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The present invention relates to a speaker unit, and more particularly to a speaker unit having improved water-proof properties.
In a conventional water-proof speaker unit. the water-proof/water-resistant material is selected for any vibration members which may be exposed, such as a vibrating edge. a diaphragm. etc., or such members are coated with a water-proof material. In addition, the rear side of the diaphragm cabinet is made water-proof and/or water resistant, with the goal being to obtain a water-proof speaker unit.
In a conventional water-proof speaker unit of the type described above, the selection of a water-proof material for the vibrating members per se will result in a high cost, and the coating of the members with a water-proof material will result in an increase in the number of manufacturing steps while also increasing the material's cost per se. In either case the resulting product is expensive.
In addition, even aside from cost. it is very difficult to provide a water-proof property to a brocade lead wire for supplying a drive current to the voice coil.
It is, therefore, an object of the present invention to provide an inexpensive water-proof speaker unit capable of providing not only the speaker unit structure but also the brocade lead wire with acceptable water-proof properties. | {
"pile_set_name": "USPTO Backgrounds"
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The invention described herein relates generally to semiconductor chip manufacturing processes. In particular, the invention relates to improved electrical contact structures and the methods for their manufacture.
One step in the manufacture of integrated circuit devices is known as xe2x80x9cpackagingxe2x80x9d and involves mechanical and environmental protection of a semiconductor chip which is at the heart of the integrated circuit as well as electrical interconnection between predetermined locations on the silicon chip and external electrical terminals.
Presently, a number of conventional technologies are employed for packaging semiconductors. Wire bonding, tape automatic bonding (TAB), and flip chip connection are among the packaging techniques used in the industry.
Wire bonding employs heat and ultrasonic energy to weld gold bonding wires between bond pads on the chip and contacts on the package.
Tape automatic bonding (TAB) employs a copper foil tape instead of bonding wire. The copper foil tape is configured for each specific die and package combination and includes a pattern of copper traces suited thereto. The individual leads may be connected individually or as a group to the various bond pads on the chip.
Flip chips are integrated circuit dies which have solder bumps formed on top of the bonding pads, thus allowing the die to be xe2x80x9cflippedxe2x80x9d circuit side down and directly soldered to a substrate. Wire bonds are not required and considerable savings in package footprint may be realized.
Additionally, a so-called xe2x80x9cT-contactxe2x80x9d connector packaging method is employed by some manufacturers. This xe2x80x9cT-contactxe2x80x9d method is described in some detail in U.S. Pat. No. 6,040,235 which is hereby incorporated by reference.
Each of the above-described technologies has certain limitations. Both wire bonding and TAB bonding are prone to bad bond formation and subject the die to relatively high temperatures and mechanical pressures. Additionally, wire bond and TAB technologies are problematic from a package size viewpoint, producing integrated circuit devices having a die-to-package area ratio ranging from about 10% to 60%.
The flip-chip technology actually refers to methods of interconnection rather than packaging methods. However, flip-chip interconnection suffers from a number of limitations. For example, variations in solder bump uniformity and thermal expansion mismatching present problems. These difficulties limit the use of available substrates to silicon materials or materials which have thermal expansion characteristics similar to those of silicon.
The xe2x80x9cT-contactxe2x80x9d method yields an interconnect structure that is extremely sensitive to process conditions and suffers from reliability problems associated with xe2x80x9cT-contactxe2x80x9d disassociation. These problems will be described in greater detail hereinbelow.
The difficulties of a known xe2x80x9cT-contactxe2x80x9d connection can be illustrated with respect to FIGS. 1(a)-1(d). FIG. 1(a) is a cross-section view depicting an edge portion of a semiconductor die 100 that has just been separated from a semiconductor wafer in a singulation process. A silicon substrate 101 having an integrated circuit formed on its surface has been sandwiched between two glass layers 102, 103. Also depicted are the backside solder balls 104 that are used to interconnect the die 100 to other electrical systems. These backside solder balls 104 are connected to front side electrical contact pads 105 by a specialized electrical connection called a xe2x80x9cT-contactxe2x80x9d. In this view, one such interconnection is shown by the metal layer 107 which makes electrical contact with one of the backside solder balls 104.
FIG. 1(b) is a close-up view depicting the xe2x80x9cT-contactxe2x80x9d electrical connection shown in the circular view 106 of FIG. 1(a). The backside glass layer 103 affixed to the substrate 101 with a thin epoxy layer 113. On the other side (the front side) of the silicon substrate 101 is a metal bonding pad 111 that is interconnected to the electronic circuitry formed on the silicon substrate 101. Also, on top of the silicon substrate 101 is a first passivation layer 112 that is typically formed of SiO2. Some manufacturers add a second passivation layer 114, formed of benzo-cyclo-butene (BCB), onto the first passivation layer 112. The metal bonding pad 111 is accessible through an opening in the passivation layers 112, 114. Into the opening in the passivation layers 112, 114 is deposited a metal plug 115. Such plugs are commonly formed of Alxe2x80x94Sixe2x80x94Cu compounds (e.g., 94.5% Al, 5.0% Si, and 0.5% Cu). A tab 116 is typically formed over a portion of the passivating layers 112, 114 as shown. The tab 116 portion includes an exposed facet 117 which has an exposed surface.
A top protective layer 102 is attached to the top surface of the substrate 101 using a thin layer of epoxy 118. A metal layer 107 formed on the side of the die 100 forms an electrical contact with the exposed facet 117 thereby forming a conducting pathway to a corresponding solder ball (not shown) on the bottom of the die 100. Commonly, the metal layer 107 is formed using a different material than the plug 115 and tab 116 materials. In one example, the metal layer 107 is constructed of a deposited layer of aluminum/copper (Al/Cu) material. Many other process steps are used to construct such structures. A full description of an example process for constructing such structures is included in the previously referenced U.S. Pat. No. 6,040,235.
Although suitable for some purposes, the aforementioned implementation has some serious drawbacks which will be described with respect to the simplified schematic illustrations of FIGS. 1(c) and 1(d). FIG. 1(c) schematically depicts a simplified cross-section view of an intact xe2x80x9cT-contactxe2x80x9d. A metal layer 151 is shown in electrical contact with a tab 152 that is electrically connected to a bonding pad (e.g., as in FIG. 1(b)). The connection between the metal layer 151 and the tab 152 is called a xe2x80x9cT-contactxe2x80x9d 153. Under processing conditions, and also under some operating conditions the xe2x80x9cT-contactxe2x80x9d 153 can undergo significant stresses. Under some conditions, a separation can occur in the xe2x80x9cT-contactxe2x80x9d 153 causing electrical connection failure and consequently chip failure. This situation is schematically depicted in FIG. 1(d), which shows a simplified cross-section view of an disconnected xe2x80x9cT-contactxe2x80x9d 154. The interconnect metal layer 151xe2x80x2 is shown with a break in electrical contact to the contact 152xe2x80x2, thereby breaking the electrical connection to the bonding pad (not shown). The depicted xe2x80x9cT-contactsxe2x80x9d are very vulnerable to this kind of connection failure. Among the advantages of the disclosed invention is that it substantially reduces the aforementioned type of connection failure.
What is needed is a manufacturable robust electrical connection that does not suffer from xe2x80x9cT-contactxe2x80x9d failure. Also needed are methodologies for fabricating such structures. The principles of the present invention are directed toward an improved electrical connection and methodologies for its fabrication.
In accordance with the principles of the present invention, the invention includes, among other things, a robust electrical connection and methods for its fabrication.
In one embodiment a semiconductor device having a plurality of edge mounted electrical contacts is disclosed. The embodiment includes an integrated circuit formed on a semiconductor substrate with first and second surfaces and edges. The first surface includes electrical contact pads electrically connected with the integrated circuit. The first surface of the semiconductor substrate includes a top protective layer that has a surface portion extending beyond the edges of the semiconductor substrate. The surface portion of the top protective layer includes electrical contact pads that are electrically connected with electrical contact pad extensions and with the integrated circuit. The second surface of the semiconductor substrate includes a multiplicity of backside electrical connectors that are in overlapping electrical contact with corresponding electrical contact pad extensions forming lap joint electrical connections between the backside electrical connectors and the corresponding electrical contact pad extensions.
Another embodiment includes a method embodiment for forming an edge mounted electrical connection to a semiconductor die. Such embodiment involves providing a substrate having a plurality of semiconductor dies and associated electrical contact pads formed thereon. Lap joint electrical connections are formed to the associated electrical contact pads. Electrical connections to the lap joints are formed and the substrate is singulated into a plurality of individual dies.
