceutically acceptable additives and/or diluents. The method of the invention is particularly intended for the treatment of neurodegenerative disorders caused by prions, that are associated with enhanced accumulation of PrP Sc into amyloid plaques and with excess of PrP Sc in the brain, such as Creutzfeldt-Jacob disease, vCJD, Kuru, GSS syndrome and FFI, specifically a Creutzfeldt-Jakob disease. In another aspect, the invention comprises the use of DMSO in the treatment and/or delay of the onset of clinical symptoms and/or delay of the progress of a neurodegenerative disorder caused by prions, such as CJD, vCJD, Kuru, GSS syndrome and FFI, specifically Creutzfeldt-Jakob disease. A further aspect of this invention is the use of DMSO in the preparation of a pharmaceutical composition for the treatment and/or delay of the onset of clinical symptoms and/or delay of progress of neurodegenerative disorders caused by prions, that are associated with enhanced accumulation of PrP Sc into amyloid plaques and with excess of PrP Sc in the brain, and are manifested as any one of the progressive neurodegenerative disorders exemplified by Creutzfeldt-Jacob disease, vCJD, Kuru, GSS syndrome and FFI, specifically a Creutzfeldt-Jakob disease. The invention will be described in more detail on hand of the following drawings. |
Method for providing design review and conformity |
A method and apparatus for updating a design knowledge base, comprising supplying a design knowledge base (14) in a selected domain, the design knowledge base configured to obtain user input (24) of a selected design and to output a design directive. A response is received from the design knowledge base to the user input of a selected design wherein the response comprises a set of design review inquiries to direct the user to incorporate the design directive. A knowledge base maintainer is supplied (35) in communication with design knowledge base wherein the knowledge base maintainer generates an output response in response to a user's response to the design review inquiries, wherein the output response directs the user to modify the user selected design to conform with the design directive or the user requests the knowledge base maintainer to confirm that the user's the design directive provided by the design knowledge base wherein the knowledge base maintainer adjusts the design knowledge base to incorporate the improvement. |
1. A method of updating a design knowledge base, comprising: (a) supplying a design knowledge base (14) containing information regarding designing in a selected domain, said design knowledge base configured to obtain user input (24) of a selected design and to output a design directive; (b) receiving a response from said design knowledge base to said user input of a selected design wherein said response comprises a set of design review inquiries to direct said user to incorporate said design directive; (c) supplying a knowledge base maintainer (35) in communication with said design knowledge base wherein said knowledge base maintainer generates an output response in response to a user's response to said design review inquiries, wherein said output response: (i) directs said user to modify said user selected design to conform with said design directive; or (ii) said user requests said knowledge base maintainer to confirm that said user's design comprises an improvement over said design directive provided by the design knowledge base wherein said knowledge base maintainer adjusts said design knowledge base to incorporate said improvement. 2. The method of claim 1 wherein said design knowledge base containing information regarding designing in a particular domain is configured for designing automotive components. 3. The method of claim 2 wherein said design knowledge base comprises historical data generated from previously utilized products and processes. 4. A method of communicating with a design knowledge base to inform a user about designing in a particular domain, comprising: (a) supplying a design knowledge base (14) containing information regarding designing in a selected domain, said design knowledge base configured to obtain user input (24) of a selected design and to output a design directive; (b) receiving a response from said design knowledge base to said user input of a selected design wherein said response comprises a set of design review inquiries to direct said user to incorporate said design directive; (c) supplying a knowledge base maintainer (35) in communication with said design knowledge base wherein said knowledge base maintainer generates an output response in response to a user's response to said design review inquiries, wherein said output response directs said user that said user selected design does not conform with said design directive. 5. The method of claim 4 wherein said design knowledge base containing information regarding designing in a particular domain is configured for designing automotive components. 6. The method of claim 5 wherein said design knowledge base comprises historical data generated from previously utilized products and processes. 7. A design system, comprising: a design knowledge database storing a plurality of design parameters, a maintenance engine adapted to change said design parameters in the design knowledge database; and a design engine adapted to interact with a design process user to give the user access to relevant information from the design knowledge database; wherein said design engine further adapted to permit said user to create a new design parameter not in said design knowledge database, store said new design parameter in said design knowledge database, and further adapted to incorporate said new design parameter in future designs. |
<SOH> BACKGROUND OF THE INVENTION <EOH>Computer systems have been utilized in an effort to develop expert systems which include the capability of learning knowledge during operation. For example, U.S. Pat. No. 5,208,768 describes an expert system including an arrangement for acquiring redesign knowledge. More specifically, the expert system in the aforementioned patent is said to perform a redesign in connection with an original design. The expert system comprises a discrepancy determination component that identifies a discrepancy between operation of the original design and the desired operation. A redesign component including at least one redesign module associated with a discrepancy generates a redesign in response to the original design and the identified discrepancy. Finally, a redesign generation component generates a redesign module in response to a previously identified discrepancy and design, the redesign module thereafter being used by the redesign component. Accordingly, a need remains to provide an improved knowledge-based engineering system which provides design, manufacturing and/or business advice. Therefore, it is a general object of this invention to provide such improved knowledge-based engineering system, and more specifically, a system which contains a closed feedback loop to the system user. More specifically, it is also an object of the invention herein to provide such a system, wherein the system provides relevant advice based upon expert knowledge from engineers, integrated databases of related engineering information along with a prioritization of attributes for the specific field. |
<SOH> SUMMARY OF THE INVENTION <EOH>A system and method of updating a design knowledge base, the method comprising the steps of receiving a response to a generated inquiry, and requesting the design knowledge base be reevaluated if a new design is conceived that is equal or better to an existing design if the response to the inquiry is negative. More specifically the present invention is directed at a method and apparatus for updating a design knowledge base, comprising supplying a design knowledge base containing information regarding designing in a selected domain, the design knowledge base configured to obtain user input of a selected design and to output a design directive. A response is received from the design knowledge base to the user input of a selected design wherein the response comprises a set of design review inquiries to direct the user to incorporate the design directive. A knowledge base maintainer is supplied in communication with the design knowledge base wherein the knowledge base maintainer generates an output response in response to a user's response to the design review inquiries, wherein the output response directs the user to modify the user selected design to conform with the design directive or the user requests the knowledge base maintainer to confirm that the user's design comprises an improvement over the design directive provided by the design knowledge base wherein the knowledge base maintainer adjusts the design knowledge base to incorporate the improvement. |
Method and a device for drying a water-damaged building |
In a method of drying a water-damaged building with the aid of drying plant (1) that includes a drying rotor (2) or some other other device which delivers dry air to the drying process, and a high-pressure turbine or a fan (3) for transportation of air, the turbine (3) is caused, alternatively, to press dry air into a water-damaged space (10a) in the building (10) or to suck moist air from such a space. In these operational modes, the turbine (3) co-acts with means, e.g. pipes (4, 5) and/or valve-equipped conduits (e.g. 7; 15) which facilitate switching between the two disparate operational modes. The invention also relates to drying plant that functions in accordance with the inventive method. |
1. A method for drying a water-damaged building with the aid of drying plant that includes a drying rotor or some other means for delivering dry air to the drying process, and a high-pressure turbine or some appropriate type of fan for air transportation, characterised by using one and the same turbine or fan for pressing dry air into a water-damaged space in the building or, alternatively, for sucking moist air from such a space; and by connecting the suction or pressure side of the turbine in respective operational modes to a conduit leading to said space, through the medium of connecting means. 2. A method according to claim 1, characterised in that when the turbine is in a suction mode there is connected, via a pipe, a suction line which connects the turbine inlet with the space while dry air from the rotor is delivered to the building; and in that moist air sucked from the space and pressurized by said turbine is passed to the building or to its external surroundings through the medium of a pipe connected to the turbine outlet. 3. A method according to claim 1, characterised in that process air is sucked from the building by means of a fan and delivered to the rotor subsequent to pressurization. 4. A method according to claim 1, characterised in that the dry air is pressurised pressurized by a fan located downstream of the rotor, prior to delivering said air to the building. 5. A method according to claim 3, characterised by using part of the air flow from the fan to regenerate the rotor. 6. A method according to claim 3, characterised by using a separate fan for rotor regeneration. 7. A method according to claim 1, characterised in that when the turbine presses dry air into the water-damaged space, dry air from the rotor is passed to the turbine inlet via a pipe, wherein air pressurized by the turbine is delivered from its outlet to the water-damaged space via a further pipe. 8. A method according to claim 1, characterised by passing a part of the dry air from the rotor to the building. 9. A method according to claim 7, characterised by connecting the outlet of the rotor and the inlet pipe of the turbine through the medium of a valve-equipped conduit system; and by setting a valve so that dry air will be delivered directly to the turbine inlet. 10. A method according to claim 9, characterised by also delivering dry air to the building through the medium of a fan in connection with said conduit system and a branch line located downstream of said fan. 11. A method according to claim 1, characterised by mutually connecting the rotor outlet and the turbine inlet through the medium of a valve-equipped conduit system; and by cutting-off the supply of dry air to the turbine inlet when the turbine is used to suck moist air from the water-damaged space, wherein said turbine inlet is connected to a suction conduit from said space via a pipe. 12. A method according to claim 11, characterised in that switching between operational modes is effected with the aid of a rotatable valve element mounted in said pipe. 13. Drying plant for drying a water-damaged space in a building, comprising a) a housing or casing which houses a drying rotor or some other device that emits dry air, and a high-pressure turbine or an appropriate type of fan for air transportation; and b) inlet and outlet openings to and from the housing respectively, characterised in that the turbine is adapted for pressing dry air into the water-damaged space and, alternatively, to suck moist air from said space; and in that the turbine co-acts with means for facilitating switching between these two operational modes. 14. Drying plant according to claim 13, characterised in that said means include pipes that can be connected to the turbine inlet and outlet, and also conduits that are or can be connected to said pipes. 15. Drying plant according to claim 14, characterised in that the pipes or the conduits are equipped with valves. 16. Drying plant according to claim 15, characterised in that at least one of said valves is a rotatable valve. 17. Drying plant according to claim 15, characterised in that at least one of the valves is a three-way valve. 18. Drying plant according to claim 14, characterised by a fan that pressurizes dry air delivered to the turbine from the rotor via a conduit. 19. Drying plant according to claim 14, characterised in that one of the conduits has the form of a flexible hose which carries at its ends respective bayonet fittings, and which has a detachable filter or sieve on at least one end. |
<SOH> DESCRIPTION OF THE BACKGROUND ART <EOH>A typical method of drying this type of construction uses a high-pressure turbine or high-pressure fan which is connected to a hose system for sucking air through the insulation, wherewith room air is sucked down through the gap between floor and wall as a result of the sub-pressure created in the insulating layer, and through the insulating layer and thereafter delivered, laden with moisture, to the surroundings via the turbine or the fan A water separator can be placed in the hose system upstream of the turbine, should the moist air sucked out from the insulation contain water. Drying can be accelerated by also placing a dehumidifier in the room, so that the air sucked down through the gap will be as dry as possible. The drying process can be continued in this way, i.e. with the so-called suction method, until the construction is dry. In the case of an alternative method, dry air is, instead, pressed or forced down into the insulation, which normally results in a more rapid drying process. In this case, the dry air passes from a dehumidifier directly into the turbine/fan and from there down into the insulation, meaning that dry air is used where required. The aforementioned methods with which separate dehumidifiers and high-pressure turbines or high-pressure fans are used, however, result in several of the following problems and drawbacks: a) Many components that require supervision and service must be seen to or taken care of. b) Installation of the systems is both difficult and time-consuming. c) The devices used have a very high sound level. d) The many different components required result in high purchasing and operating costs. e) The plant used delivers energy to the surroundings, which delays the drying process. f) The plant is difficult to control and regulate. Thus, such plants require the use of a plurality of components, such as dehumidifiers, high-pressure fans, hoses, pipes, hose clips, etc., causing handling and installation of such plants a complicated process. The plants also take up a large amount of space, which is unnecessarily expensive and difficult to regulate in view of the many different components used. Another problem that is not readily solved is connected with the high sound level of high-pressure turbines and high-pressure fans. This noise subjects those staying or living in a water-damaged area under treatment to a great deal of discomfort. In some instances, there is a requirement that the sound level shall not be allowed to exceed a given number of decibels, therewith rendering this type of drier unusable. SE C2-502635 (Swedish Application No. 9500069-1) (Corroventa Avfuktning AB) teaches a method and an air-drying plant that solves some of the aforesaid problems. This document thus teaches a method and a plant for enhancing the yield of an air-drying process in which the process air is delivered to a rotating drying rotor in a defining wall of a first process air chamber in an insulated building. The process air is dehumidified and dried by moisture exchange with heated regenerating air. The dried and heated process air is sucked into a second process air chamber that houses a high-pressure fan equipped with an electric motor. The pressurised process air of elevated temperature is then delivered directly to a water-damaged layer or area. DE-A1-19914846 (Dörrie) describes a similar method, in which air that has been dried and heated by the rotor is delivered through a conduit to the inlet of the high-pressure fan. These methods and devices can only be used when the water-damaged construction shall be dried by pressing dry air down into the water-damaged layer or strata. Although pressure drying provides a quicker result, there are many instances in practice where the suction method must be used, e.g. 1) if the pressure method is used when free water is present in the insulation, the water will be forced out into the construction instead of being removed from the insulation, as opposed to the result when using the suction method. 2) when using the pressure method, moist air will pass from the construction through the gap between floor and wall and out into the room, which may be suitable or permitted in certain cases. 3) if the insulation contains fibres, such as glass wool or mineral wool, these fibres are liable enter the room, which is forbidden in many instances. 4) when pressure drying and the moist air enters the room, foreign odours may be manifested during the first days of the drying process, which cannot be accepted at times. When the construction cannot be dried by the pressure method, e.g. with the aid of the method described in the above-mentioned Swedish document, for the aforesaid reasons or for other reasons, it has hitherto been necessary to dismantle the existing plant and to install separate dehumidifiers, high-pressure fans, hoses, etc., for the purpose of thereafter sucking moisture from the construction. The following associated drawbacks are obvious: a) Increased costs. b) Longer drying times. c) Greater installation work. d) Higher investments in respect of substantially more components. In addition, a plant that includes separate dehumidifiers, high-pressure fans, hoses, etc., will suffer all of the drawbacks described above. |
<SOH> SUMMARY OF THE INVENTION <EOH>These objects are fulfilled by a method according to the preamble of claim 1 and having the particular features set forth in the characterising clause of said claim. Because the turbine is used both to force dry air to the water-damaged space and, alternatively, to suck moist air from such a space, and because the turbine is connected in the stated manner in both types of operation, one and the same turbine and drying arrangement can be readily used for both radically different types of operation. When the drying plant is in place, the type of operation preferred can be determined on the basis of existing circumstances and the drying plant can be adapted to the chosen mode of operation by carrying out a few simple manual operations. If a reason is found to switch to the other operational mode at a later stage, this can be achieved readily and quickly with the aid of earlier used major components, which can be readily supplemented in the manner necessary if so required. One method of applying the invention is defined in claim 2 . The pipe used in this respect is an example of a device with which the turbine can work in order to facilitate switching between the different operational modes. The effect of the applied suction method is further enhanced by delivering dry air to the building from the rotor of the drying plant. Some of the dry air delivered will be sucked into the water-damaged space, through the gap located between floor and wall. The pressurised moist air sucked-in by the turbine can be led to the surroundings of the building via a pipe connected to the turbine outlet, this pipe also constituting an example of a given type of connecting means. The operation is suitably carried out via an outlet line connected to said pipe. In one of the aforesaid operational modes, there may be provided upstream of the rotor, as seen in the flow direction a fan that sucks process air from the building and, after pressurising the air, delivers said air to the rotor. Alternatively, the drying air may be pressurised by a fan positioned downstream of the rotor, prior to delivering said air to the building. Part of the flow emanating from the fan in said alternative positions upstream and downstream of the rotor, as seen in the flow direction, can therewith be used to regenerate the rotor. Another alternative is to use a separate fan for regeneration of the rotor. In the alternative method of utilising the high-pressure turbine, namely to force dry air into the water-damaged area, dry air is passed from the rotor through a pipe to the turbine inlet, and air that is pressurised in the turbine is delivered to the water-damaged area through a further pipe connected to the turbine outlet. It will be realised that said pipes constitute simple elements by means of which the drying plant can be switched effectively and readily between the two operational modes. When applying the pressure mode, part of the dry air can be led to the building from the rotor through the medium of a separate pipe. In an alternative application of the pressure method, the rotor outlet and the turbine inlet are interconnected by a valve-equipped conduit system, which includes a valve that can be set so as to cause the air to be delivered directly to the turbine inlet. This enables dry air to be delivered also to the building via a fan connected to the conduit system and a branch line located downstream of the fan. When the turbine is to be used to suck moist air from the water-damaged space, instead of utilising a conduit system of the aforedescribed kind, the supply of dry air to the turbine inlet is cut-off, for instance via a valve, and connected to a suction line from said space through the medium of a pipe. The invention also relates to a drying plant for drying a water-damaged space, the essential features of the inventive plant being set forth in claim 13 . Further developments of such a drying plant are set forth in the dependent claims. The invention will now be described in more detail with reference to a number of exemplifying embodiments and also with reference to the accompanying schematic drawings. |
VECTOR CONTROL INVERTOR |
A vector control inverter comprises at least one of a set of a torque estimating unit that estimates an output torque of a motor from excitation current and torque current and a pulse transmitting unit that outputs a torque estimation value estimated by the torque estimating unit as positive-negative identifiable pulse stream signals, and a set of a pulse array input unit that receives pulse stream signals input from outside as positive and negative values and a torque instruction converting unit that converts the received pulse stream signals into a torque instruction to be transferred to the motor as a torque. |
1-9. (canceled) 10. A vector control inverter comprising: a speed detecting unit that detects a rotation speed of a motor; a current detecting unit that detects a primary current applied to the motor from an inverter circuit; a current converting unit that splits the primary current into an excitation current and a torque current; a calculating unit that calculates an excitation voltage and a torque voltage based on the rotation speed; a voltage converting unit that outputs a three-phase output voltage from the excitation voltage and the torque voltage; a modulating unit that outputs, based on the three-phase output voltage, a signal to control switching devices of the inverter circuit; an estimating unit that estimates an output torque of the motor from the excitation current and the torque current; and a pulse transmitting unit that outputs the output torque as a positive-negative identifiable pulse stream signal. 11. A vector control inverter comprising: a speed detecting unit that detects a rotation speed of a motor; a current detecting unit that detects a primary current applied to the motor from an inverter circuit; a current converting unit that splits the primary current into an excitation current and a torque current; a calculating unit that calculates an excitation voltage and a torque voltage based on the rotation speed; a voltage converting unit that outputs a three-phase output voltage from the excitation voltage and the torque voltage; a modulating unit that outputs, based on the three-phase output voltage, a signal to control switching devices of the inverter circuit; a pulse stream inputting unit that receives a pulse stream signal from outside; and a torque instruction converting unit that converts the pulse stream signal into a torque instruction. 12. The vector control inverter according to claim 11, wherein the torque instruction converting unit converts the pulse stream signal into the torque instruction based on a sampling pulse produced separately. 13. The vector control inverter according to claim 12, wherein a period of the sampling pulse is variable. 14. A vector control inverter comprising: a speed detecting unit that detects a rotation speed of a motor; a current detecting unit that detects a primary current applied to the motor from an inverter circuit; a current converting unit that splits the primary current into an excitation current and a torque current; a calculating unit that calculates an excitation voltage and a torque voltage based on the rotation speed; a voltage converting unit that outputs a three-phase output voltage from the excitation voltage and the torque voltage; a modulating unit that outputs, based on the three-phase output voltage, a signal to control switching devices of the inverter circuit; an estimating unit that estimates an output torque of the motor from the excitation current and the torque current; a pulse transmitting unit that outputs the output torque as a positive-negative identifiable pulse stream signal; a pulse stream inputting unit that receives a pulse stream signal from outside; and a torque instruction converting unit that converts the pulse stream signal into a torque instruction. 15. The vector control inverter according to claim 14, wherein when performing a synchronous operation of at least two of the vector control inverters by setting one vector control inverter as a master side being a reference, and setting other vector control inverter as a slave side following the master side, the pulse transmitting unit outputs the output torque as the torque instruction at the master side, and the torque instruction converting unit converts the pulse stream signal into the torque instruction at the slave side. 16. The vector control inverter according to claim 15, wherein the slave side comprises two or more separate vector control inverters. 17. The vector control inverter according to claim 14, wherein the torque instruction converting unit converts the pulse stream signal into the torque instruction based on a sampling pulse produced separately. 18. The vector control inverter according to claim 17, wherein a period of the sampling pulse is variable. |
<SOH> BACKGROUND ART <EOH>FIG. 5 is a block diagram of a conventional vector control apparatus. The vector control apparatus includes a three-phase alternating current source, a rectifying circuit 2 including a diode, etc. for obtaining direct current voltage from the three-phase alternating current source 1 , an electrolytic capacitor 3 that smoothens the direct current voltage, an inverter circuit 4 including switching elements such as transistor, etc., an induction electric motor (hereinafter “a motor”) 5 to which a load is connected, a speed detector 6 that detects the rotation speed of the motor 5 , a current detector 7 that detects the three-phase primary current Iu, Iv, and Iw flowing into the motor 5 , a speed command circuit 8 that assigns a speed instruction ω* of the motor 5 , a three-phase-to-two-phase current converter 9 that calculates an excitation current I 1 d and a torque current I 1 q from the three-phase current Iu, Iv, and Iw, a vector control calculating circuit 10 that calculates primary voltage instruction values V 1 d * and V 1 q * to be assigned to the motor by inputting the speed instruction value ω* of the speed instruction circuit 8 and a detection value ωr of the speed detector 6 as well as the two-phase calculation values I 1 d and I 1 q of the current detector 7 , and a two-phase-to-three-phase voltage converter 11 that calculates three-phase output voltage instruction values Vu*, Vv*, and Vw* from the two-phase primary current instruction values V 1 d * and V 1 q*. The vector control apparatus further includes an output torque estimator 12 that calculates an output torque of the motor 5 from the calculation values I 1 d and I 1 q of the three-phase to two-phase current converter 9 , an analog output unit 13 that digital-to-analog converts the output torque estimation value of the output torque estimator 12 and outputs an analog voltage, and an analog input unit 14 that analog-to-digital converts the analog voltage signal and converts the digital analog voltage signal to a torque instruction. In the circuit shown in FIG. 5 , although all three, namely, the output torque estimator 12 , the analog output unit 13 , and the analog input unit 14 are present, if only a masterlis involved, the output torque estimator 12 and the analog output unit 13 are necessary, and if only a slave is involved, the analog input unit 14 alone is necessary. Explained next is a control method for the synchronous operation of two vector control inverters that have the structure described above. In the synchronous operation, given that q axis current 12 q is controlled such that it is zero as regards the flux of a secondary side rotor, the following expression (1) is used for calculating the output torque by the output torque estimator 12 based on the calculation result of the three-phase-to-two-phase current converter 9 in the master vector control inverter. in-line-formulae description="In-line Formulae" end="lead"? Tm=Kt·l 1 q·l 1 d (1) in-line-formulae description="In-line Formulae" end="tail"? where Kt is a torque coefficient corresponding to the motor. In the analog output circuit 1 . 