Another embodiment discloses a method for producing electrical die contact structures for integrated circuit devices. The method involves providing a plurality of integrated circuits on a semiconductor wafer having a front side and a backside. Each of the integrated circuits are delineated from other integrated circuits on the wafer by a plurality of saw streets and each integrated circuit includes a multiplicity of electrical contact pads with contact pad extensions that extend into the saw streets. A protective layer is attached to a front side surface of the wafer. Material is removed from the backside of the wafer in the saw streets until a bottom surface of the contact pad extensions is exposed defining notches along edges of the integrated circuit devices. Backside electrical connections are formed such that a portion of the backside electrical connections overlaps the bottom surface of the contact pad extensions. Solderable electrical contacts that are electrically interconnected with the backside electrical connections are formed on the backside of the wafer. The wafer is separated into a plurality of individual integrated circuit devices.
These and other aspects of the invention will be disclosed in greater detail in the following detailed description. | {
"pile_set_name": "USPTO Backgrounds"
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1. Field of the Invention
The present invention relates to a sheet nipping mechanism applicable to an image forming apparatus, such as electrophotographic copiers, laser printers or facsimile machines. The present invention also relates to an image forming apparatus provided with the sheet nipping mechanism.
2. Description of the Related Art
There has heretofore been known a sheet nipping mechanism applied to an image forming apparatus as represented by electrophotographic copiers, laser printers or facsimile machines. This nipping mechanism is provided in a fixing device disposed downstream of a transfer belt for transporting a sheet having a toner image transferred thereonto through a photosensitive drum. The nipping mechanism comprises a fixing roller having a heater embedded therein, and a pressure roller disposed in opposed relation to the fixing roller while allowing the lower portion thereof to be in close contact with the fixing roller. The fixing roller is formed in a so-called reverse-crown (bow-tie-like, concave or reverse-tapered) shape whose diameter is gradually reduced in a direction extending from each of the opposite transverse ends to the central region of the fixing roller.
Thus, when a sheet is sandwiched between the fixing and pressure rollers, both transverse edges of the sheet are nipped more strongly than its central region to thereby receive forces oriented outward in opposite directions, respectively. The resulting tensile force prevents the sheet from being crimpled.
Such a nipping mechanism is disclosed, for example, in Japanese Parent Laid-Open Publication Nos. 9-114292 and 2000-293060. Specifically, the Japanese Parent Laid-Open Publication No. 9-114292 discloses a nipping mechanism in which each of fixing and pressure rollers is formed in a reverse-crown shape designed such that the amount of reverse crown in each of the rollers is set at 100 μm or more, and the total amount of reverse crown in the rollers is set in the range of 250 to 500 μm. Further, a guide plate to be disposed between a transfer belt and a nip zone is designed such that the height position of the guide plate is located below a line extending in a direction of the tangent to the nip zone between the fixing and pressure rollers. The publication describes that the nipping mechanism employing the above measure could drastically reduce crimples otherwise occurring on a sheet.
Further, the Japanese Parent Laid-Open Publication No. 2000-293060 discloses a nipping mechanism in which an embossed protrusion is formed in the transversely central region of a guide plate to be disposed between a transfer belt and a nip zone. The shape of the embossed protrusion is designed to guide a sheet being transported such that the trailing edge of the sheet is lowered as it gets close to the nip zone. The publication describes that the nipping mechanism employing the embossed protrusion can prevent image distortions due to bouncing in the trailing edge of a large-size sheet.
However, under the recent circumstances where the speeding up in the sheet-feeding and sheet-discharge to/from an image forming apparatus are driven forward, such a high-speed image forming apparatus is essentially required to have more enhanced nipping conditions for a sheet in a nip zone defined by fixing and pressure rollers. The conventional nipping mechanisms as disclosed in the Japanese Parent Laid-Open Publication Nos. 9-114292 and 2000-293060 cannot reliably prevent crimples occurring on a sheet in a nip zone and distortions in a transferred image due to the bouncing phenomenon, and it has been strongly expected to provide an improved nipping mechanism. | {
"pile_set_name": "USPTO Backgrounds"
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Genomic damage, if left unrepaired, can lead to malignant transformation, or cell death by senescence (aging), necrosis or apoptosis. Among the variables that can affect the ultimate biological consequence of DNA damage to a particular cell are (i) the amount, type, and location of the DNA damage and (ii) the efficiency and bioavailability of the cellular DNA repair mechanism.
The activation of poly(ADP-ribose) polymerase (PARP) by DNA strand breaks is often one of the first cellular responses to DNA damage. PARP catalyzes the conversion of nicotinamide adenine dinucleotide (NAD) to multi-branched polymers containing up to 200 ADP-ribose residues. Increases in polymer levels of more than 100-fold may occur within minutes of DNA damage. Once synthesized, polymers are rapidly turned over, being converted to free ADP-ribose by the action of poly(ADP-ribose) glycohydrolase (PARG) (1). An ADP-ribosyl protein lyase has been proposed to catalyze removal of protein-proximal ADP-ribose monomers (2). FIG. 1 illustrates these processes schematically.
The process of activating PARP upon DNA damage can rapidly lead to energy depletion because each ADP-ribose unit transferred by PARP consumes one molecule of NAD, which in turn, requires six molecules of ATP to regenerate NAD. Additionally, NAD is a key carrier of electrons needed to generate ATP via electron transport and oxidative phosphorylation or by glycolysis. The overactivation of PARP due to substantial DNA damage can significantly deplete the cellular pools of NAD and ATP (3). ADP-ribose polymer metabolism, and thus PARP and PARG have been linked to the enhancement of DNA repair (4), limitation of malignant transformation (5), enhancement of necrotic cell death (6), and involvement in programmed cell death (7). To date, studies of the structure and function of the enzymes of ADP-ribose polymer metabolism have been mainly limited to PARP (8). Little is known about the function and regulation of PARG. | {
"pile_set_name": "USPTO Backgrounds"
} |
A variety of surgical instruments include a tissue cutting element and one or more elements that transmit RF energy to tissue (e.g., to coagulate or seal the tissue). An example of such a device is the ENSEAL® Tissue Sealing Device by Ethicon Endo-Surgery, Inc., of Cincinnati, Ohio. Further examples of such devices and related concepts are disclosed in U.S. Pat. No. 6,500,176 entitled “Electrosurgical Systems and Techniques for Sealing Tissue,” issued Dec. 31, 2002, the disclosure of which is incorporated by reference herein; U.S. Pat. No. 7,112,201 entitled “Electrosurgical Instrument and Method of Use,” issued Sep. 26, 2006, the disclosure of which is incorporated by reference herein; U.S. Pat. No. 7,125,409, entitled “Electrosurgical Working End for Controlled Energy Delivery,” issued Oct. 24, 2006, the disclosure of which is incorporated by reference herein; U.S. Pat. No. 7,169,146 entitled “Electrosurgical Probe and Method of Use,” issued Jan. 30, 2007, the disclosure of which is incorporated by reference herein; U.S. Pat. No. 7,186,253, entitled “Electrosurgical Jaw Structure for Controlled Energy Delivery,” issued Mar. 6, 2007, the disclosure of which is incorporated by reference herein; U.S. Pat. No. 7,189,233, entitled “Electrosurgical Instrument,” issued Mar. 13, 2007, the disclosure of which is incorporated by reference herein; U.S. Pat. No. 7,220,951, entitled “Surgical Sealing Surfaces and Methods of Use,” issued May 22, 2007, the disclosure of which is incorporated by reference herein; U.S. Pat. No. 7,309,849, entitled “Polymer Compositions Exhibiting a PTC Property and Methods of Fabrication,” issued Dec. 18, 2007, the disclosure of which is incorporated by reference herein; U.S. Pat. No. 7,311,709, entitled “Electrosurgical Instrument and Method of Use,” issued Dec. 25, 2007, the disclosure of which is incorporated by reference herein; U.S. Pat. No. 7,354,440, entitled “Electrosurgical Instrument and Method of Use,” issued Apr. 8, 2008, the disclosure of which is incorporated by reference herein; U.S. Pat. No. 7,381,209, entitled “Electrosurgical Instrument,” issued Jun. 3, 2008, the disclosure of which is incorporated by reference herein; U.S. Pub. No. 2011/0087218, entitled “Surgical Instrument Comprising First and Second Drive Systems Actuatable by a Common Trigger Mechanism,” published Apr. 14, 2011, now U.S. Pat. No. 8,939,974, issued Jan. 27, 2015, the disclosure of which is incorporated by reference herein; and U.S. patent application Ser. No. 13/151,481, entitled “Motor Driven Electrosurgical Device with Mechanical and Electrical Feedback,” filed Jun. 2, 2011, published as U.S. Pub. No. 2012/0116379, now U.S. Pat. No. 9,161,803, issued Oct. 20, 2015, the disclosure of which is incorporated by reference herein.
In addition, a variety of surgical instruments include a shaft having an articulation section, providing enhanced positioning capabilities for an end effector that is located distal to the articulation section of the shaft. Examples of such devices include various models of the ENDOPATH® endocutters by Ethicon Endo-Surgery, Inc., of Cincinnati, Ohio. Further examples of such devices and related concepts are disclosed in U.S. Pat. No. 7,380,696, entitled “Articulating Surgical Stapling Instrument Incorporating a Two-Piece E-Beam Firing Mechanism,” issued Jun. 3, 2008, the disclosure of which is incorporated by reference herein; U.S. Pat. No. 7,404,508, entitled “Surgical Stapling and Cutting Device,” issued Jul. 29, 2008, the disclosure of which is incorporated by reference herein; U.S. Pat. No. 7,455,208, entitled “Surgical Instrument with Articulating Shaft with Rigid Firing Bar Supports,” issued Nov. 25, 2008, the disclosure of which is incorporated by reference herein; U.S. Pat. No. 7,506,790, entitled “Surgical Instrument Incorporating an Electrically Actuated Articulation Mechanism,” issued Mar. 24, 2009, the disclosure of which is incorporated by reference herein; U.S. Pat. No. 7,549,564, entitled “Surgical Stapling Instrument with an Articulating End Effector,” issued Jun. 23, 2009, the disclosure of which is incorporated by reference herein; U.S. Pat. No. 7,559,450, entitled “Surgical Instrument Incorporating a Fluid Transfer Controlled Articulation Mechanism,” issued Jul. 14, 2009, the disclosure of which is incorporated by reference herein; U.S. Pat. No. 7,654,431, entitled “Surgical Instrument with Guided Laterally Moving Articulation Member,” issued Feb. 2, 2010, the disclosure of which is incorporated by reference herein; U.S. Pat. No. 7,780,054, entitled “Surgical Instrument with Laterally Moved Shaft Actuator Coupled to Pivoting Articulation Joint,” issued Aug. 24, 2010, the disclosure of which is incorporated by reference herein; U.S. Pat. No. 7,784,662, entitled “Surgical Instrument with Articulating Shaft with Single Pivot Closure and Double Pivot Frame Ground,” issued Aug. 31, 2010, the disclosure of which is incorporated by reference herein; and U.S. Pat. No. 7,798,386, entitled “Surgical Instrument Articulation Joint Cover,” issued Sep. 21, 2010, the disclosure of which is incorporated by reference herein.
While several medical devices have been made and used, it is believed that no one prior to the inventors has made or used the invention described in the appended claims.
The drawings are not intended to be limiting in any way, and it is contemplated that various embodiments of the technology may be carried out in a variety of other ways, including those not necessarily depicted in the drawings. The accompanying drawings incorporated in and forming a part of the specification illustrate several aspects of the present technology, and together with the description serve to explain the principles of the technology; it being understood, however, that this technology is not limited to the precise arrangements shown. | {
"pile_set_name": "USPTO Backgrounds"
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The present invention relates to a device for fastening at least two members to each other.
More particularly, the invention relates to devices for fastening two members using a screw and a transfer nut which are adapted in order to engage in recesses in the said members.
Devices of this type are already known in the state of the art, for example from document FR-A-2,351,297, in which the transfer nut is fixed to the end of branches of a fastening member, these branches being deformable during tightening of this nut onto the screw in order to abut against a bearing surface of one of the members in order to hold this nut in position and to fix the members together.
However, these devices have a number of drawbacks, owing to the complexity of their structure and to their cost.
A cap nut is also known in the state of the art, for example from document FR-A-1,429,545, consisting of a body forming the nut proper, which is internally threaded, and by an elastic cage of small thickness, characterised in that the cage has expandable elastic lugs arranged and shaped so as to engage in recesses or notches made in a flange of the body of the nut and to produce anchoring on the edge of the hole by virtue of the axial displacement of this body of the nut when the latter is tightened, the point of curvature of the tabs carried by the cage being situated towards the outside at a distance from the hole of the cage intended for the screw such that the tabs are inclined and diverge in the direction of the body of the nut, the diameter of their periphery being, in the untightened state, tests less than the diameter of the hole.
However, this cap nut has a number of drawbacks, because it does not remain in position when the screw is removed. | {
"pile_set_name": "USPTO Backgrounds"
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This invention relates to a novel flag-tag device and to an improved ball and socket coupling for such devices.
In prior flag type games, a flag has been attached to the belt or other waist encircling arrangement of a wearer by releasable coupling parts in such manner that the flag is pulled away from its attachment to the belt by a predetermined pull-away tension on the belt serving to detach the flag coupling part from the cooperative belt coupling part. Usually these coupling parts have been designed as cooperating ball and socket devices, as shown in U.S. Pat. Nos. 2,966,356; 3,251,109; 3,345,070; and 3,579,745. Such coupling parts are usually formed of plastic material. It has been found that where resiliency of the socket part is relied upon for the attachment and release of the ball part, the resiliency varies under different conditions of climate and particularly in colder climates, where the socket part may shrink to such a degree that the pullaway force to separate the coupling parts becomes excessive. Enlarging the socket or female part as compensation also results in non-uniform performances of the coupling in varied climates.
Bifurcating the ball does not fully solve this problem and reduces the durability of the ball.
Another problem associated with the prior art ball and socket designs for the coupling portion of the device is the excessive force required to re-insert the ball in the socket during the game, which is particularly a problem for younger players and can delay the game, even with older players. | {
"pile_set_name": "USPTO Backgrounds"
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Liver is an important organ which participates in most of metabolisms and regulation thereof in a living body including metabolization of carbohydrate, protein, lipid, nucleic acid, vitamin, and hormone, production of bilirubin, secretion of bile, detoxification of endogeneous or exogeneous substances by oxidation, reduction and conjugation .degree. and excretion of them into bile or water-solubilization of them to accelerate excretion into urine. These functions may be damaged by toxic substances, medicines, alcohols, radiation and viruses to cause diseases such as medicinal liver diseases, alcoholic liver diseases, virus-caused hepatitis, fatty liver, jaundice, and the like. If these diseases are protracted, sometimes liver cirrhosis and liver cancer are developed.
However, medicines effective to cure these liver diseases have not yet been developed and at present, treatments therefor are only alimentotherapy and rest cure.
On the other hand, recently, it has been reported that pyrrolo quinoline quinone and pyrrolo quinoline quinone salts (hereinafter generically referred to as "PQQ") found as novel coenzymes of oxido-reductase inhibit liver diseases when administered intraperitoneally. (Japanese Patent Kokai No. 63-192717).
However, this activity was not observed when they are orally administered. (Watanabe et al, "Current Therapeutic Research", Vol. 44, No. 6, pp 896-901 (1988)). Furthermore, it has been clarified that "PQQ" has kidney toxicity (Watanabe et al, "Hiroshima J.Med. Sci.", Vo.1 38, No. 1, pp49-51 (1989)).
Thus, it has been desired to develop medicines which are low in toxicity, especially kidney toxicity, high in membrane permeability and can inhibit liver diseases not only through intraperitoneal administration, but also oral administration. | {
"pile_set_name": "USPTO Backgrounds"
} |
The invention concerns a sorter with a symmetric screen which is arranged concentrically in an essentially symmetric housing. In the interior of the housing there is concentrically contained a rotor drum featuring on its outer circumference sorting elements that sweep across the screen and circulate at least parts of the suspension being sorted around the walls of the drum. The sorting elements have a design such that they generate a vortex flow of the suspension in the housing. The housing features on its periphery at least a removal duct for heavy contaminants, and in one of its end walls a central lightweight dirt drain.
A sorter of that type is known from DE-C 25 48 578. On this sorter, the drum supports the sorting elements, which are installed in the screen space formed between the drum and the screen concentrically surrounding it. The drum and the sorting elements are part of the rotor, the axis of rotation of which essentially coincides with the longitudinal axis of the screen basket, which at the same time also is the axis of rotational symmetry of the screen basket. This arrangement creates a recirculation of the suspension--preferably fiber suspension in the waste paper industry--between screen space and drum interior, that is, practically around the walls of the drum. This is meant to improve the separation of contaminants. In this described arrangement, the removal space for the heavy contaminants borders on the housing area which accommodates the screen and the drum and is relatively narrow, the outside diameter of the housing being considerably larger than the largest inside diameter of the cylindrical screen. The lightweight contaminants are removed from the central, axial area of the housing on an end wall of it, which is located opposite the end wall adjacent to the inlet space of the housing.
The problem underlying the invention is to provide an arrangement for the separation of fiber suspensions which are heavily laden with contaminants, especially for an end-stage sorting. By "end-stage sorting" is meant the process step in which the collected reject shares of the individual sorting stages are to be cleaned once again in order to reclaim usable fibers. Such a machine would then be able to additionally clean suspensions with a medium-heavy content of contaminants. | {
"pile_set_name": "USPTO Backgrounds"
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In the field of audio communications, utilizing magnetic tape, the present state of the art is limited in flexibility. This excludes magnetic tape from many applications that require rapid retrieval or random access to specific tape increments of recorded materials. Some of these applications are as follows: "jukebox" music; certain types of computer data; storage banks of educational units of study; broadcast spot announcements; random access to recorded musical selections stored, for example, in automobile trunks; emergency or sales promotion announcements in public buildings; and airport flight announcements, which may be multi-lingual recordings.
All of the above presently excluded applications and many more may be made practical or improved by the present invention.