3 , the digital value is converted into an analog value such that the calculation result of the output torque estimator 12 is normalized to match the bit count of the analog-to-digital converter in the analog. input circuit 14 on the slave side and an analog voltage is output to the slave vector control inverter. In the slave vector control inverter, the analog voltage that is output from the master vector control inverter is input to the analog input circuit 14 and converted into a torque instruction and the motor 5 is rotated in a torque control mode. Thus, in the synchronous operation that employs the conventional vector control inverters, the torque is-estimated by the master vector control inverter, the estimated digital torque value is once converted to an analog signal and output to the slave vector control inverter. The analog signal received from the master vector control inverter is converted into a digital torque value by the slave vector control inverter and the motor 5 on the slave side is rotated in the torque control mode. The transfer for synchronization signals involves conversion of a digital value to an analog signal (a process that takes place in the master vector control inverter) and conversion of the analog signal back to the digital value (a process that takes place in the slave vector control inverter). Therefore, any offset in the analog signal or a fluctuation in the level of the analog signal affects functioning of both the master side and the slave side (for instance, discord or fluctuation, etc. of the slave side with regard to the master side). Besides, since an analog signal is used between the master side and the slave side, the noise factor also casts a considerable effect on the functioning of the master side and the slave side. As an alternative method, data is transferred as a digital signal by employing a serial communication network between the master and the slave. In this case, for the synchronous operation, it is necessary to transmit the torque signal of the master vector control inverter in realtime to the slave vector control inverter. In the case where plural slave vector control inverters are used, the torque signal of the master vector control inverter is required to be transmitted to all the slave control inverters simultaneously. Consequently, carrying out the synchronous operation in a serial communication network necessitates a complex system with requirement of communication control hardware for fast data transmission between the master and the slave, and communication software for receiving signals for obtaining synchronization between the inverters and for the inverters to receive data and carry out processes in accordance with the synchronization signals. In Japanese Patent Laid Open Publication No. H9-182481, a speed difference control apparatus is disclosed that, using a pulse array control, drives a slave servo motor to rotate at a predetermined speed difference with respect to the rotation speed of a master servo motor. This speed difference control apparatus pulse array controls the rotation speed of the slave servo motor based on the sum or difference of the detected pulse array frequency value of the rotation speed of the master servo motor and the pulse array frequency of the predetermined speed difference. However, in this method, synchronous operation is possible only if the structure comprises a single master servo motor and a single-slave servo motor. In a structure, that comprises two or more slave servo motors, it is not possible to keep the conditions identical, since the sum or difference are obtained for each slave servo motor with respect to the master servo motor. In Japanese Patent Laid Open Publication No. H11-41967, a driving apparatus in the form of an operation control apparatus that includes plural rotation-driven wheels is disclosed. This operation control apparatus includes a speed control mode inverter that speed-controls one of the wheels based on the operation speed set by a target speed setting unit and a torque control mode inverter that produces a torque equal to that of the speed control mode inverter and torque-controls the wheels excluding the wheel that is speed-controlled by the speed control mode inverter. However, this conventional technology does not allow removal or addition of a slave axis during the synchronous operation. Therefore, it is an object of the present invention to obtain a vector control inverter that allows transfer of synchronization signals (digital signals) without the necessity for a conversion process from digital signals to analog signals and vice versa. It is another object of the present invention to allow synchronous operation in a system comprising a single master vector control inverter and two or more slave vector control inverters, and further allow removal or addition of slave axes during synchronous operation. |
<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG. 1 is a block diagram of a vector control inverter according to an embodiment of the present invention; FIG. 2 is a block diagram of a system in which a synchronous operation is carried out using two of the vector control inverters; FIG. 3 is a torque instruction timing chart of a slave axis with respect to a rotation speed of a master axis in the vector control inverter; FIG. 4 illustrates three types of pulse stream signals used in the synchronous operation of the vector control inverter; and FIG. 5 is a block diagram of a conventional vector control apparatus. detailed-description description="Detailed Description" end="lead"? |
Novel glycolipid and medicine for autoimmune disease containing the same as active ingredient |
The invention is a glycolipid useful in treating autoimmune diseases and a medicine thereof as active ingredient for autoimmune diseases, wherein R1 is an aldopyranose group, R2 is a hydrogen atom or a hydroxyl group, R3 is —CH2—, —CH(OH)—CH2— or —CH═CH—, R4 is a hydrogen atom or CH3, x is 0-35, y and z represent integers satisfying y+z=0-3. |
1. A glycolipid represented by the formula below (I). wherein, R1 is an aldopyranose group, R2 is a hydrogen atom or a hydroxyl group, R3 is —CH2—, —CH(OH)—CH2— or —CH═CH—, R4 is a hydrogen atom or CH3, x is 0-35, y and z represent integers satisfying y+z=0-3. 2. The glycolipid as in claim 1 wherein R1 is α-D-galactopyranosyl. 3. The glycolipid as in claim 2 wherein R3 is —CH2— or —CH(OH)—CH2— and x is 10-32. 4. The glycolipid as in claim 3 wherein R3 is —CH(OH)—CH2—. 5-8. (canceled) 9. The glycolipid as in claim 1 wherein R2 and R4 are hydrogen atoms, x is 11-23 and z is 0. 10. The glycolipid as in claim 3 wherein R2 and R4 are hydrogen atoms, x is 11-23 and z is 0. 11. A pharmaceutical composition comprising as the active ingredient the glycolipid as in claim 1. 12. A pharmaceutical composition comprising as the active ingredient the glycolipid as in claim 2. 13. A pharmaceutical composition comprising as the active ingredient the glycolipid as in claim 9. 14. A pharmaceutical composition comprising as the active ingredient the glycolipid as in claim 10. 15. A method of treatment for autoimmune disease which comprises administering an effective amount of the glycolipid as in claim 1 to a patient in need thereof. 16. A method of treatment for autoimmune disease which comprises administering an effective amount of the glycolipid as in claim 9 to a patient in need thereof. 17. The method as in claim 15, wherein said immune disease is multiple sclerosis, rheumatoid arthritis, psoriasis, Crohn's disease, vitiligo vulgaris, Behcet's disease, collagen diseases, Type 1 diabetes, uveitis, Sjogren's syndrome, autoimmune type myocarditis, autoimmune liver diseases, autoimmune gastritis, pemphigus, Guillain-Barre syndrome or HTLV-1 associated myelopathy. 18. The method as in claim 16, wherein said immune disease is multiple sclerosis, rheumatoid arthritis, psoriasis, Crohn's disease, vitiligo vulgaris, Behcet's disease, collagen diseases, Type 1 diabetes, uveitis, Sjogren's syndrome, autoimmune type myocarditis, autoimmune liver diseases, autoimmune gastritis, pemphigus, Guillain-Barre syndrome or HTLV-1 associated myelopathy. 19. A method of treatment for the diseases in which the Th1/Th2 immune balance is shifted toward Th1 bias or diseases wherein Th1 cells aggravated the pathologic conditions, which comprises administering as active ingredient the glycolipid as in claim 1 to a patient. 20. A method of treatment for the diseases in which the Th1/Th2 immune balance is shifted toward Th1 bias or diseases wherein Th1 cells aggravated the pathologic conditions, which comprises administering as active ingredient the glycolipid as in claim 10 to a patient. 21. A method of inducing selectively IL-4 production which comprises administering as active ingredient the glycolipid as in claim 1. 22. A method of inducing selectively IL-4 production which comprises administering as active ingredient the glycolipid as in claim 10. |
<SOH> BACKGROUND OF THE PRIOR ART <EOH>Living bodies have a function to prevent and inhibit the occurrence of autoimmune diseases, and this function is referred to as the “immune modulatory function”. NKT cells recently attracted attention as a lymphocyte having the “immune modulatory function”. (Saishin Igaku Vol. 55, No. 4, pp. 858-863.) The inventors have been working on the development of medicines that act upon NKT cells (a pharmaceutical drug material that appropriately stimulates NKT cells and effectively expresses their immune modulatory function). The conventional treatment methods for autoimmune diseases focused mainly on “non-specific immunosuppressive therapy” involving glucocorticoids and immunosuppressants. “Non-specific immunosuppressive therapy” refers to methods of treatment that suppress many of the biological functions of immune cells without special selectivity and distinction. These methods of treatment, therefore, suppress biological reactions inducing and aggravating diseases but they also suppress biological reactions necessary to living bodies (side effects). Therefore, the development of specific immunosuppressants (pharmaceutical drug agents that suppress only the biological reactions that induce and aggravate diseases) is urgently desired. Auto-antigen peptide treatments were recently tested with this goal in mind. However, since peptides are manifested by the major histocompatibility gene complex (MHC) molecules that have individual differences, the difference in efficacy varied tremendously among individuals, and allergic reactions also posed a problem. Alpha-galactosylceramide has been identified so far as a substance capable of stimulating NKT cells by other researchers. [Science, Vol. 278, pp. 1626-1629 (1997), Proc. Natl. Acad. Sci. USA Vol. 95, pp. 5690-5693 (1998), J. Med. Chem. 1995, 38, pp. 2176-2187, Japanese Patent Application Public Disclosure (Kokai) Hei 5-9193, Japanese Patent Application Public Disclosure (Kokai) Hei 5-59081, Japanese Patent No. 3088461 and U.S. Pat. No. 5,936,076.] The inventors administered the alpha-galactosylceramide described in the publications to treat autoimmune diseases such as the animal model for multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), and collagen induced arthritis, the animal model of rheumatoid arthritis. However, this alpha-galactosylceramide induces both IL-4, a cytokine that suppresses autoimmune diseases, as well as IFN-γ, a cytokine that aggravates autoimmune diseases. Therefore, this alpha-galactosylceramide was found to be clearly not effective in suppressing or treating autoimmune diseases. (American Immunology Society Journal, the Journal of Immunology, Jan. 1, 2001, Vol. 166, pp. 662-669.) That is, conventional alpha-galactosylceramide is not an appropriate medicine for autoimmune disease since it induces a simultaneous manifestation of conflicting functions (a function to suppress disease and a function to aggravate the disease) of NKT cells. |
<SOH> SUMMARY OF THE INVENTION <EOH>The inventors synthesized a number of glycolipids that are the derivatives of conventional alpha-galactosylceramide and tested their biological activities. As a result, the inventors discovered that the substances, obtained by modifying these glycolipids to shorten the length of the carbon chain in the sphingosine base, displayed the capability to induce only the function (produces IL-4) useful in suppressing autoimmune disease, which is the same one that NKT cells possesses. The derivative was administered to treat EAE, the animal model for multiple sclerosis, and was confirmed to have preventive and treatment effects on EAE. That is, the present invention is to provide an glycolipid represented by the formula (I) shown below. In the formula R 1 is an aldopyranose group. As this aldopyranose radical, α-D-glycosyl, α-D-galactosyl, α-D-mannosyl, β-D-glucosyl, β-D-galactosyl, β-D-mannosyl, 2-deoxy-2-amino-α-D-galactosyl, 2-deoxy-2-amino-β-D-galactosyl, 2-deoxy-2-acetylamino-α-D-galactosyl, 2-deoxy-2-acetylamino-β-D-galactosyl, β-D-allopyranosyl, β-D-altropyranosyl, β-D-idosyl and the like can be mentioned, and α-isomer is more effective as the glycolipid of the present invention. Of these, α-D-galactopyranosyl represented by the formula below is preferred as R 1 . R 2 represents a hydrogen atom or a hydroxyl group, and preferably hydrogen atom. R 3 represents —CH2—, —CH(OH)—CH 2 — or —CH═CH—, preferably —CH 2 — or —CH(OH)—CH 2 —, and most preferably —CH(OH)—CH 2 —. R 4 represents a hydrogen atom or CH 3 , preferably hydrogen atom. x is zero to 35, preferably zero to 26 , more preferably eleven to 26, even more preferably eleven to 23 and most preferably eighteen to 23. y and z represent the integers that satisfy y+z=zero to three. Here, —(CH 2 ) y (CH(CH 3 )) z — does not mean that (CH 2 ) and (CH(CH 3 )) are aligned in this order but only indicates simply a quantitative relationship. For example, —(CH 2 ) y (CH(CH 3 )) z — represents one of —CH(CH 3 )CH 2 CH 2 —, —CH 2 CH(CH 3 )CH 2 — or —CH 2 CH 2 CH(CH 3 )— when y=2 and z=1. In addition, y and z are preferably z=0 and y=0-3, and more preferably z=0 and y=1-3. The present invention is to provide a medicine comprising these glycolipids as active ingredients for treatment of an autoimmune disease. In addition, it is to provide a medicine comprising these glycolipids as active ingredients for treatment of diseases wherein the Th1/Th2 immune balance is shifted toward Th1 bias or diseases wherein Th1 cells aggravate the pathologic conditions. Furthermore, the present invention is to provide a selective IL-4 production inducing agent comprising these glycolipids as active ingredients. |
Forgery-proof marking for objects and method for identifying such a marking |
The invention relates to forgery-proof marking for objects, such as check cards, banknotes, labels, and the like, comprising a plastic transparent film (1) having a first and second surface, whereby a series of layers is applied to the second surface. When viewed from the first surface, the color of this series of layers changes according to the viewing angle, and the series of layers is formed from an absorber layer provided on the second surface, from a spacer layer (3) overlying the absorber layer, and from a mirror layer (2) overlying the spacer layer (3). In order to improve the machine identification of the authenticity of the marking, the invention provides that the absorber layer is comprised of metallic clusters (4). |