Most magnetic tapes in the audio communications field are of the reel-to-reel type. Accordingly, considerable time is required to wind or rewind such tapes to position the tape at a given recorded message. This curtails the utilization of such reel-to-reel tapes for quick retrieval. Furthermore, the cost of complex handling equipment has been prohibitive. | {
"pile_set_name": "USPTO Backgrounds"
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Monolayer materials, such as graphene and hexagonal boron nitride (h-BN), are materials with great potential for electronics and other future device architectures based on atomically thin (monolayer) sheets. Graphene is a single atomic layer of sp2-bonded carbon (C) atoms densely packed into the form of a two-dimensional honeycomb crystal lattice. Graphene has been shown to be a zero-bandgap material whose charge carriers behave as massless Dirac fermions. It has remarkably high room-temperature charge carrier mobility with individual carriers exhibiting long-range ballistic transport. In the form of a monolayer sheet, h-BN is a single atomic layer of alternating boron and nitrogen atoms. In the bulk, h-BN has a graphite-like structure, in which such planar BN sheets are stacked on top of each other in a regular fashion. The large band gap of h-BN (both in the bulk and as a monolayer sheet) make this material capable of emitting deep ultraviolet radiation, which can be particularly beneficial for incorporation into a variety of optoelectronic devices, especially used for, as an example, nanometer lithography and white light in LED's.
Monolayers of graphene and h-BN are an attractive pair of materials that can be integrated to form 2D hetero structures in individual monolayer membranes. They are isostructural, nearly lattice-matched, and isoelectronic. As will be shown below, h-BN attaches preferentially to existing graphene domains and does not produce any secondary nuclei during growth at high temperature, which is consistent with the preferential incorporation of boron and nitrogen at the graphene edge.
The different band structures between graphene and h-BN generate a potential for interesting functional properties arising from the integration of the two materials in a heterogeneous monolayer membrane. Some of the unusual electronic properties that have been predicted in connection with the interfaces between monolayer graphene and h-BN include the opening of a variable bandgap, magnetism, unique thermal transport properties, robust half-metallic behavior without applied electric fields, and interfacial electronic reconstructions analogous to those observed in oxide heterostructures. Some of these unusual properties result because monolayer graphene boron nitride heterostructures have the potential to overcome the limitations due to the vanishing energy-gap of graphene.
Despite the extraordinary potential associated with interfaces between monolayer graphene and h-BN, access to these properties depends on methods for adequately controlling the formation of the interfaces between the monolayer graphene and h-BN domains within a single atomic layer. Harnessing these properties in large scale practical applications requires the identification of growth protocols and processing conditions tailored to their unique physical and chemical properties. Beyond the synthesis of the individual constituents (graphene, h-BN) as monolayer membranes, the synthesis of heterostructured 2D membranes with well-defined interfaces presents unique challenges, and raises fundamental questions on materials integration, such as interface formation and reduction of intermixing along boundary interfaces.
Techniques for the synthesis of two-dimensional (2D) materials and their heterostructures on metal substrates have become increasingly well developed. For instance, one investigation indicated that few-layer hybrids on Cu provide evidence for separate graphene and boron nitride domains on the nanoscale. (See Ci, L.; Song, L.; Jin, C.; Jariwala, D.; Wu, D.; Li, Y.; Srivastava, A.; Wang, Z. F.; Storr, K.; Balicas, L.; Liu, F.; Ajayan, P. M. Nat Mater 2010, 9, (5), 430-435, incorporated by reference in its entirety.) However, this investigation did not address interface formation between graphene and boron-nitride domains. Nor did it offer any insight into the ways that a metal substrate can cause modifications to the phase behavior of graphene and boron nitride domains.
Many of the unique properties predicted for monolayer graphene/h-BN heterostructures depend on the ability to fabricate such heterostructures with atomically sharp boundaries between the two constituents, that is graphene being bonded directly to h-BN without an intermixed ternary C—B—N “alloy” phase in between. However, in principle, several mechanisms could lead to mixing or alloying between graphene and h-BN. For example, substitution of carbon by boron or nitrogen at the graphene edge, direct substitution of carbon for boron or nitrogen (or vice versa) inside an existing domain, or carbon incorporation during the growth h-BN domains could result in substantial intermixing along the monolayer graphene/h-BN interfaces within monolayer graphene boron nitride heterostructures. All of these effects would lead to non-abrupt boundaries, in which the pure phases (graphene, h-BN) are separated by an intermixed zone containing C, B, and N instead of the desired atomically sharp boundary. Such non-abrupt, non-atomically sharp interfaces between monolayer graphene and h-BN hinder exploitation of the extraordinary potential associated with these interfaces in monolayer graphene boron nitride hetero structures. Consequently, identifying the extent of intermixing and controlling the formation of monolayer graphene/h-BN interfaces that limits a possible intermixing so as to achieve atomically sharp interfaces remains a challenge and has not heretofore been known or understood. | {
"pile_set_name": "USPTO Backgrounds"
} |
The heart is a hollow muscular organ having four pumping chambers separated by four heart valves: aortic, mitral (or bicuspid), tricuspid, and pulmonary. Heart valves are comprised of a dense fibrous ring known as the annulus, and leaflets or cusps attached to the annulus.
Prosthetic heart valves can be used to treat cardiac valvular disorders. The native heart valves (such as the aortic, pulmonary, tricuspid, and mitral valves) serve critical functions in assuring the forward flow of an adequate supply of blood through the cardiovascular system. These heart valves can be rendered less effective by congenital, inflammatory, or infectious conditions. Such conditions can eventually lead to serious cardiovascular compromise or death. It is possible to surgically repair or replace the valve during open heart surgery, where a prosthetic valve is sutured in place, but such surgeries are time-consuming, dangerous and prone to complication.
Transvascular and transapical techniques can be used for introducing and implanting a prosthetic heart valve using a flexible catheter in a manner that is less invasive than open heart surgery. In these techniques, a prosthetic valve can be mounted in a crimped state on the end portion of a flexible catheter and advanced through a blood vessel of the patient until the valve reaches the implantation site. The valve at the catheter tip can then be expanded to its functional size at the site of the defective native valve, such as by inflating a balloon on which the valve is mounted. Alternatively, the valve can have a resilient, self-expanding stent or frame that expands the valve to its functional size when it is advanced from a delivery sheath at the distal end of the catheter. These are sutureless techniques which greatly reduces the procedure time.
Balloon-expandable valves can be used for treating heart valve stenosis, a condition in which the leaflets of a valve (e.g., an aortic valve) become hardened with calcium. The hardened leaflets provide a good support structure on which the valve can be anchored within the valve annulus. Further, the catheter balloon can apply sufficient expanding force to anchor the frame of the prosthetic valve to the surrounding calcified tissue. There are several heart conditions, however, that do not involve hardened valve leaflets but which are still desirably treated by valve replacement. For example, aortic insufficiency (or aortic regurgitation) occurs when an aortic valve does not close properly, allowing blood to flow back into the left ventricle. One cause for aortic insufficiency is a dilated aortic annulus, which prevents the aortic valve from closing tightly. In such cases, the leaflets are usually too soft to provide sufficient support for a balloon-expandable prosthetic valve. Additionally, the diameter of the aortic annulus may continue to vary over time, making it dangerous to install a prosthetic valve that is not reliably secured in the valve annulus. Similar problems can occur with other heart valves as well. For example, mitral insufficiency (or mitral regurgitation) involves these same conditions but affects the mitral valve.
Self-expanding prosthetic valves can suffer from other problems. For example, if a self-expanding prosthetic valve is placed within the patient's defective heart valve (e.g., the aorta or mitral valve), it could continues to exert an outward force on the valve annulus. This continuous outward pressure could cause the valve annulus to dilate further, exacerbating the condition the valve was intended to treat. Additionally, when implanting a self-expanding valve, the outward biasing force of the valve's frame could cause the valve to be ejected very quickly from the distal end of a delivery sheath. This makes delivery of the valve very difficult and dangerous to the patient.
The size of the prosthetic valve to be implanted into a patient can also be problematic when treating aortic or mitral insufficiency. Specifically, the size of a prosthetic valve used to treat aortic or mitral insufficiency would generally need to be larger than a prosthetic valve used to treat aortic or mitral stenosis. This larger valve size can make the delivery procedure much more difficult and dangerous to the patient.
Another potential issue with sutureless valves is valve migration. For example, when an aortic prosthetic valve is implanted, 100-200 mmHg pressure loads on the aortic valve immediately. The pressure times the valve surface area produces a substantial load force on the prosthetic valve and could cause valve migration towards the aortic arch. Another potential cause of valve migration is a tilted valve landing. When tilted, the prosthetic valve will have a larger surface area facing the blood flow, which could push the prosthetic valve into the aorta.
Treatment of the mitral valve can present additional challenges, and methods and an apparatus appropriate for the aortic valve may not be well suited for use with the mitral valve. For instance, the mitral valve includes clusters of chordae tendineae extending from the valve leaflets to the walls of the ventricle that may interfere with placement of the prosthesis. The shape of the mitral valve, rather than being circular and uniform like the aortic valve, can be an oval or kidney-like shape that may not be well suited for supporting conventional stents of cylindrical configuration. Further, whereas the aortic valve annulus is often entirely surrounded by muscular tissue, the mitral valve annulus may be bounded by muscular tissue on the outer (posterior) wall only. The anterior side of the mitral valve annulus is bounded by a thin vessel wall adjacent the left ventricular outflow tract (“LVOT”), which must remain open to allow blood to pass into the aorta. As a result, the stent-type fixation may not be suitable for the mitral valve because the anterior side of the native valve has insufficient radial strength and can distort, risking occlusion of the left ventricular outflow tract. Moreover, mitral valve disease often is accompanied by (or caused by) gradual enlargement of the native annulus and/or the left ventricle. Thus, treatment approaches which rely upon radial engagement with or outward compression against the native annulus are subject to failure as the size and shape of the annulus changes.
There is a need for improved methods, systems, and apparatus for delivering expandable prosthetic heart valves (e.g., balloon-expandable or self-expandable prosthetic valves). Embodiments of the methods, systems, apparatus, devices, components, etc. disclosed herein can be used to replace native heart valves even when they do not have calcified leaflets (e.g., aortic valves suffering from aortic insufficiency). | {
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Data organization is important in relational database systems that deal with complex queries against large volumes of data. Relational database systems allow data to be stored in tables that are organized as both a set of columns and a set of rows. Standard commands are used to define the columns and rows of tables and data is subsequently entered in accordance with the defined structure. The defined table structure is logically maintained, but may not correspond to the physical organization of the data. For example, the data corresponding to a particular table may be split up among a number of physical hardware storage facilities.
Users of relational database systems require the minimum time possible for execution of complex queries against large amounts of data. Different physical types of storage, for example random access memory and hard drives, incur different length delays. In addition, writing to memory or a hard drive is often slower than reading an equivalent amount of data from memory or a hard drive. The organization of data corresponding to tables defined in a relational database system may determine the number of writes and reads that need to be performed in order to execute a common request. If the data is properly organized, performance can be improved by searching a part of the data for queries that can take advantage of that organization. If the data is not organized in a useful way for a request, it will often need to be searched in its entirety to satisfy a request or copied and restructured into a useful organization. | {
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1. Technical Field
The present disclosure relates to a fundus photographing apparatus with wavefront compensation that photographs a fundus image of an examinee's eye, and a method for photographing the fundus image.
2. Related Art
In a known fundus photographing apparatus, for example, a wavefront sensor such as a Shack-Hartmann sensor is used to detect the wavefront aberrations of an eye. Furthermore, a wavefront compensating device is controlled based on the detection result, and a fundus image after wavefront compensation is captured at a cell level. The fundus image obtained by such a device can be used for, for example, image processing related to fundus cells, such as cell density analysis (see, for example, JP-A-2014-110825). | {
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When a dynamic range of a scene exceeds a dynamic range of a camera sensor, a photographed image may be overexposed or underexposed and content of the scene cannot be truly restored. HDR (High Dynamic Range, high dynamic range) synthesis means that one highly dynamic image is obtained by synthesizing images with different exposure, and a dynamic range of the image that is obtained by means of synthesis can truly reflect content of a current scene. Therefore, before HDR synthesis is performed, multiple images with different exposure (generally two or three sheets) need to be photographed. Exposure needs to be determined according to a current scene, and desired exposure ensures that the images with different exposure may record details of a bright location and a dark location in the scene. In this way, the content of the current scene can be truly recorded only by using an HDR synthesis technology.
In the prior art, the images with different exposure that are required for the HDR synthesis are generally acquired in a manner of exposure bracketing. The so-called exposure bracketing is to increase or decrease exposure on the basis of normal exposure, to acquire the images with different exposure. The increased or decreased exposure is generally fixed, and there is a time interval between the images with different exposure.
The prior art has at least the following technical problem:
Because in the prior art, images with different exposure are acquired by increasing or decreasing fixed exposure on the basis of an image with normal exposure, there is a technical problem that a required group of desired exposure cannot be determined according to a current scene. | {
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The invention relates generally to boots, such as cowboy boots and work boots, which employ a comfort system, relying upon vertically aligned foamed plastic pads, at strategic areas, of high impact, such as the ball and heel areas of the boot. The comfort system is compact and fits easily into the interior of the boot. One pair of pads is secured to an insole liner backing board, while another pair of pads is secured to the upper surface of the midsole.
The Goodyear welt system is widely used in the manufacture of boots and shoes. The Goodyear welt stitch is applied to the shoe or boot with a great amount of pressure, and a rigid inner sole board must be strong enough to withstand such pressure. However, the rigid inner sole board presents a source of discomfort to the wearer, and resilient cushioning pads have been employed in some boots, in an effort to minimize such discomfort.
To illustrate, U.S. Pat. No. 5,911,491, granted to Marvin O Huff, discloses a comfort system for a shoe or boot, including a rigid inner sole board (10). Full-length cushioning pad (15) is placed on top of the innersole board, and precut detachable pieces (11a, 11b) are defined on the innersole board. Removing the detachable pieces allows rectangular cushioning pads (20a, 20b) to contact the cushioning pad to provide additional cushioning effect. The rectangular pads are located at the heel of the boot, and under the ball of the foot of the wearer, the points of maximum impact for the wearer of the boot.
While the comfort system disclosed in Huff represented a step forward, such comfort system exhibited shortcomings. The amount of cushioning achieved by such system was limited by the compression of pad (15) and cushioning pads (20a, 20b). While the full length pad is of uniform thickness, the polyurethane cushioning pad located at the heel of the boot may be considerably thicker than the polyurethane cushioning pad attached at the forepart of the innersole board, as noted in column 3 lines 25-35 of Huff. | {
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The present invention relates to semiconductor wafers, and more particularly to a method of manufacturing a silicon on insulator (SOI) wafer from a monocrystalline silicon substrate.
As is known in the microelectronics industry, monocrystalline silicon wafers are the most widely used substrate for the manufacture of electronic devices. As an alternative to silicon wafers, composite SOI wafers have been proposed which are formed of two silicon layers, one thinner than the other and separated by a silicon dioxide layer.
A method of manufacturing SOI wafers is the subject of European patent application No. 98830007.5 filed on Jan. 13, 1998 to the assignee of the present invention. A similar method is described below with reference to FIGS. 1 to 8.
First, a first silicon dioxide layer between 20 and 60 nm thick is grown on a major surface 3 of a substrate formed of a monocrystalline silicon wafer 2. Then a first layer of silicon nitride between 90 and 150 nm thick and a second silicon dioxide layer between 100 and 600 nm thick produced by decomposition of tetraethyl orthosilicate (TEOS), are deposited thereon. A resist layer and a masking operation are used to define in plan view, for example, a grid of rectangular areas. Dry etching of the uncovered portions of the TEOS oxide layer, of the first nitride layer, and of the first oxide layer is then carried out and the residual resist is then removed producing the structure shown in cross-section in FIG. 1. The portions of the first oxide layer, of the first nitride layer, and of the TEOS oxide layer remaining after the dry etching are indicated as 4, 5 and 6, respectively. Together these define protective plaques 7 covering portions 8xe2x80x2 of the monocrystalline silicon substrate 2.
The protective plaques 7 form a mask, generally indicated 9, for subsequent selective anisotropic etching of the silicon substrate 2. This treatment etches the portions of the substrate 2 indicated 8xe2x80x3, which are not protected by the mask 9, so that initial trenches 10 are formed (FIG. 2).
As shown in FIG. 3, the structure is then subjected to an oxidation step which leads to the formation of a third silicon dioxide layer 11, between 20 and 60 nm thick, which covers the walls and the bases of the initial trenches 10. A second silicon nitride layer 12 between 90 and 150 nm thick is then deposited.
The method continues with dry anisotropic etching without masking, during which the horizontal portions of the second silicon nitride layer 12 are removed. During the dry etching, the first nitride layer 5 is protected by the TEOS oxide layer 6. The third oxide layer 11 which is disposed in the bases of the initial trenches 10 is removed by a wet process. This produces the structure shown in FIG. 4, in which it is possible to see the portions 8xe2x80x2, still covered on the top by the mask 9 and on the sides (on the vertical walls of the initial trenches 10) by portions 11xe2x80x2 and 12xe2x80x2 of oxide and nitride, respectively, and the uncovered bases 15 of the initial trenches 10.
Anisotropic etching of the silicon is then carried out with the use, of the mask 9 modified by the addition of the oxide and nitride portions 11xe2x80x2 and 12xe2x80x2, respectively. The uncovered silicon in the bases 15 of the initial trenches 10 is etched for a predetermined period to give final trenches 16 having a desired depth. It will be noted that the difference between the depth of the final trenches 16 and that of the initial trenches 10 determines the dimensions of the buried oxide layer, and, hence, the electrical characteristics of the SOI wafer, as will be explained further below. The etching depths are therefore selected on the basis of the specifications of the SOI wafer to be produced.