1. A forgery-proof marking for an object, comprising a transparent film (1) produced from plastic and having a first and second surface, a series of layers being provided on the second surface, whose color changes as a function of the viewing angle, the series of layers being formed from an absorber layer (4), a spacer layer (3) overlying the absorber layer (4) and a mirror layer (2) overlying the spacer layer (3), characterized in that the absorber layer comprises metallic clusters (4). 2. The forgery-proof marking as claimed in claim 1, the clusters (4) forming discrete islands with a size of at most 100 nm, in at least one spatial direction. 3. The forgery-proof marking as claimed in claim 1, the thickness of the spacer layer (3) being chosen such that the absorption of light incident on the cluster layer (4) is a maximum. 4. The forgery-proof marking as claimed in claim 1, the series of layers having, at a viewing angle of 45° in the wavelength range between 300 and 800 nm, an absorption with a maximum value of at least 60%. 5. The forgery-proof marking as claimed in claim 1, the clusters (4) being formed from a metal selected from the group consisting of gold, silver, platinum, palladium, tin, aluminum, copper, and indium. 6. The forgery-proof marking as claimed in claim 1, the cluster layer (4) being joined firmly or detachably to the spacer layer (3). 7. The forgery-proof marking as claimed in claim 1, the spacer layer (3) being joined firmly or detachably to the mirror layer (1). 8. The forgery-proof marking as claimed in claim 1, the spacer layer (3) having a thickness of 40 to 2000 nm. 9. The forgery-proof marking as claimed in claim 1, the spacer layer (3) being produced from a material selected from the group consisting of a metal oxide, metal nitrite, metal oxynitride, metal carbide, and a polymer. 10. The forgery-proof marking as claimed in claim 1, the film (1) having a layer thickness of 5 to 100 μm. 11. The forgery-proof marking as claimed in claim 1, the film being produced from polyethylene terephthalate. 12. The forgery-proof marking as claimed in claim 1, the first or the second surface of the film (1) having a structure in order to produce a holographic effect. 13. The forgery-proof marking as claimed in claim 12, the structure for producing a holographic effect being in the range from 0.1 μm to 1.0 μm. 14. The forgery-proof marking as claimed in claim 1, an adhesive layer being applied to the mirror layer (2). 15. The forgery-proof marking as claimed in claim 1, the mirror layer (2) being applied to a carrier film (6). 16. The forgery-proof marking as claimed in claim 15, an adhesive layer being applied to the carrier film (6). 17. The forgery-proof marking as claimed in claim 16, the adhesive layer being produced from a pressure-sensitive adhesive or from a hot-melt adhesive. 18. The forgery-proof marking as claimed in claim 16, the adhesive layer being covered with a protective film that can be pulled off. 19. The forgery-proof marking as claimed in claim 1, the series of layers applied to the second surface being present in the form of layered flakes which are accommodated in a transparent matrix. 20. A method for the machine identification of the forgery-proof marking as claimed in claim 1, having the following steps: a) registering the spectrum of light reflected by the forgery-proof marking at a predefined viewing angle, b) measuring values for determining (i) the position and/or (ii) the shape and/or (iii) the intensity of one or more absorption peaks characteristic of the marking within a predefined spectral range, c) comparing the values (i) to (iii) measured in step b with predefined corresponding values and d) identifying of the marking by using the result of the comparison. 21. The method as claimed in claim 20, the spectrum being registered at a viewing angle of 5° to 50°. 22. The method as claimed in claims claim 20, the absorption peak being used as a detection feature for the presence of an absorption spectrum produced by the cluster layer (4). 23. The method as claimed in claim 20, the absolute intensity of the absorption peaks being measured. 24. The method as claimed in claim 20, the marking being identified as such only if the measured values (i) to (iii) lie within a predefined value range around the corresponding values. 25. The method as claimed in claim 20, the light being produced by means of an incandescent lamp, laser, fluorescent lamp, light-emitting diode or xenon lamp. 26. The method as claimed in claim 20, the marking being identified by registering the reflected spectrum at various viewing angles. 27. The forgery-proof marking as claimed in claim 1, said object selected from the group consisting of a check card, a banknote, and a label. 28. The forgery-proof marking as claimed in claim 2, the clusters (4) forming discrete islands with a size of about 5 nm to about 35 nm in at least one spatial direction. 29. The forgery-proof marking as claimed in claim 3, wherein the spacer layer (3) is a dielectric spacer layer. 30. The forgery-proof marking as claimed in claim 4, the series of layers having, at a viewing angle of 45° in the wavelength range between 300 and 800 nm, an absorption with a maximum value of at least 80%. 31. The forgery-proof marking as claimed in claim 4, the series of layers having, at a viewing angle of 45° in the wavelength range between 300 and 800 nm, an absorption with a maximum value of at least 90%. 32. The method as claimed in claim 21, the spectrum being registered at a viewing angle of 15° to 40°. 33. The forgery-proof marking as claimed in claim 9, wherein said metal oxide is selected from the group consisting of silicon oxide, tin oxide, and aluminum oxide. 34. The forgery-proof marking as claimed in claim 9, wherein said metal nitrite is selected from the group consisting of silicon nitrite, tin nitrite, and aluminum nitrite. 35. The forgery-proof marking as claimed in claim 9, wherein said metal carbide is silicon carbide. 36. The forgery-proof marking as claimed in claim 9, wherein said polymer is selected from the group consisting of polycarbonate (PC), polyethylene (PE), polypropylene (PP), polyurethane (PU), polyimide (PI), polystyrene (PS) or polymethacrylates (PMA), polyvinyl alcohol (PVA), polyacrylates (PA), nitrocellulose (NC), and polyethylene terephthalate (PET). |
Osmotic desalination process |
An energy efficient desalination process that does not produce waste products involves the extraction of water from a first solution, such as seawater, by using a second concentrated solution to draw the water from the first solution across a semi-permeable membrane. By manipulating the equilibrium of the soluble and insoluble species of solute within the second solution in favor of the soluble species of the solute, a saturated second solution can be used to generate osmotic pressure on the first solution. Also, by adjusting the equilibrium in favor of the less soluble species after the water has been drawn from the first solution, a portion of the solute can easily be precipitated out. Heating the second solution decomposes the solute into its constituent gasses. The constituent gasses and precipitated solute may be recycled through the process to affect the changes in equilibrium and eliminate waste products. Additionally, by using the waste steam from industrial sources and a heat pump to effectively distribute heat through the present method, the present method exhibits greater energy efficiency than prior art methods. |
1. An osmotic method for extracting a solvent from a first solution comprising the steps of: a. exposing the first solution to a first surface of a semi-permeable membrane; b. adjusting the equilibrium in a second solution to increase the amount of a soluble species of solute in the second solution by adding a first reagent such that the concentration of the second solution is greater than that of the first solution; c. exposing the second solution to a second opposed surface of the membrane; d. drawing a solvent from the first solution through the membrane and into the second solution producing a solvent-enriched second solution; e. precipitating a portion of the solute out of the solvent-enriched second solution; f. filtering the precipitated solute out of the solvent-enriched second solution; and g. heating the solvent-enriched second solution to decompose the remaining solute into its constituent gasses to produce a solvent. 2. The method of claim 1 wherein said first solution is seawater, brackish water, wastewater, contaminated water, or other aqueous solution. 3. The method of claim 1 wherein the portion of solute is precipitated out of the solvent-enriched second solution by adjusting the equilibrium of the solvent-enriched second solution to increase the amount of a less-soluble species of solute present in the solution by adding a second reagent causing a portion of the less-soluble species of solute to precipitate out of the solvent-enriched second solution. 4. The method of claim 1 wherein the second solution is comprised of a concentrated solution of ammonia and carbon dioxide, ammonium carbonate, ammonium bicarbonate, and ammonium carbamate. 5. The method of claim 1 wherein the second solution is heated to about 50 to 58° C. to increase the concentration of the second solution. 6. The method of claim 5 wherein the solvent-enriched second solution is cooled to about 18 to 25° C. prior to precipitating a portion of the solute out of the solvent-enriched second solution. 7. The method of claim 1 wherein the semi-permeable membrane allows the passage of water, but excludes the dissolved solutes sodium chloride, ammonium carbonate, ammonium bicarbonate, and ammonium carbamate. 8. The method of claim 3 wherein the second reagent is comprised of carbon dioxide gas. 9. The method of claim 1 wherein said first reagent is comprised of a mixture of carbon dioxide and ammonia gasses. 10. The method of claim 3 wherein the precipitated less-soluble species are reintroduced to the second solution and allowed to redissolve therein to maintain concentration of said second solution. 11. The method of claim 1 wherein the constituent gasses are ammonia and carbon dioxide. 12. The method of claim 1 wherein the constituent gasses are reintroduced as the first reagent. 13. The method of claim 1 where the heat used to decompose the remaining soluble and less-soluble species of solute is comprised of at least one of waste steam, solar, geothermal, and heat pumped by heat exchange. 14. The method of claim 1, where the heat used to decompose the remaining soluble and less soluble species of solute is heat produced by exothermic reactions that occur when the equilibrium of the solutes is adjusted. 15. The method of claim 1 comprising the further step of subjecting the solvent to at least one of pH balancing and supplementing with additional solutes. 16. The method of claim 1 comprising the further step of pumping a concentrated first solution to solar evaporation tanks. 17. The method of claim 1 comprising the further step of filtering a precipitate from a concentrated first solution. 18. The method of claim 3 further comprising the steps of: h. introducing a remaining portion of the first reagent, as a second reagent, to the solvent-enriched solution; i. recycling the precipitated less-soluble species to the second solution after filtration; and j. recycling the constituent gasses, as the first reagent, after heating the solvent-enriched second solution. 19. The method of claim 1 wherein the concentration of the second solution is at least 6 molal. 20. The method of claim 1 wherein the solvent is water. 21. An osmotic method for extracting water from an aqueous solution comprising the steps of: a. exposing the aqueous solution to a first surface of a semi-permeable membrane; b. adjusting the equilibrium of a second solution to increase the amount of ammonium carbamate present in the solution by adding a first gas comprised of ammonia and carbon dioxide, wherein the ammonia is preferentially adsorbed by the second solution, such that the concentration of the second solution is greater than that of the aqueous solution; c. exposing the second solution to a second opposed surface of the membrane; d. drawing the water from the aqueous solution across the membrane and into the second solution generating a water-enriched solution; e. adjusting the equilibrium of the water-enriched solution to increase the amount of ammonium bicarbonate present in the solution by adding a second gas, comprised of carbon dioxide gas remaining from the first equilibrium adjustment, causing a portion of the ammonium bicarbonate to precipitate out of the water-enriched solution; f. filtering the precipitated ammonium bicarbonate out of the water-enriched solution; g. recycling the precipitated ammonium bicarbonate to the second solution; h. heating the water-enriched solution to decompose the remaining ammonium carbamate and ammonium bicarbonate into ammonia and carbon dioxide to produce potable water; and i. recycling the ammonia and carbon dioxide, as the first gas. 22. An apparatus for the extraction of a solvent from a first solution using osmosis comprising: a. a first chamber having an inlet and an outlet, the inlet of the first chamber being connected to a source of the first solution; b. a semi-permeable membrane separating the first chamber from a second chamber; c. the second chamber having an inlet and a first and second outlet; d. a third chamber having an inlet to receive a solvent-enriched second solution from the first outlet of the second chamber and a reagent from the second outlet of the second chamber and having an outlet; e. a filter for filtering the solvent-enriched second solution connected to the outlet of the third chamber, the filter having a first and second outlet, the first outlet is connected to the inlet of the second chamber in order to recycle a precipitated solute to the second chamber; and f. a fourth chamber receiving the solvent-enriched second solution from the second outlet of the filter, having a heater for heating a solvent-enriched second solution, a first outlet for returning constituent gasses to the inlet of the second chamber, and a second outlet by which the final product exits the apparatus. 23. The apparatus of claim 22 wherein the filter comprises a hydrocyclone, sedimentation tank, column filter, or screen filter. 24. The apparatus of claim 22 wherein the first outlet for the fourth chamber incorporates a device for generating airflow. 25. The apparatus of claim 23 wherein the device for generating an airflow comprises a vacuum or a fan. 26. The apparatus of claim 22 wherein the heater is comprised of at least one of a solar collector, geothermal collector, electrical heater, steam condenser, heat exchanger, and heat circulator. 27. An osmotic method for extracting a solvent from a first solution comprising the steps of: a. exposing the first solution to a first surface of a semi-permeable membrane; b. adjusting the equilibrium in a second solution to increase the amount of a soluble species of solute in the second solution by adding a first reagent such that the concentration of the second solution is greater than that of the first solution; c. exposing the second solution to a second opposed surface of the membrane; d. drawing a solvent from the first solution through the membrane and into the second solution to produce a solvent-enriched second solution; and e. removing soluble species of solute from the solvent-enriched second solution to obtain only the solvent. 28. The method of claim 27 wherein the step of removing the soluble species of solute from the solvent-enriched second solution is accomplished by precipitating a portion of the solute out of the solvent-enriched second solution. 29. The method of claim 28, further including the step of filtering precipitated solute out of the solvent-enriched second solution. 30. The method of claim 28, wherein the portion of solute is precipitated out of the solvent-enriched second solution by adjusting the equilibrium of the solvent-enriched second solution to increase the amount of a less-soluble species of solute present in the solution, wherein the equilibrium of the solvent-enriched second solution is adjusted by adding a second reagent to cause a portion of the less-soluble species of solute to precipitate out of the solvent-enriched second solution. 