The monocrystalline silicon substrate thus treated is now formed by a base portion, indicated 2xe2x80x2, and by a plurality of pillars 18 extending from the base portion 2xe2x80x2. The structure shown in FIG. 5 is thus produced, in which the nitride portions 5 and 12xe2x80x2 are no longer separate and are generally indicated 19, and the oxide portions 4 and 11xe2x80x2 are generally indicated 20. The portions 19 and 20 with the overhanging TEOS oxide portions 6 together form a mask 30.
The silicon substrate is then subjected to selective oxidation with the use of the mask 30 to protect the silicon on the tops of the pillars 18 from oxidation. The process continues until the portions of the pillars 18 which are not protected by the mask 30 are completely converted into silicon dioxide. In practice, a gradual growth of the oxide regions takes place at the expense of the silicon regions, starting from the side walls of the final trenches 16, towards the interior of the pillars and partially also into the base portion 2xe2x80x2. Since the volume of silicon dioxide which is formed is greater than that of the initial silicon, the oxide regions being formed gradually occupy the space in the final trenches 16 until they close them completely and are joined together. The oxidation step terminates automatically when the pillars 18 are completely oxidized (naturally apart from their tops or tips 21, which are protected by the mask 30). A continuous oxide region 22 is thus formed, most of which is buried, as shown in FIG. 6, in which vertical lines indicate the surfaces on which the oxide regions join.
The TEOS oxide portions 6 and the nitride portions 19 and oxide portions 20 which form the mask 30 are then eliminated by selective etching so as to uncover the tips 21 which are intended to form the seeds for subsequent epitaxial growth. The resulting structure is shown in perspective in FIG. 7. The epitaxial growth step is performed in a manner such as to prevent nucleation of polycrystalline silicon in the uncovered areas of the buried oxide region 22. Moreover, a high lateral/vertical growth ratio is selected so as to achieve, first of all, growth of the silicon sideways around the tips 21 until the trench portions which are still open are filled, and then growth of an epitaxial layer 23 in a direction perpendicular to the major surface of the substrate. After an optional chemical-mechanical lapping or polishing step to level the surface of the layer 23, the final structure of the SOI wafer shown in FIG. 8 is obtained.
An SOI wafer is thus formed from a normal monocrystalline silicon substrate with the use of process steps which are common in microelectronics, with much lower costs than those of the methods currently used for the production of SOI wafers. However, the implementation of the method described above imposes constraints. To produce a continuous buried oxide layer it is necessary for the areas between adjacent trenches, which define the widths of the pillars, to be as narrow as possible. On the other hand, the minimum width of the pillars is fixed by the minimum thickness required for the residual monocrystalline silicon on the buried oxide layer (that is the tips 21 on the layer 22, with reference to FIG. 7), to ensure an adequate crystallographic quality of the epitaxial layer subsequently grown. Moreover, the widths of the pillars cannot be as large as may be desired but must be selected so as to ensure that the silicon disposed between adjacent trenches is completely converted into oxide. It is also necessary for the trenches to be as narrow as possible consistent with the thicknesses required by the method for the nitride and oxide layers deposited or grown. Finally, the known method described above is greatly limited by the dimensional ratios between the trenches and the pillars.
An object of the present invention is to provide a method of manufacturing an SOI wafer which is not limited by the dimensional ratios between the trenches and the pillars.
This and other objects can be achieved by the method according to the invention including the steps of: selective anisotropic etching to form trenches, in a monocrystalline silicon substrate, which extend to a predetermined depth from an upper surface of the substrate and which define portions of the substrate therebetween; selective isotropic etching to enlarge the trenches, beginning at a predetermined distance from the upper surface, thus reducing the thicknesses of the portions of the substrate between adjacent trenches; selective oxidation to convert the substrate portions of reduced thickness into silicon dioxide and to fill the trenches with silicon dioxide, substantially from the predetermined distance from the upper surface; and epitaxially growing a silicon layer on the upper surface of the substrate.
The selective anisotropic etching may comprise the formation of a mask of material resistant to etching and protective against oxidation of the silicon. After at least part of the anisotropic etching, the mask may extend to side walls of the trenches as far as the predetermined depth. Also the mask may comprise a silicon nitride layer and/or a silicon dioxide layer produced by decomposition of tetraethyl orthosilicate (TEOS). Additionally, the step of selective isotropic etching may be performed with xenon difluoride gas. | {
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Persons who have suffered a trauma such as an accident or who have undergone surgical bone implants or artificial joint surgery often have difficulty in assuming a sleeping position which does not apply pressure to the surgical incision, or torch to the surgical implants and traumatized body parts. Underlying skeletal structures are protected by virtue of the sleeping (resting) position. Many such patients therefore sleep in a chair because of the technical problems associated with torch and pressure while attempting to sleep on the back or stomach A need has existed for a pillow device which will permit the side sleeping that significantly reduces the torch and pressures that inhibit the healing process. An effective resting period will shorten the healing time, decrease morbidity, decrease medical expenses and, return the patient to an active independent status more readily.
Various proposals for supporting the body of a user during sleep have been heretofore proposed. See, for example, U.S. Pat. No. 4,624,021, issued to Hofstetter on Nov. 25, 1986. In this patent a cushion-like support is suggested which is placed between the knees of the user who sleeps or rests on his side. A different device is shown in U.S. Pat. No. 4,901,384, issued Feb. 20, 1992 to Eary. In the pillow suggested therein, various attached together cushion sections of differing thicknesses are assembled to support a reclining user in a fixed position. That design, however, calls for supporting of both feet of the user in an elevated position.
While these and other examples of pillows and cushions enable a user to remain in one or more positions with varying degrees of comfort, there are no currently marketed or available pillows which are custom designed to fit the skeletal dimensions of an individual user to thus provide optimum support for the user based on his or her bodily dimensions. Thus, a need has continued to exist for an improved pillow especially adapted to situations in which proper rest is critical but difficult. | {
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1. Field of the Invention
The present invention relates generally to a dispensing arrangement for partially solidified materials such as sherbets, soft ice creams and yogurts, and more particularly pertains to a dispenser of the aforementioned kind which delivers a precisely quantified portion of such materials on a controlled and repetitive basis.
2. Description of the Prior Art
Many types of apparatus are known in the prior art for dispensing partially solidified desserts such as sherbets soft ice creams, and yogurts. The dispensing arrangments normally have a dispensing nozzle, a valve associated therewith to control the dispensing operation, and a pump for feeding soft desserts to the nozzle. Manually controlled dispensing arrangements, wherein an operator controls operation of the dispensing valve, have some serious disadvantages associated therewith. The operator should maintain the dispensing valve open for a relatively constant time period over and over again in a repetitive manner, as the time the valve is open substantially determines the amount of dessert delivered for collection on top of cones, cups, wafers or the like. Moreover, a further disadvantage of this type of dispensing arrangment is that it often requires the presence of supervisory personnel to assist unskilled operators in the performance of their duties to prevent the delivery of either too little dessert, resulting in customer dissatisfaction, or too much dessert, resulting in an overdelivery for that purchase. This can be a relatively severe problem as the profits from this type of retail business are often related directly to the quantity of dessert dispensed on a repetitive basis.
An improvement over manually controlled dispensers is the provision of a timer controlled dispensing arrangement wherein the dispensing valve is maintained open for a given period of time determined by a timer. Simonich U.S. Pat. No. 3,399,809 discloses an ice cream vending machine having a mechanical timer therein such that a motor driven rotation of a mechanism results in a dispensing operation over a given fixed time period. Vollmer, Sr. U.S. Pat. No. 3,054,534 and Glisenti U.S. Pat. No. 3,456,839 disclose dispensing arrangements wherein an electrical timing circuit measures a given time period during which a soft dessert such as ice cream is dispensed. Unfortunately, these prior art dispensing arrangements do not offer a sufficient amount of flexibility to accommodate changes in important parameters which affect the dispensing operation, particularly those which influence the quantity of dessert dispensed during a given time period. | {
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In a typical cellular radio system, also referred to as a wireless communication system, User Equipments (UEs) communicate via a Radio Access Network (RAN) to one or more core networks. The user equipments may also be known as mobile terminals and/or wireless terminals. In particular, the user equipments may be mobile stations or user equipment units, such as mobile telephones (e.g., “cellular” telephones), and laptops with wireless capability (e.g., mobile termination). User equipments may therefore be portable, pocket, hand-held, computer-included, or car-mounted mobile devices which communicate voice and/or data with the radio access network.
The radio access network covers a geographical area which is divided into cell areas, with each cell area being served by a base station, e.g., a Radio Base Station (RBS), which in some networks is also called “eNB”, “NodeB” or “B node” and which in this document is referred to as a base station. A cell is a geographical area where radio coverage is provided by the radio base station equipment at a base station site. The base stations communicate over the air interface, operating on radio frequencies, with user equipment units that are within range of the base stations.