31. The method of claim 27, wherein the step of removing the soluble species of solute from the solvent-enriched second solution is accomplished by decomposing the soluble species of solute into their constituent gasses and vaporizing the constituent gasses out of the solvent-enriched second solution. 32. The method of claim 27 wherein the soluble species of solute is removed from the solvent-enriched second solution by: a. precipitating a portion of the solute out of the solvent-enriched second solution; b. filtering the precipitated solute out of the solvent-enriched second solution; and c. heating the solvent-enriched second solution to decompose the remaining solute into its constituent gasses and vaporizing the constituent gasses out of the solvent-enriched second solution to obtain only the solvent. 33. The method of claim 27, including the step of applying an external pressure to the first solution to increase the amount of solvent drawn from the first solution through the membrane and into the second solution. 34. The method of claim 28, including the step of heating the solvent-enriched second solution to decompose the remaining solute into its constituent gasses and vaporizing the constituent gasses out of the solvent-enriched second solution to obtain only the solvent. 35. An apparatus for the extraction of a solvent from a first solution using osmosis, the apparatus comprising: a first chamber for receiving a first solution; a second chamber for receiving a second solution; a semi-permeable membrane disposed intermediate and coupling the first chamber and the second chamber, wherein the semi-permeable membrane allows solvent from the first chamber to pass through to the second chamber, thereby producing a solvent-enriched second solution in the second chamber; and solute removing means, coupled to the second chamber, for removing soluble species of solute from the solvent-enriched second solution to obtain only the solvent. 36. The apparatus as claimed in claim 35, wherein the solute removing means comprises a precipitator for precipitating solute out of the solvent-enriched second solution. 37. The apparatus as claimed in 36, wherein the solute removing means comprises a filtration device, coupled to the precipitator, for filtering precipitated solute from the solvent-enriched second solution. 38. The apparatus as claimed in claim 37, wherein the solute removing means comprises a heater, coupled to the filtration device, for heating the solvent-enriched second solution; wherein the remaining solute in the solvent-enriched second solution is decomposed into its constituent gasses and the constituent gasses are vaporized out of the solvent-enriched second solution. 39. The apparatus as claimed in claim 36, wherein the solute removing means comprises a heater, coupled to the precipitator, for heating the solvent-enriched second solution; wherein the remaining solute in the solvent-enriched second solution is decomposed into its constituent gasses and the constituent gasses are vaporized out of the solvent-enriched second solution. 40. The apparatus as claimed in claim 35, wherein the solute removing means comprises a heater, coupled to the second chamber, for heating the solvent-enriched second solution; wherein soluble species of solute are decomposed into their constituent gasses and the constituent gasses are vaporized out of the solvent-enriched second solution. 41. The apparatus of claim 35, comprising means for applying an external pressure to the first solution to increase the amount of solvent drawn from the first solution through the membrane and into the second solution. 42. The apparatus as claimed in claim 35, wherein the first chamber includes an inlet connected to a source of the first solution and the second chamber includes an inlet connected to a source of the second solution. 43. The apparatus as claimed in claim 35, including recycling means for recycling solutes from the solute removing means back into the second chamber; whereby a desired concentration of the second solution is maintained in the second chamber. 44. The apparatus as claimed in claim 38, including recycling means for recycling gasses from the solvent-enriched second solution back into the second chamber; whereby a desired concentration of the second solution is maintained in the second chamber. 45. The apparatus as claimed in claim 38, including recycling means for recycling gasses from the solvent-enriched second solution back into the second chamber; and and means for permitting the gasses to move between the second chamber and the precipitator; whereby a desired concentration of the second solution is maintained in the second chamber. 46. The apparatus as claimed in claim 35, wherein the first chamber and the second chamber are contained within a single vessel that is partitioned into two chambers by the semi-permeable membrane. 47. An apparatus for the extraction of a solvent from a first solution using osmosis, the apparatus comprising: a first chamber for receiving a first solution; a second chamber for receiving a second solution; a semi-permeable membrane disposed intermediate and coupling the first chamber and the second chamber, wherein the semi-permeable membrane allows solvent from the first chamber to pass through to the second chamber, thereby producing a solvent-enriched second solution in the second chamber; and one or more chambers which are coupled to the second chamber, for removing soluble species of solute from the solvent-enriched second solution to obtain only the solvent. 48. The apparatus as claimed in claim 47, including a third chamber for precipitating solute out of the solvent-enriched second solution. 49. The apparatus as claimed in 48, including a filtration device, coupled to the third chamber, for filtering precipitated solute from the solvent-enriched second solution. 50. The apparatus as claimed in claim 49, comprising a heating chamber, coupled to the filtration device, for heating the solvent-enriched second solution; wherein solute remaining in the solvent-enriched second solution is decomposed into its constituent gasses and the constituent gasses are vaporized out of the solvent-enriched second solution. 51. The apparatus as claimed in claim 48, comprising a heating chamber, coupled to the third chamber, for heating the solvent-enriched second solution; wherein solute remaining in the solvent-enriched second solution is decomposed into its constituent gasses and the constituent gasses are vaporized out of the solvent-enriched second solution. 52. The apparatus as claimed in claim 47, comprising a heating chamber, coupled to the second chamber, for heating the solvent-enriched second solution; wherein soluble species of solute are decomposed into their constituent gasses and the constituent gasses are vaporized out of the solvent-enriched second solution. 53. The apparatus of claim 47, comprising means for applying an external pressure to the first solution to increase the amount of solvent drawn from the first solution through the membrane and into the second solution. 54. The apparatus as claimed in claim 47, wherein the first chamber includes an inlet connected to a source of the first solution and the second chamber includes an inlet connected to a source of the second solution. 55. The apparatus as claimed in claim 47, including recycling means for recycling solutes from the third chamber back into the second chamber; whereby a desired concentration of the second solution is maintained in the second chamber. 56. The apparatus as claimed in claim 51, including recycling means for recycling gases from the heating chamber back into the second chamber; whereby a desired concentration of the second solution is maintained in the second chamber. 57. The apparatus as claimed in claim 51, including recycling means for recycling gases from the heating chamber back into the second chamber; and and means for permitting the gases to move between the second chamber and the third chamber; whereby a desired concentration of the second solution is maintained in the second chamber. 58. The apparatus as claimed in claim 35, wherein the first chamber and the second chamber are contained within a single vessel that is partitioned into two chambers by the semi-permeable membrane. |
<SOH> FIELD OF THE INVENTION <EOH>The invention relates generally to the field of desalination involving osmosis. More particularly, the invention relates to seawater desalination, brackish water desalination, wastewater purification, contaminated water remediation, or any other separation of solutes and water from an aqueous solution. |
<SOH> SUMMARY OF THE INVENTION <EOH>The invention provides a method of obtaining a high yield of solvent from desalination without the excessive energy demands and/or environmentally harmful waste discharge associated with the prior art methods of desalination. The invention achieves this by using a method of forward osmosis in which the concentration of a second solution is increased, through equilibrium shifts in the solutes contained within the second solution, to a point where the second solution can withdraw most of the solvent from a first solution. Through this manipulation of equilibrium, the present invention is able to separate a solvent from undesirable solutes in an energy efficient manner that results in high yields and permits the recycling of the solutes within the process. The inventive osmotic method of desalination is illustrated by a first embodiment of the invention in which a first solution is exposed to a first surface of a semi-permeable membrane. A second solution that has a concentration greater than that of the first solution is exposed to a second opposed surface of this membrane. The concentration of the second solution is increased by using a first reagent to adjust the equilibrium of solutes within the second solution to increase the amount of a soluble species of solute within second solution. The concentration gradient between the first and second solutions then draws the solvent from the first solution through the semi-permeable membrane and into the second solution producing a solvent-enriched solution. A portion of the solutes are then precipitated and filtered out of the solvent enriched second solution. The remaining solutes within the solvent-enriched second solution are removed by heating the solvent-enriched second solution to decompose the remaining soluble and less-soluble species of solutes into their constituent gasses to produce a solvent. In one embodiment, the first solution may be seawater, brackish water, wastewater, contaminated water, or other aqueous solutions. Additionally, the solvent in the present invention may be water in preferred embodiments. In a further preferred embodiment, the second solution may be a concentrated solution of ammonia and carbon dioxide, with resultant aqueous species: ammonium carbonate, ammonium bicarbonate, and ammonium carbamate. In another embodiment, the semi-permeable membrane may allow the passage of water, but exclude the dissolved solutes sodium chloride, ammonium carbonate, ammonium bicarbonate, and ammonium carbamate. In another embodiment, the first reagent may be comprised of a mixture of carbon dioxide and ammonia gasses. The first reagent may also be the constituent gasses which are recycled after being released from solution when the solute is decomposed. In a further embodiment, the second solution may be heated to about 50 to 58° C. to increase the concentration of the second solution. The concentration of the second solution may be at least 6 molal in a preferred embodiment. In one embodiment, the solvent-enriched second solution may be cooled to about 18 to 25° C. prior to subjecting the solvent-enriched second solution to the second reagent if the second solution was previously heated. In another embodiment, the concentrated first solution resulting from the forward osmosis process may be pumped to solar evaporation tanks. In an alternative embodiment, precipitates may be filtered from the concentrated first solution. In a further embodiment, the portion of solute may be precipitated out of the solvent-enriched second solution by adjusting the equilibrium of the solvent-enriched second solution to increase the amount of a less-soluble solute present in the solution. This may be done by adding a second reagent causing a portion of the less-soluble species to precipitate out of the solvent-enriched second solution. In one embodiment, the second reagent may be carbon dioxide gas. In yet another embodiment, the heat used to decompose the remaining soluble and less-soluble species may be waste steam from power or industrial plants, solar, geothermal, or heat pumped by heat exchange the heat being produced by the exothermic introduction of the first and second solutes into the second solution. The constituent gasses released upon heating of the solvent-enriched solution may be ammonia and carbon dioxide. In a preferred embodiment, the osmotic method may include the additional steps of introducing a remaining portion of the first reagent, as the second reagent, to the solvent-enriched solution; recycling the precipitated less-soluble species of so the second after filtration; and recycling the constituent gasses, as the first reagent, after heating the solvent-enriched second solution. In a further embodiment, the solvent may be subjected to at least one of the processes of pH balancing and supplementing with additional solutes. In a second embodiment, the osmotic method for extracting water from an aqueous solution starts by exposing the aqueous solution to a first surface of a semi-permeable membrane. The equilibrium of a second solution may be adjusted to increase the amount of ammonium carbamate present in the solution by adding a first gas of ammonia and carbon dioxide, wherein the ammonia present in the first gas is preferentially adsorbed by the second solution. This increases the concentration of the second solution so that it is greater than that of the aqueous solution. The second solution may then be exposed to a second opposed surface of the semi-permeable membrane. Water may then be drawn from the aqueous solution through the semi-permeable membrane and into the second solution generating a water-enriched solution. The equilibrium of the water-enriched solution may then be adjusted to increase the amount of ammonium bicarbonate present in the solution by adding a second gas which may be the carbon dioxide gas remaining from the first equilibrium adjustment. This equilibrium adjustment causes a portion of the ammonia bicarbonate to precipitate out of the water-enriched solution and is then filtered out of the water-enriched solution. This precipitated ammonia bicarbonate may be recycled to the second solution. The remaining water-enriched solution may be heated to decompose the remaining ammonia carbamate and ammonium bicarbonate into ammonia and carbon dioxide to produce potable water. The ammonia and carbon dioxide gasses released from solution may then be recycled as the first gas in the present osmotic method. The present invention also relates to an apparatus for the extraction of a solvent from a first solution using osmosis comprising. In an embodiment of the apparatus, the apparatus has a first chamber with an inlet and an outlet. The inlet of the first chamber may be connected to a source of the first solution. A semi-permeable membrane separates the first chamber from a second chamber. The second chamber has an inlet and a first and second outlet. A third chamber receives a solvent-enriched second solution from the first outlet of the second chamber and a reagent from the second outlet of the second chamber. The third chamber has an outlet which is connected to a filter for filtering the water-enriched second solution. The filter has a first and second outlet: the first outlet is connected to the inlet of the second chamber in order to recycle a precipitated solute to the second chamber, and a fourth chamber receives the solvent-enriched second solution from the second outlet of the filter. The fourth chamber has a heater for heating a solvent-enriched second solution. A first outlet in the fourth chamber returns constituent gasses to the inlet of the second chamber. A second outlet in the fourth chamber permits the final product, the solvent, to exit the apparatus. Additional features, advantages, and embodiments of the invention may be set forth or apparent from consideration of the following detailed description, drawings, and claims. Moreover, it is to be understood that both the foregoing summary of the invention and the following detailed description are exemplary and intended to provide further explanation without limiting the scope of the invention as claimed. |
Composites and methods for their production |
Intercalates and exfoliates formed from layered materials and dendritic polymers are disclosed, together with the uses of these materials, e.g. in producing composite materials. The dispersion of layered materials in a dendritic polymer matrix (hyperbranched polymers, star shaped polymers or star branched polymers) or has not been disclosed in the prior art. The high number of end-groups per molecule of dendritic polymer combined with their unique globular architectures leads to large intergallery spacings when intercalated in layered silicates and particularly facile exfoliation in spite of the high molar mass of the dendritic polymer. The excellent processability and potential high reactivity of dendritic polymers makes them extremely promising for thermoset applications, and coatings. |
1. An intercalate or exfoliate formed by contacting a layered material and a dendritic polymer so that molecules of the dendritic polymer are intercalated between adjacent spaced layers of the layered material. 2. The intercalate or exfoliate of claim 1, wherein the layered material comprises less than 75 wt % of the intercalate or exfoliate. 3. The intercalate or exfoliate of claim 1, wherein the layered material is a layered silicate. 4. The intercalate or exfoliate of claim 1, wherein the layered silicate is sodium montmorillonite. 5. The intercalate or exfoliate of claim 1, wherein the dendritic polymer is a dendrimer, a hyperbranched polymer, a polymer having dendron based architecture, a star shaped polymer or a star branched polymer, or a derivative of any of said polymers. 6. The intercalate or exfoliate of claim 1, wherein the dendritic polymer has one or more functional end groups. 7. The intercalate or exfoliate of claim 6, wherein the dendritic polymer has an average of at least 16 end groups per molecule. 8. The intercalate or exfoliate of claim 6, wherein the dendritic polymer has an average of at least 32 end groups per molecule. 9. The intercalate or exfoliate of claim 6, wherein the end groups are hydroxyl, thiol or amine groups. 10. The intercalate or exfoliate of claim 1, wherein the dendritic polymer is an aliphatic polymer comprising hydroxyl end groups. 11. The intercalate or exfoliate of claim 1, wherein the dendritic polymer is a hyperbranched polymer having a polydispersity which is less than 5. 12. The intercalate or exfoliate of claim 1 wherein the spacing between adjacent layers is approximately equal to the unperturbed molecular diameter of the polymers. 13. A method of producing an intercalate or exfoliate, the method comprising mixing a layered material with a dendritic polymer in a solvent. 14. The method of claim 13, wherein intercalation takes place in the absence of onium ions, silanes or other low molar mass or monomeric coupling agents. 15. The method of claim 13, further comprising drying the intercalate or exfoliate to remove the solvent. 16. The method of claim 13, wherein the layered material comprises less than 75 wt % of the intercalate or exfoliate. 17. The method of claim 13, wherein the layered material is a layered silicate. 18. The method of claim 13, wherein the layered silicate is sodium montmorillonite. 19. The method of claim 13, wherein the dendritic polymer has one or more functional end groups. 20. The method of claim 19, wherein the dendritic polymer has an average of at least 16 end groups per molecule. 21. The method of claim 19, wherein the end groups are hydroxyl, thiol or amine groups. 22. The method of claim 13, wherein the dendritic polymer is a hyperbranched polymer having a polydispersity which is less than 5. 23. The method of claim 13, wherein the spacing between adjacent layers is approximately equal to the unperturbed molecular diameter of the polymers. 24. The method of claim 13, further comprising reacting the end functional groups of the dendritic polymer in the intercalate or exfoliate. 25. The method of claim 24, wherein the end functional groups are reacted to crosslink them. 26. The method of claim 13, further comprising drying the intercalate or exfoliate. 27. An intercalate or exfoliate produced by the method of claim 13. 28. A method of producing a composite material which is a gel or pourable liquid, the method comprising dispersing the intercalate or exfoliate of claim 1 in a solvent to produce the gel or pourable liquid. 29. The method of claim 28, wherein the solvent is water or tetrahydrofuran. 30. The method of claim 28, further comprising the initial step of drying the intercalate or exfoliate. 31. The method of claim 28, wherein the intercalate or exfoliate is dispersed in a solvent to produce a thixotropic gel. 32. The method of claim 28, wherein the intercalate or exfoliate is dispersed in a solvent to produce a solution or suspension. 33. A method of producing a composite material, the method comprising obtaining an intercalate or exfoliate of claim 1 and crosslinking the dendritic polymer to form a crosslinked composite material. 34. The method of claim 33, wherein the dendritic polymer is crosslinked by mixing the intercalate or exfoliate with a diisocyanate. 35. A method of producing a composite material, the method comprising mixing a polymer matrix with an intercalate or exfoliate of claim 1 to produce the composite material. 36. The method of claim 35, wherein the polymer matrix is a thermoplastic polymer. 37. The method of claim 35, wherein the polymer matrix is polyethylene glycol, polyethylene oxide, polyacrylic acid, polyethylene, polypropylene, polystyrene or polymethyl methacrylate. 38. A composite material produced by the method of claim 28. 39. A composite material produced by the method of claim 33. 40. A composite material produced by the method of claim 35. 41. A composite material produced by the method of claim 37. |
<SOH> BACKGROUND OF THE INVENTION <EOH>Nanocomposite technologies based on the dispersion of layered materials such as layered silicates in a polymeric matrix are expected to become extremely important in the plastics industry over the next few decades. They offer huge opportunities in a broad range of markets through unprecedented enhancement of physical properties, pushing the performance envelope well beyond the domain of known composite technologies. This is because dispersed exfoliated layered silicates consist of approximately 1 nm thick platelets with aspect ratios that can exceed 2,000, leading to a much greater specific contact area with a polymer matrix than for an equivalent volume fraction of a conventional filler. Polypropylene nanocomposites with nearly twice the stiffness and a significantly higher softening temperature (heat deflection temperature) compared with the neat resin are achievable with no loss in surface quality and a specific gravity less than 0.95. At the same time substantial increases in adhesion are anticipated, with adhesive bond strength increasing 7-fold in epoxy nanocomposites, for example. Barrier properties, flame retardance or electrical conductivity may also be improved (Ruiz-Hitzky, et al. Adv. Mater. 7, (1995) 180; Kato et al. Clays and Clay Mater. 5, (1993) 1694), and the presence of exfoliated silicate layers can result in increased viscosity and elasticity in fluids, including polymer melts. Improvements in properties such as mechanical strength, stiffness and softening temperature have been disclosed in U.S. Pat. No. 4,739,007; U.S. Pat. No. 4,810,734; U.S. Pat. No. 5,385,776. Considerable work has consequently been devoted to the development of new synthetic methods for combining polymers and layered materials, such as smectite clays, and sodium montmorillonite in particular, by in situ polymerization of intercalated monomeric precursors (Alexandre and Dubois, Mat. Sci. & Eng. 28, (2000) 1). Nevertheless, for practical and economic reasons, fabricating such composites by melt or solution processing of readily available and cheap materials with minimal modification is a primary goal. There has been particular interest in identifying conditions or molecular characteristics that favor exfoliation of the layered materials in the polymer matrix (Singh and Balazs, Polymer International 49, (2000) 469; Ginzburg et al., Macromolecules 33, (2000) 1089; Zhulina et al., Langmuir 15, (1999) 3935), since the consequent percolation of interlayer contacts at very low loadings is thought to be determinant for many physical properties (Kojima et al., J. Mater. Res. 6, (1993) 1185; Messersmith and Giannelis, Chem. Mater. 6, (1994) 1719; Lan and Pinnavaia, Chem. Mater. 6, (1994) 2216). As described in WO93/04118, the incorporation of individual platelets of a highly hydrophilic exfoliated smectite clay into a polymer can be achieved by converting the hydrophilic clay into an organophilic clay by adsorption of a silane coupling agent or an onium cation, which is compatible with the polymer matrix and significantly increases the interlayer spacings. Intercalation of the organic polymer molecules between the organophilic silicate layers substantially increases the interlayer spacings still further, and the layers can be separated by high shear mixing, for example. The most widely used swellable layered materials have negative charges or basic sites on the layers, with a commensurate number of exchangeable cations in the interlayer spaces. These include smectite clay minerals such as montmorillonite, nontronite, beidellite, volkonskoite, hectorite, saponite, sauconite, magadiite, and kenyaite. Hectorite and montmorillonite, with between about 20 basic sites and about 150 basic sites per 100 g material are among the most suitable layered materials for exfoliation or intercalation in polymer matrices. However, the exchangeable inorganic cations such as sodium or calcium ions characteristic of the native clay, the interlayer spacings do not usually exceed 0.4 nm in the dry state in air and the interlayer cohesive energy is generally too strong to permit facile exfoliation and direct dispersion into a polymer or a polymer precursor matrix. Another important factor in facile dispersion of exfoliated layers into a polymer matrix is the strength of specific interactions between the polymer and the layers. For example, polypropylene (PP) is relatively inert and itself shows little affinity for smectite clays. However, melt intercalation and exfoliation have been reported in PP/smectite clay mixtures modified by grafting maleic anhydride to the PP, increasing its polarity and hence the strength of its interactions with the layer surfaces (Hasegawa, N. et al., J. Appl. Poly. Sci. 67, (1998) 87). In the case of highly functional polymers, including highly polar polymers and ionomers, for example, intrinsically strong bonding between the polymer and the silicate layers can occur through ion exchange, electrostatic complexes, direct hydrogen bonding or hydrogen bonding via water bridges in aqueous solution, chelation, dipole-dipole interactions and dispersive forces. In native smectite clays, electronegative species including oxygen in hydroxyl groups or sulfur in thiol groups may sorb to interlayer cations, such as sodium ions in sodium montmorillonite. The electronegativity should ideally be 2 or more on the Pauling scale for strong sorption to occur. Strong interactions between a polymer and the layers in a smectite silicate nevertheless do not necessarily lead to facile exfoliation, since the presence of large numbers of functional groups on individual linear polymer molecules can give rise to bridging effects. Thus, aqueous suspensions of linear water soluble polymers such as poly vinyl pyrrolidone, poly vinyl alcohol and poly ethylene oxide have been reported to result in intercalation of smectite clays with relatively small silicate inter-gallery layer spacings, unsuitable for dispersion by high shear mixing (Ogata et al., J. Appl. Polym. Sci. 66, (1997) 573; Levy and Francis, J. Colloid Interface Sci. 50, (1975) 442; Greenland, J. Colloid Sci. 18 (1963) 647). Melt intercalation with polymers of this type has also been reported, but again leads to relatively small increases in gallery spacing, even after long heat treatment times (Vaia et al. Chem. Mater. 5, (1993) 1694). |
<SOH> SUMMARY OF THE INVENTION <EOH>Broadly, the present invention relates to intercalates and exfoliates formed from layered materials and dendritic polymers, and to the further uses of these materials, e.g. in producing composite materials. To our knowledge, the dispersion of layered materials in a dendritic polymer matrix has not been disclosed in the prior art. The present invention shows, however, that there are nevertheless significant and surprising advantages in combining these technologies. The high number of end-groups per molecule of dendritic polymer combined with their unique globular architectures leads to large intergallery spacings when intercalated in layered silicates and particularly facile exfoliation in spite of the high molar mass of the dendritic polymer. The excellent processability and potential high reactivity of dendritic polymers makes them extremely promising for thermoset applications, and coatings in particular, where dispersion of layered silicates is of particular interest for improving durability and barrier properties, for example. Hydroxy terminated and polyhydroxy terminated monomers have previously been disclosed to produce intercalates and exfoliates from unmodified layered silicates, including sodium montmorillonite, from aqueous dispersions in U.S. Pat. No. 6,083,559 and U.S. Pat. No. 5,830,528, but these make no specific mention of polymers as exfoliants, nor any mention of hyperbranched polymers or dendrimers or related substances. Accordingly, in a first aspect, the present invention provides an intercalate or exfoliate formed by contacting a layered material and a dendritic polymer so that molecules of the dendritic polymer are intercalated between adjacent spaced layers of the layered material. In a further aspect, the present invention provides a method of producing an intercalate or exfoliate, the method comprising mixing a layered material with a dendritic polymer. Preferably, this reaction takes place in the absence of onium ions, silanes or other low molar mass or monomeric coupling agents. The method may comprise the further step of drying the intercalate or exfoliate to remove the solvent, reacting the end functional groups of the dendritic polymer in the intercalate or exfoliate, e.g. to cross-link it. The intercalates and exfoliates of the present invention can be subjected to further processing to make composite materials. Accordingly, in one embodiment, the present invention provides a method of forming a composite material which comprises redispersing the intercalate or exfoliate in a solvent, such as water or tetrahydrofuran, and