In wireless communication systems, the radio UpLink (UL) is the transmission path from the user equipment to a base station and the radio DownLink (DL) is the transmission path from a base station to the user equipment. In Release 8, of the 3GPP Long Term Evolution (LTE) standard, the arrival of new UL data of higher priority than the already existing data, or of any priority when there is no previous data, to the UE buffer triggers a so-called Regular Buffer Status Report (BSR). There are, of course, side conditions to this. For example, new UL data only triggers a BSR if it is data for a logical channel belonging to a Logical Channel Group (LCG). Further, the “arrival of new UL data” is defined as when UL data becomes available for transmission in a Radio Link Controller (RLC) entity, or in the Packet Data Convergence Protocol (PDCP) entity. The PDCP is an upper layer of the RLC entity
However, notwithstanding these side conditions, the arrival of new UL data generally triggers a regular BSR. The regular BSR, in turn, triggers the generation of a Scheduling Request (SR) trigger. The SR trigger then triggers an SR to be conveyed to the base station, thereby informing the base station that the user equipment has new data that it would like to transmit. The SR is transmitted to the base station either on (1) the user equipment's preallocated scheduling request resource on a Physical Uplink Control Channel (PUCCH), in which case the SR is known as dedicated SR (D-SR) since it is transmitted on a resource dedicated to the user equipment, or (2) on the Physical Random Access Channel (PRACH), in which case the SR is known as a random access SR (RA-SR). In both cases, there is a fixed periodicity associated with the opportunities to transmit an SR. This means that, in order to transmit an SR, the user equipment has to wait until such an opportunity is available.
When the base station receives a D-SR, the base station typically issues an UL grant. When the user equipment transmits on that grant, it will transmit a MAC Packet Data Unit (PDU) that includes a BSR in the shape of a so-called BSR Medium Access Control (MAC) control element, describing the size of its buffers. The BSR is mandated to reflect the buffer status after the MAC PDU, including the BSR MAC control element, is built. A BSR is always included if a BSR trigger is pending in the user equipment at the time of building the MAC PDU, unless all data can fit in the MAC PDU but there is not room enough for a BSR in addition to the data.
Once the size of the user equipment buffer has been reported to the base station, there is no need for the user equipment to send additional SRs as the base station now knows how much data the user equipment has to transmit. The SR trigger can hence be cancelled in the user equipment, so that the user equipment will not send any D-SR at the next D-SR opportunity.
Please note that in the description below, the following terminology will be used:
The term “arrival of new data” is used to indicate arrival of new UL data in the user equipment buffer, with all side conditions for triggering a Regular BSR satisfied.
The term “reception of grant” is used to indicate the reception of a Physical Downlink Control Channel (PDCCH) grant for Uplink Shared Channel (UL-SCH) resources for a new transmission.
The term “transmission of data” is used to indicate transmission of UL data on UL-SCH resources that have been made available for a new transmission.
The term “SR” and “scheduling request” is used to indicate signalling of D-SR on the PUCCH.
The term “SR trigger” and “scheduling request trigger” is used to indicate a pending SR.
When expressions such as “buffer status report accounts for first data” are used, it means that the buffer status report reflects whatever is left of the first data after the transmission in which the buffer status report is included has been received.
An SR is considered pending until cancelled, i.e. an SR trigger that triggers the transmission of an SR, is considered pending until cancelled. It was first agree upon, in a prior version of the LTE standard, that an SR would be cancelled in the first possible Transmission Time Interval (TTI), also known as subframe, when UL-SCH resources for a new transmission are granted. However, some argued that it was unclear exactly when UL-SCH resources for a new transmission are granted, whether it be when a PDCCH grant is received or in the TTI when the UL-SCH resources are actually available. It was subsequently agreed upon that all pending SRs should be cancelled in the TTI when UL-SCH resources are actually available for a new transmission. | {
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One conventional infrared human body detector which has a wider sensitive angle than ordinary infrared human body detectors and has been evaluated as excellent is disclosed in U.S. Pat. No. 4,644,147. The disclosed infrared human body detector has a sensitive angle which is 90 degrees on both sides of a central sensitivity axis of the detector. The disclosed infrared human body detector is suitably mounted on a flat wall or ceiling.
There has not been available an infrared human body detector having a sensitive angle ranging from 180 to 270 degrees, suitable in an arrangement as shown in FIG. 4 of the accompanying drawings for monitoring an entire region P around a rectangular house H with infrared human body detectors S, nor has there been an infrared human body detector having a sensitive angle ranging from 270 to 360 degrees for monitoring a large room with a high ceiling, a garden, or the like. To monitor these areas, a plurality of infrared human body detectors have to be combined with each other, but such a combination is very uneconomical. Specifically, for monitoring a corner (270 degrees) of a house with infrared human body detectors, it has heretofore been necessary to install two infrared human body detectors, each having a sensitive angle of 180 degrees, on respective surfaces that jointly make up the corner. This system is highly disadvantageous because the price of the required infrared human body detectors and the expenses needed to install them are about twice those which would be necessary to employ one infrared human body detector.
Monitoring a large room with a high ceiling, a garden, or the like with a conventional infrared human body detector D2, as shown in FIG. 11(b) of the accompanying drawings, having a sensitive angle of 180 degrees, is also highly disadvantageous in that the initial and running costs are about twice those of an infrared human body detector according to the present invention for the reasons described above. | {
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1. Field of the Invention
The present invention relates generally to non-volatile memory devices (“flash memory devices”) and, more particularly, to independently controlling a read voltage (or a program-verify voltage) and temperature co-efficient associated with the voltage
2. Background of the Invention
Semiconductor memory devices have become popular for use in various electronic devices. For example, non-volatile semiconductor memory is used in cellular telephones, digital cameras, personal digital assistants, mobile computing devices, non-mobile computing devices and other electronic devices. Electrical Erasable Programmable Read Only Memory (EEPROM) and flash memory are among the most popular non-volatile semiconductor memories.
One example of a flash memory system uses the NAND structure, which includes arranging multiple transistors in series, sandwiched between two select gates. A NAND array has a number of memory cells (or storage units, used interchangeably throughout this specification), such as 4, 8, 16, or even 32, connected in series string (NAND string) between a bit line and a reference potential through select transistors at either end. Word lines are connected with control gates of cells in different series strings. Relevant examples of NAND arrays and their operation are given in the following U.S. patents that are incorporated herein in their entirety by this reference: U.S. Pat. Nos. 5,570,315, 5,774,397 and 6,046,935.
Individual memory cells of such flash memory devices typically include one or more storage elements that store a variable amount of static charge. The storage elements are most commonly conductive floating gates, so this is the example primarily described herein, but can also be areas of a charge trapping dielectric. The level of charge stored by the floating gate represents the data value stored by the data storage element. The floating gate typically overlies a channel region of a transistor.
Data is read from a storage location by applying a voltage to a control gate overlying the floating gate. The level of charge stored by the floating gate, in combination with the voltage applied to the control gate, determines whether the transistor will conduct current through its channel. The level of charge stored by the floating gate can therefore be determined by either measuring that current or finding the control gate voltage required to make the transistor conduct. In either case, the measured quantity is compared with reference levels in order to determine the state of the cells.
Binary state memory cells may be used in flash memories. These memory cells have two states: “programmed” (usually representing a one) and “erased” (usually representing a zero). However, such cells do not efficiently use the valuable real estate of the integrated circuit, since only one bit of information is stored per floating gate. Many flash memories therefore use multiple charge levels (more than two) for the floating gates, so that each floating gate may store more than one bit of information.
As the number of charge level states of the operation of individual floating gates increases, the voltage difference between the states necessarily decreases. The increasing proximity of the voltage level ranges for an increased number of states makes discerning one state from another difficult.
Since the operating characteristics of the memory cell transistors change with temperature, the control gate voltage required to turn on the transistor also should vary with temperature, even as the charge level carried by the floating gate remains unchanged. Any mismatch in the thermal variation of the control gate voltage and the thermal variation of the operating characteristics of the memory cell transistors can result in inaccurate reading of data from memory cells, due to the close proximity of the voltage levels of the floating gate.
During a read or program-verify operation of a multilevel memory cell (MLC) a plurality of predetermined voltages are applied from a voltage generator to the control gate of the selected memory cell. A resulting threshold voltage Vt varies with temperature, which is denoted by a temperature coefficient. Temperature coefficient is a temperature dependent multiplication factor. In flash memories the threshold voltage temperature co-efficient (TCO) has a typical value of approximately −1.7 mV/° C. The intrinsic TCO value of a memory cell can vary from −1.2 mV/° C. to −2.2 mV/° C.
Data is stored in a memory cell at one temperature and may be read at another temperature. The read voltage applied to a memory cell gate should be greater than the threshold voltage of the memory cell and this difference should remain substantially constant over a temperature. Thus, it is desirable that the TCO for various voltages applied to the memory cell be substantially similar to the intrinsic TCO of the memory cell.