composite materials produced by the method. The method optionally comprises the initial step of drying the intercalate or exfoliate to remove any solvent remaining in the material after its production. The composites produced by redispersing the intercalate or exfoliate in a solvent can be gels, especially thixotropic gels, or pourable liquids, such as solutions and suspensions. In a further embodiment, the present invention provides a method of producing a composite material, the method comprising crosslinking the dendritic polymer to form a crosslinked solid, and composite materials produced by the method. Conveniently, this can be accomplished by mixing the intercalate or exfoliate with a diisocyanate, e.g. in a proportion of 0 to 50% by total weight of the intercalate or exfoliate and reacting the composite thermally after drying to give a crosslinked solid. In a further embodiment, the present invention provides a method of producing a polymer composite, the method comprising mixing a polymer matrix with an intercalate or exfoliate, and polymer composites produced by the method. Examples of polymer matrices suitable for use in this embodiment of the invention are thermoplastic matrices, e.g. poly ethylene glycol, poly ethylene oxide or poly acrylic acid. Further examples are provided below. When layered materials such as layered silicates are combined with dendrimers or hyperbranched polymers with a dense globular architecture, with a large number of end-groups per molecule that have a high affinity for the layer surfaces, and with skeletal groups that may have little affinity for the layer surfaces, complete collapse of the polymer onto the substrate is hindered for steric or entropic reasons. It will be further hindered by any lack of interaction or repulsion between the skeletal groups and the layer surfaces. Intercalation of dendrimers or hyperbranched polymers therefore results in composites containing layered materials with relatively large gallery spacings, which are easy to exfoliate by subsequent mechanical processing or which may exfoliate during mixing. The large number of functional groups per molecule of dendritic polymers also means that not all the functional groups are required to promote exfoliation and a part of the functional groups may be assigned to other functions by chemical modification before or after mixing with the layered material. Dry exfoliated or intercalated composites may be re-dispersed in a suitable solvent for chemical modification or mixing, without re-aggregation of the layers. Modified functional groups or the original functional groups can be chosen to allow chemical, thermal or radiation crosslinking, if necessary by mixing with a co-reagent either in solution or by melt mixing. Crosslinking will give new composite materials with a range of properties from elastomers, to hard, tough materials, suitable for durable, high barrier coatings, for example. Alternatively, the dendritic polymers may be grafted to, or mixed with long chain linear polymers, such as poly ethylene, polypropylene, polystyrene or poly methyl methacrylate or any of the other examples set out in the detailed description below, or polymers with other architectures, including short and long branched, dendritic or comb-shaped architectures. When used as additives to other polymers, master batches containing layered materials and dendritic polymers have the potential to fulfil the dual role of introducing exfoliated or intercalated layers for improved properties and acting as a processing aid, for example, leading to new combinations of properties. Embodiments of the present invention will now be described by way of example and not limitation with reference to the accompanying figures. |
Use of associations between at least one nucleic sequence polymorphism of the sh2 gene and at least one seed quality characteristic in plant selection methods |
The invention relates to the use of a nucleotide probe or of a nucleotide primer in a process for selecting plants having improved phenotypic seed quality characteristics, for detecting a polymorphic base or a polymorphic nucleotide sequence defining an allele of a polymorphic site of the Sh2 gene of sequence SEQ ID No. 1, said polymorphic base or said polymorphic nucleotide sequence being contained in a nucleic acid included in an Sh2 gene. Application to the production of transformed plants capable of producing seeds with improved industrial or agrofoods qualities. |
1. A process for selecting plants having improved phenotypic seed quality characteristics, which comprises detecting a polymorphic base or a polymorphic nucleotide sequence with a nucleotide probe or a nucleotide primer; wherein the polymorphic base or polymorphic nucleotide sequence defines an allele of a polymorphic site of the Sh2 gene of sequence SEQ ID No. 1, said polymorphic base or said polymorphic nucleotide sequence being contained in a nucleic acid included in an Sh2 gene, said nucleic acid being a member selected from the group consisting of: (a) a nucleic acid in which the nucleotide corresponding to the nucleotide at position −921 of the Sh2 gene is a G; (b) a nucleic acid in which the nucleotides corresponding to the nucleotides at positions −830 to −824, of sequence 5′-TGAGAAA-3′, of the Sh2 gene are absent; (c) a nucleic acid in which the nucleotides corresponding to the nucleotides at positions −580 to −573, of sequence 5′-TCACCTAT-3′, of the Sh2 gene are absent; (d) a nucleic acid in which the nucleotide corresponding to the nucleotide at position −438 of the Sh2 gene is a G; (e) a nucleic acid in which the nucleotide corresponding to the nucleotide at position −362 of the Sh2 gene is an A; (f) a nucleic acid in which the nucleotide corresponding to the nucleotide at position −347 of the Sh2 gene is a T; (g) a nucleic acid in which the nucleotide corresponding to the nucleotide at position −296 of the Sh2 gene is a T; (h) a nucleic acid in which the nucleotide corresponding to the nucleotide at position −277 of the Sh2 gene is a T; (i) a nucleic acid in which the nucleotide corresponding to the nucleotide at position −266 of the Sh2 gene is a C; (j) a nucleic acid in which the nucleotide corresponding to the nucleotide at position −168 of the Sh2 gene is an A; (k) a nucleic acid in which the nucleotide corresponding to the nucleotide at position −15 of the Sh2 gene is an A; (l) a nucleic acid in which the nucleotide corresponding to the nucleotide at position +35 of the Sh2 gene is a T; (m) a nucleic acid in which an additional T is found after the nucleotide at position +304 of the Sh2 gene; (n) a nucleic acid in which the nucleotide corresponding to the nucleotide at position +515 of the Sh2 gene is a C; (o) a nucleic acid in which the nucleotide corresponding to the nucleotide at position +587 of the Sh2 gene is a C; (p) a nucleic acid in which the nucleotide corresponding to the nucleotide at position +678 of the Sh2 gene is an A; (q) a nucleic acid in which the nucleotide corresponding to the nucleotide at position +960 of the Sh2 gene is an A; (r) a nucleic acid in which the nucleotide corresponding to the nucleotide at position +1059 of the Sh2 gene is a G; (s) a nucleic acid in which the nucleotide corresponding to the nucleotide at position +1068 of the Sh2 gene is a G; (t) a nucleic acid in which the nucleotide A corresponding to the nucleotide at position +1081 of the Sh2 gene is absent; (u) a nucleic acid in which the nucleotide corresponding to the nucleotide at position +1473 of the Sh2 gene is a C; (v) a nucleic acid in which an additional T is present after the nucleotide at position +1505 of the Sh2 gene; (w) a nucleic acid in which an additional T is present after the nucleotide at position +1542 of the Sh2 gene; (x) a nucleic acid in which the nucleotide corresponding to the nucleotide at position +1867 of the Sh2 gene is a C; (y) a nucleic acid in which the nucleotide T corresponding to the nucleotide at position +2514 of the Sh2 gene is absent; (z) a nucleic acid in which an additional T is present after the nucleotide at position 2771 of the Sh2 gene; (ab) a nucleic acid in which the nucleotide corresponding to the nucleotide at position +2939 of the Sh2 gene is a G; (ac) a nucleic acid in which the nucleotide corresponding to the nucleotide at position +2983 of the Sh2 gene is a C; and (ad) a nucleic acid comprising the insertion of the sequence 5′-GTTTTTATTTA-3′ after the nucleotide corresponding to the nucleotide at position +3123 of the Sh2 gene. 2. The process as claimed in claim 1, wherein the nucleotide probe or the nucleotide primer makes it possible to discriminate between the presence of a first nucleic acid (1) and of a second nucleic acid (2), said nucleic acids (1) and (2) being chosen from the following: (a) Site −921: the nucleic acid (1) of sequence SEQ ID No. 2 in which the nucleotide at position 41 is a base G and the nucleic acid (2) of sequence SEQ ID No. 2 in which the nucleotide at position 41 is a base A; (b) Site −438: the nucleic acid (1) of sequence SEQ ID No. 3 in which the nucleotide at position 41 is a base G and the nucleic acid (2) of sequence SEQ ID No. 3 in which the nucleotide at position 41 is a base A; (c) Site −362: the nucleic acid (1) of sequence SEQ ID No. 4 in which the nucleotide at position 41 is a base A and the nucleic acid (2) of sequence SEQ ID No. 4 in which the nucleotide at position 41 is a base G; (d) Site −347: the nucleic acid (1) of sequence SEQ ID No. 5 in which the nucleotide at position 41 is a base T and the nucleic acid (2) of sequence SEQ ID No. 5 in which the nucleotide at position 41 is a base C; (e) Site −296: the nucleic acid (1) of sequence SEQ ID No. 6 in which the nucleotide at position 41 is a base T and the nucleic acid (2) of sequence SEQ ID No. 6 in which the nucleotide at position 41 is a base C; (f) Site −277: the nucleic acid (1) of sequence SEQ ID No. 7 in which the nucleotide at position 41 is a base T and the nucleic acid (2) of sequence SEQ ID No. 7 in which the nucleotide at position 41 is a base C; (g) Site −266: the nucleic acid (1) of sequence SEQ ID No. 8 in which the nucleotide at position 41 is a base C and the nucleic acid (2) of sequence SEQ ID No. 8 in which the nucleotide at position 41 is a base T; (h) Site −168: the nucleic acid (1) of sequence SEQ ID No. 9 in which the nucleotide at position 41 is a base A and the nucleic acid (2) of sequence SEQ ID No. 9 in which the nucleotide at position 41 is a base G; (i) Site −15: the nucleic acid (1) of sequence SEQ ID No. 10 in which the nucleotide at position 41 is a base A and the nucleic acid (2) of sequence SEQ ID No. 10 in which the nucleotide at position 41 is a base G; (j) Site +35: the nucleic acid (1) of sequence SEQ ID No. 11 in which the nucleotide at position 41 is a base T and the nucleic acid (2) of sequence SEQ ID No. 11 in which the nucleotide at position 41 is a base C; (k) Site +515: the nucleic acid (1) of sequence SEQ ID No. 12 in which the nucleotide at position 41 is a base C and the nucleic acid (2) of sequence SEQ ID No. 12 in which the nucleotide at position 41 is a base T; (l) Site +587: the nucleic acid (1) of sequence SEQ ID No. 13 in which the nucleotide at position 41 is a base C and the nucleic acid (2) of sequence SEQ ID No. 13 in which the nucleotide at position 41 is a base T; (m) Site +678: the nucleic acid (1) of sequence SEQ ID No. 14 in which the nucleotide at position 41 is a base A and the nucleic acid (2) of sequence SEQ ID No. 14 in which the nucleotide at position 41 is a base G; (n) Site +960: the nucleic acid (1) of sequence SEQ ID No. 15 in which the nucleotide at position 41 is a base A and the nucleic acid (2) of sequence SEQ ID No. 15 in which the nucleotide at position 41 is a base G; (o) Site +1059: the nucleic acid (1) of sequence SEQ ID No. 16 in which the nucleotide at position 41 is a base G and the nucleic acid (2) of sequence SEQ ID No. 16 in which the nucleotide at position 41 is a base C; (p) Site +1068: the nucleic acid (1) of sequence SEQ ID No. 17 in which the nucleotide at position 41 is a base G and the nucleic acid (2) of sequence SEQ ID No. 17 in which the nucleotide at position 41 is a base T; (q) Site +1473: the nucleic acid (1) of sequence SEQ ID No. 18 in which the nucleotide at position 41 is a base C and the nucleic acid (2) of sequence SEQ ID No. 18 in which the nucleotide at position 41 is a base T; (r) Site +1867: the nucleic acid (1) of sequence SEQ ID No. 19 in which the nucleotide at position 41 is a base C and the nucleic acid (2) of sequence SEQ ID No. 19 in which the nucleotide at position 41 is a base T; (s) Site +2939: the nucleic acid (1) of sequence SEQ ID No. 20 in which the nucleotide at position 41 is a base G and the nucleic acid (2) of sequence SEQ ID No. 20 in which the nucleotide at position 41 is a base T; (t) Site +2983: the nucleic acid (1) of sequence SEQ ID No. 21 in which the nucleotide at position 41 is a base C and the nucleic acid (2) of sequence SEQ ID No. 21 in which the nucleotide at position 41 is a base T; (u) Site −830 to −824: the nucleic acid (1) of sequence SEQ ID No. 23 and the nucleic acid (2) of sequence SEQ ID No. 22; (v) Site −580 to −573: the nucleic acid (1) of sequence SEQ ID No. 25 and the nucleic acid (2) of sequence SEQ ID No. 24; (w) Site +304: the nucleic acid (1) of sequence SEQ ID No. 27 and the nucleic acid (2) of sequence SEQ ID No. 26; (x) Site +1081: the nucleic acid (1) of sequence SEQ ID No. 29 and the nucleic acid (2) of sequence SEQ ID No. 28; (y) Site +1505: the nucleic acid (1) of sequence SEQ ID No. 31 and the nucleic acid (2) of sequence SEQ ID No. 30; (z) Site +1542: the nucleic acid (1) of sequence SEQ ID No. 33 and the nucleic acid (2) of sequence SEQ ID No. 32; (aa) Site +2514: the nucleic acid (1) of sequence SEQ ID No. 35 and the nucleic acid (2) of sequence SEQ ID No. 34; (ab) Site +2771: the nucleic acid (1) of sequence SEQ ID No. 37 and the nucleic acid (2) of sequence SEQ ID No. 36; and (ac) Site +3123: the nucleic acid (1) of sequence SEQ ID No. 39 and the nucleic acid (2) of sequence SEQ ID No. 38. 3. The process as claimed in claim 1, wherein: a) the nucleotide probe hybridizes specifically with a nucleic acid of a first allelic form of the polymorphic base or of the polymorphic nucleotide sequence defining a first allele of a polymorphic site of the Sh2 gene and does not hybridize with a nucleic acid of a second allelic form of the polymorphic base or of the polymorphic nucleotide sequence defining a second allele of a polymorphic site of the Sh2 gene; or b) the nucleotide primer hybridizes specifically with a nucleotide sequence contained in an Sh2 gene, said nucleotide sequence being located upstream of an allelic form of a polymorphic base or of a polymorphic nucleotide sequence the presence or absence of which defines an allele of a polymorphic site of the Sh2 gene. 4. The process as claimed in claim 1, wherein the improved phenotypic seed quality characteristics are chosen from the number of seeds per ear, the seed mass, the protein content of the seeds, the starch content of the seeds, the amylose content of the seeds and the protein/starch weight ratio in the seeds, or a combination of these phenotypic characteristics. 5. A process for determining the identity of the allele of a polymorphic site within a nucleic acid derived from an Sh2 gene for the purpose of selecting a plant having improved phenotypic seed quality characteristics, characterized in that it comprises a step consisting of characterizing the identity of the polymorphic base or of the polymorphic nucleotide sequence present at at least one nucleotide position of said nucleic acid corresponding to at least one of the nucleotides at position −921, −830 to −824, −580 to −573, −438, −362, −347, −296, −277, −266, −168, −15, +35, +304, +515, +587, +678, +960, +1059, +1068, +1081, +1473, +1505, +1542, +1867, +2514, +2771, +2939, +2983 and +3123 of the Sh2 gene of sequence SEQ ID No. 1. 6. The process as claimed in claim 5, which comprises carrying out the characterization of the identity of the polymorphic site by sequencing said nucleic acid. 7. The process as claimed in claim 5, characterized in that the characterization of the identity of the polymorphic site is carried out by hybridization of a nucleotide probe which hybridizes specifically with a polymorphic base or with a polymorphic nucleotide sequence defining an allele of a given polymorphic site of the Sh2 gene. 8. The process as claimed in claim 5, which comprises carrying out the characterization of the polymorphic site by extending a nucleotide primer which hybridizes specifically with a nucleotide sequence located upstream of a polymorphic base or of a polymorphic nucleotide sequence defining an allele of a given polymorphic site of an Sh2 gene. 9. The process as claimed in claim 5, which comprises, in order to select a plant having a modified number of seeds, determining the identity of the base or of a sequence of bases present at at least one nucleotide position of said nucleic acid corresponding to at least one of the nucleotides at position −168, +1473, +1542 and +2983 of the Sh2 gene of sequence SEQ ID No. 1. 10. The process as claimed in claim 5, which comprises, in order to select a plant with a modified seed mass, determining the identity of the base or of a sequence of bases present at at least one nucleotide position of said nucleic acid corresponding to at least one of the nucleotides at position −168, +1473, +1542 and +2983 of the Sh2 gene of sequence SEQ ID No. 1. 11. The process as claimed in claim 5, which comprises, in order to select a plant having a modified protein content in the seed, determining the identity of the base or of a sequence of bases present at at least one nucleotide position of said nucleic acid corresponding to at least one of the nucleotides at position −168, +1473, +1542, +2983, −830 to −824, −362, −347, −296, −15, +515, +587, +1068, +1505 and +2939 of the Sh2 gene of sequence SEQ ID No. 1. 12. The process as claimed in claim 5, which comprises, in order to select a plant having a modified starch content in the seed, determining the identity of the base or of a sequence of bases present at at least one nucleotide position of said nucleic acid corresponding to at least one of the nucleotides at position −830 to −824, −362, −347, −296, −15, +515, +587, +1068, +1505 and +2939 of the Sh2 gene of sequence SEQ ID No. 1. 13. The process as claimed in claim 5, which comprises, in order to select a plant having a modified amylose content in the seeds, determining the identity of the base or of a sequence of bases present at at least one nucleotide position of said nucleic acid corresponding to at least one of the nucleotides at position −438, −266, +678, +960, −921, −580 to −573, −277, +35, +304, +1059, +1081, +1867, +2514, +2771 and +3123 of the Sh2 gene of sequence SEQ ID No. 1. 14. The process as claimed in claim 5, which comprises, in order to select a plant having a modified protein/starch ratio in the seed, determining the identity of the base or of a sequence of bases present at at least one nucleotide position of said nucleic acid corresponding to at least one of the nucleotides at position −168, +1473, +1542, +2983, −830 to −824, −362, −347, −296, −15, +515, +587, +1068, +1505 and +2939 of the Sh2 gene of sequence SEQ ID No. 1. 15. The process as claimed in claim 5, which is carried out on the DNA taken from plants at the plantlet stage and/or at the early stage and/or at the vegetative stage. 16. The process as claimed in claim 5, wherein the plant is a cereal. 17. The process as claimed in claim 16, wherein the plant is maize or sorghum. 18. A nucleotide probe or a nucleotide primer, characterized in that it makes it possible to distinguish between the various alleles of a polymorphic site at at least one of the positions −921, −830 to −824, −580 to −573, −438, −362, −347, −296, −277, −266, −168, −15, +35, +304, +515, +587, +678, +960, +1059, +1068, +1081, +1473, +1505, +1542, +1867, +2514, +2771, +2939, +2983 and +3123 of the Sh2 gene of sequence SEQ ID No. 1. 19. The use process which comprises marking at least one polymorphic site of the Sh2 gene with a probe or a primer as claimed in claim 18. 20. A diagnostic set or kit to predict the phenotypic plant seed quality characteristics, which comprises: a) a probe or a plurality of probes or primers as claimed in claim 18; and b) where appropriate, reagents required to carry out a hybridization or amplification reaction. 21. A nucleic acid as claimed in claim 39 capable of conferring on a plant a modified number of seeds compared to the reference “wild-type” maize, wherein said nucleic acid comprises the allelic form associated with the expression of the modified phenotypic seed quality characteristic at at least one polymorphic site chosen from the polymorphic sites −168, +1473, +1542 and +2983 of the Sh2 gene of sequence SEQ ID No. 1. 22. A nucleic acid as claimed in claim 39 capable of conferring on a plant a modified seed mass compared to the reference “wild-type” maize, wherein said nucleic acid comprises the allelic form associated with the expression of the modified phenotypic seed quality characteristic at at least one polymorphic site chosen from the polymorphic sites −168, +1473, +1542 and +2983 of the Sh2 gene of sequence SEQ ID No. 1. 23. A nucleic acid as claimed in claim 39 capable of conferring on a plant a modified protein content in the seeds compared to the reference “wild-type” maize, wherein said nucleic acid comprises the allelic form associated with the expression of the modified phenotypic seed quality characteristic at at least one polymorphic site chosen from the polymorphic sites −168, +1473, +1542, +2983, −830 to −824, −362, −347, −296, −15, +515, +1068, +1505 and +2939 of the Sh2 gene of sequence SEQ ID No. 1. 24. A nucleic acid as claimed in claim 39 capable of conferring on a plant a modified starch content in the seeds compared to the reference “wild-type” maize, wherein said nucleic acid comprises the allelic form associated with the expression of the modified phenotypic seed quality characteristic, at at least one polymorphic site chosen from the polymorphic sites −830 to −824, −362, −347, −296, −15, +515, +587, +1068, +1505 and +2939 of the Sh2 gene of sequence SEQ ID No. 1. 25. A nucleic acid as claimed in claim 39 capable of conferring on a plant a modified amylose content in the seeds compared to the reference “wild-type” maize, wherein said nucleic acid comprises the allelic form associated with the expression of the modified phenotypic seed quality characteristic at at least one polymorphic site chosen from the polymorphic sites −438, −266, +678, +960, −921, −580 to −573, −277, +35, +304, +1059, +1081, +1867, +2514, +2771 and +3123 of the Sh2 gene of sequence SEQ ID No. 1. 26. A nucleic acid as claimed in claim 39 capable of conferring on a plant a modified protein/starch ratio in the seed compared to the reference “wild-type” maize, wherein said nucleic acid comprises the allelic form associated with the expression of the modified phenotypic seed quality characteristic at at least one polymorphic site chosen from the polymorphic sites −168, +1473, +1542, +2983, −830 to −824, −362, −347, −296, −15, +515, +587, +1068, +1505 and +2939 of the Sh2 gene of sequence SEQ ID No. 1. 27. A recombinant vector comprising a nucleic acid as claimed in claim 39. 28. A method which comprises transforming a host cell with a nucleic acid or with a recombinant vector comprising a nucleic acid, and wherein the nucleic acid is a nucleic acid as claimed in claim 39. 29. A method as claimed in claim 28, wherein the host cell is a bacterial host cell or plant host cell. 30. A host cell transformed with a nucleic acid or with a recombinant vector comprising a nucleic acid, wherein the nucleic acid as claimed in claim 39. 31. The transformed host cell as claimed in claim 30, which is a bacterial cell or a plant cell. 32. A method which comprises producing seeds with improved industrial or agrofoods qualities with a) a nucleic acid, b) a recombinant vector comprising a nucleic acid, c) a host cell transformed with a nucleic acid, or d) a host cell transformed with a recombinant vector comprising a nucleic acid, wherein the nucleic acid is a nucleic acid as claimed in claim 39, and the host cell is, optionally, a bacterial cell or a plant cell. 33. A transformed plant comprising a plurality of host cells as claimed in claim 30. 34. A process for obtaining a transformed plant capable of producing seeds with improved industrial or agrofoods qualities, which comprises the following steps: a) transforming at least one plant cell with a nucleic acid or with a recombinant vector comprising a nucleic acid, wherein the nucleic acid is a nucleic acid as claimed in claim 39; b) selecting the transformed cells obtained in step a) which have integrated into their genome at least one copy of a nucleic acid as claimed in claim 39; and c) regenerating a transformed plant from the transformed cells obtained in step b). 35. A transformed plant or a part of a transformed plant which can be obtained by the process as claimed in claim 34. 36. A product of transformation of a grain or seed as claimed in claim 35. 37. An antibody specific for an SH2 polypeptide encoded by a nucleic acid as claimed in claim 39. 38. A pack or kit for diagnosing phenotypic plant seed quality characteristics, which comprises: a) an antibody or a combination of antibodies as claimed in claim 37; b) where appropriate, the reagents required for the detection of a complex formed between said antibody or antibodies and an SH2 polypeptide. 39. A nucleic acid capable of conferring on a plant: a) a modified number of seeds compared to a reference “wild-type” maize, b) a modified seed mass compared to a reference “wild-type” maize, c) a modified protein content in the seeds compared to a reference “wild-type” maize, d) a modified starch content in the seeds compared to a reference “wild-type” maize, e) a modified amylose content in the seeds compared to a reference “wild-type” maize, or f) a modified protein/starch ratio in the seed compared to a reference “wild-type” maize; wherein said nucleic acid comprises the allelic form associated with the expression of the modified phenotype seed quality characteristic, for each of a) and b), as defined in the present description, at at least one polymorphic site chosen from the polymorphic sites −168, +1473, +1542 and +2983 of the Sh2 gene of sequence SEQ ID No. 1; for c), as defined in the present description, at at least one polymorphic site chosen from the polymorphic sites −168, +1473, +1542, +2983, −830 to −824, −362, −347, −296, −15, +515, +587, +1068, +1505 and +2939 of the Sh2 gene of sequence SEQ ID No. 1; for d), as defined in claim 1, at at least one polymorphic site chosen from the polymorphic sites −830 to −824, −362, −347, −296, −15, +515, +587, +1068, +1505 and +2939 of the Sh2 gene of sequence SEQ ID No. 1; for e), as defined in claim 1, at at least one polymorphic site chosen from the polymorphic sites −438, −266, +678, +960, −921, −580 to −573, −277, +35, +304, +1059, +1081, +1867, +2514, +2771 and +3123 of the Sh2 gene of sequence SEQ ID No. 1; and for f), as defined in claim 1, at at least one polymorphic site chosen from the polymorphic sites −168, +1473, +1542, +2983, −830 to −824, −362, −347, −296, −15, +515, +587, +1068, +1505, and +2939 of the Sh2 gene of sequence SEQ ID No. 1. |
<SOH> FIELD OF THE INVENTION <EOH>The present invention relates to the field of the selection of varieties of plants having improved agronomic characteristics, in particular improved phenotypic seed quality characteristics. It relates to the detection of the improved phenotypic seed quality characteristics by analysis of the polymorphism of an Sh2 gene in order to select plants with improved seed quality, and also to means for implementing this detection. |
<SOH> SUMMARY OF THE INVENTION <EOH>The invention provides, for the first time, a set of means for selecting plant varieties for their improved phenotypic seed quality characteristics by analyzing polymorphisms newly identified in the Sh2 gene, which polymorphisms are statistically associated with a precise phenotypic seed quality characteristic, or with a combination of phenotypic seed quality characteristics. It has in fact been shown, according to the invention, that a given allele of each of the new polymorphic sites of the Sh2 gene is statistically associated with the expression of one or more phenotypic characteristics defining seed quality. A subject of the invention is the use of a nucleotide probe or primer in a process for selecting plants having improved phenotypic seed quality characteristics, characterized in that said nucleotide probe or said nucleotide primer allows the detection of a polymorphic base or of a polymorphic nucleotide sequence defining an allele of a polymorphic site of the Sh2 gene of sequence SEQ ID No. 1, said polymorphic base or said polymorphic nucleotide sequence being contained in a nucleic acid included in the Sh2 gene, chosen from the nucleic acids comprising a polymorphic nucleotide site associated with a characteristic or a combination of phenotypic characteristics linked to seed quality, in particular the number of seeds per ear, the mass of the mature seed, the protein content of the seed, the starch content of the seed, the amylose content of the seed or the protein/starch weight ratio in the seed. It also relates to a process for determining the identity of the allele of a polymorphic site within a nucleic acid derived from an Sh2 gene for the purpose of selecting a plant having improved phenotypic seed quality characteristics, characterized in that it comprises a step consisting of characterizing the identity of the polymorphic base or of the polymorphic nucleotide sequence present at at least one nucleotide position of said nucleic acid corresponding to at least one of the nucleotides included in a newly identified polymorphic nucleotide site of the Sh2 gene. According to this process, the determination of the identity of the allele of a polymorphic site or of a combination of polymorphic sites makes it possible to predict the seed quality phenotype of the analyzed plant, without requiring direct analysis of the phenotypic characteristics themselves. The invention also relates to nucleotide probes and primers for determining the allelic form of a polymorphic site of the Sh2 gene, useful in particular as means for determining the identity of the polymorphic base or of the polymorphic nucleotide sequence at the polymorphic site associated with a phenotypic seed quality characteristic or with a combination of phenotypic seed quality characteristics. A subject of the invention is also a nucleic acid derived from the Sh2 gene and comprising at least one polymorphic site as defined in the present description, and also recombinant vectors comprising such a nucleic acid. The invention also relates to a host cell transformed with a nucleic acid or a recombinant vector described above, preferably a bacterial or plant host cell. It also relates to a plant transformed with a nucleic acid or with a recombinant vector described above. It also relates to antibodies directed specifically against an SH2 polypeptide encoded by a nucleic acid derived from the Sh2 gene comprising a polymorphic site as defined in the present description, and also to a pack or kit comprising one of these antibodies or else a combination of several of these antibodies. |
Process for the manufacture of 2-keto-l-gulonic acid |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.