Conventional systems fail to independently control the voltage level and the TCO. This has disadvantages because the TCO of the memory cell may not match the TCO of the applied voltage. Conventional systems fail to adjust the TCO to compensate for variations in the memory cells intrinsic TCO and/or compensate for variations in the circuits that generate the TCO.
Conventional systems fail to efficiently trim TCO values during flash memory testing.
Therefore, there is a need for a system and method to efficiently/independently control the applied voltage level and TCO and efficiently trim TCO values during flash memory testing. | {
"pile_set_name": "USPTO Backgrounds"
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This invention relates to nasal packing made from sponge-like materials that are expansible from a dry state to form soft, resilient, absorbent bodies.
In U.S. Pat. No. 1,732,697, Ryan discloses a medicated, compressed sponge that is adapted for insertion into the nose, and that swells into contact with the irregular surface portions of the nasal cavity, when moistened. Similarly, Stevens U.S. Pat. No. 2,179,964, Kriwkowitsch U.S. Pat. No. 3,049,125, Gottschalk U.S. Pat. No. 3,570,494, Doyle U.S. Pat. Nos. 4,030,504, 4,646,739, and Des. 287,880, Rangaswamy U.S. Pat. No. 4,568,326, Brennan U.S. Pat. No. 4,950,280, and Sweden Patent No. 220,978 provide nasal hemostats and the like. Medical, catamenial, and like devices are disclosed in the following United States patents: Gearon U.S. Pat. No. 1,537,992, Munro U.S. Pat. No. 2,110,962, Robell U.S. Pat. No. 2,499,414, McLaughlin U.S. Pat. No. 2,739,593, Maro et al U.S. Pat. No. 3,084,689, Penska U.S. Pat. No. 3,306,294, Crockford U.S. Pat. No. 3,369,544, Burnhill U.S. Pat. No. 3,762,414, Davis et al U.S. Pat. No. 3,791,385, and Hirschman U.S. Pat. No. 4,175,561, and in Canada Patent No. 550,047 and France Patent No. 718,042.
Efficient hemostasis, such as after septal, sinus, or rhinoplastic surgery, or to abate nasal hemorrhage, requires the application of gentle pressure to ruptured major arteries and blood vessels over substantially all parts of the nasal cavity. It is not believed that the hemostatic devices provided heretofore function entirely adequately in those respects. | {
"pile_set_name": "USPTO Backgrounds"
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Optical communication techniques, including fiber optics and lasers, are the workhorses of the Internet and high-capacity computing. Meeting the computing and telecommunications needs of the next decades will require advances across a broad front of research and development, including optical signal generation, transmission, switching and routing, as well as intelligent and seamless networking. Although institutions and companies have access to such rapidly growing, high-speed global telecommunication networks, the infrastructure is not yet in place to provide the individual user access that fully exploits the power of light in FO installations.
Known FO diagnostic instruments consist of two expensive categories: 1) long-range units with relatively low resolution for telecommunications and large data networks, where such units generally use optical time domain reflectometery (OTDR) and provide tens of km of span with a resolution of 0.1 to 1 m; and 2) very-high resolution laboratory instruments which utilize optical frequency domain reflectometery (OFDR) providing less than 1 mm resolution.
As used herein, the terms “coherent” or “coherence” mean a uniform wavelength (or frequency). Thus, the term “coherence length” means a distance of air over which the wavelength of laser light is uniform in air.
OFDRs use a tunable wavelength high-coherence laser source. OFDR lasers can provide a wide optical frequency sweep which can translate to very high spatial resolution in a reflectometer, but the cost of the laser source is very high and suppliers are limited. A standard distributed feedback (DFB) laser is much less expensive and can be tuned over a smaller wavelength range, but the DFB laser tunability is sufficient for resolution in the region of 1 cm or less. However, the DFB source does not typically provide sufficient coherence to be used for measurements beyond about 1 m of fiber length.
To support continued large-scale FO deployment, such as in communications networks from homes to data centers, there is an identified need for testing these FO installations at much lower cost, and with high resolution to localize faults in these more compact environments. | {
"pile_set_name": "USPTO Backgrounds"
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1. Field of the Invention
The present invention relates to a semiconductor device having a plurality of kinds of operation contents and, particularly, to a configuration for setting a test mode of the semiconductor memory device. More particularly, the present invention relates to a configuration for a test mode entry for setting a test mode of a semiconductor memory device and, specifically, to a configuration for a test mode entry of a pseudo SRAM which operates similarly to an SRAM (Static Random Access Memory).
2. Description of the Background Art
In an application of a portable equipment, an SRAM is used as an internal memory because of its high processing speed and simple control. The memory cell of the SRAM is, however, constructed by four transistors and two load elements. Consequently, the occupying area of SRAM memory cell is large, and it is difficult to implement a memory of a large storage capacity in a limited area.
As the functions of a portable equipment are enhanced, it is necessary to process data of a larger amount such as image data and audio data. A memory of a large storage capacity is required for a memory device of the portable equipment. In the case of using an SRAM, it is difficult to implement the memory of the large storage capacity in a small occupying area, so that a demand of down sizing and lightening of high-function portable equipment cannot be met.
On the other hand, the memory cell of a dynamic random access memory (DRAM) is constructed of one transistor and one capacitor. The DRAM has therefore an advantage that the occupying area of the memory cell is smaller, as compared to the memory cell of the SRAM. The DRAM can be said to be suitable for constructing a memory of a large storage capacity with a small occupying area. The DRAM has a further advantage that the occupying area of the memory cell is smaller and a cost per bit is lower as compared with an SRAM.
However, since the DRAM stores data in the capacitor, in order to prevent the stored data from being lost by a leak current, refreshing operation for rewriting data has to be periodically performed. During execution of the refreshing operation, an external device such as a processor cannot access the DRAM and has to wait, so that the processing efficiency of the system deteriorates. There is another problem that the load for the refreshing control of an external memory controller is heavy.
The DRAM is held in a standby mode such as a sleep mode in a waiting time in a portable equipment or the like. Also in such a standby mode, however, stored data has to be held and refreshing has to be executed periodically. Therefore, an ultra low standby current condition of the order of xcexcA required in a specification or the like for an operation period for holding data such as a sleep mode cannot be satisfied.
In order to implement the memory of a large storage capacity with the small occupying area at low cost, a DRAM-based memory has to be used. In the case of using such a DRAM-based memory, called an SRAM alternative memory hereinbelow, the memory replacement has to be done without significantly changing a conventional system configuration. In other words, compatibility of pins is required. The xe2x80x9cmemoryxe2x80x9d indicates a memory device connected to a device such as an external processor via pin terminals.
The SRAM alternative memory is required to operate under the same operating conditions, or the same signal timings, as those of the SRAM.
In the case of fabricating the SRAM alternative memory, in order to assure the reliability, a product test has to be sufficiently performed. In the case of using a DRAM-based memory, however, different from a conventional DRAM, for the operation control signals, a chip enable signal CE#, a write enable signal WE#, and an output enable signal OE# have to be used in view of compatibility with an SRAM. Therefore, the configuration of using signals RAS, CAS, and WE to set a test mode in a conventional DRAM mode cannot be used.
In the case of designating a special operation mode of the SRAM alternative memory as well, similarly, a mode setting condition used in a conventional DRAM cannot be used as it is. In the SRAM alternative memory, a new configuration has to be provided to designate a special mode such as a test mode. The configuration for designating a special mode has to be formed using an interface having compatibility with an interface of an SRAM.
An object of the present invention is to provide a configuration for designating a special operation mode of an SRAM alternative memory.
Another object of the present invention is to provide an SRAM alternative memory capable of designating a test mode while maintaining compatibility with an SRAM.
Further object of the present invention is to provide a semiconductor memory device that can reliably enter a test mode without exerting an adverse influence on a normal operation mode.
A semiconductor device according to the present invention includes: determining circuitry for determining whether an external signal satisfies a predetermined condition or not; and internal state setting circuitry enabled when a determination result of the determining circuitry indicates that the predetermined condition is satisfied, for setting, in accordance with an internal state designation signal designating a specific operation content, an internal state to a state designated by the internal state designation signal.
When the external signal satisfies the predetermined condition, a mode capable of setting a specific mode of operation is set, and the operation content in the specific mode is designated. By setting the predetermined condition in accordance with signals used in a normal SRAM, the specific mode can be designated while maintaining the compatibility with an SRAM.
An operation content is set in the specific mode only when the predetermined condition is satisfied, so that the operation content in the specific mode can be set accurately.
By constructing such that a predetermined condition is determined to be satisfied when a specific condition is met a plurality of times successively, a semiconductor device can enter a specific mode under the condition which is not used in a normal mode of operation. Consequently, the semiconductor memory device can be prevented from entering the specific mode erroneously in the normal mode of operation. Thus, highly reliable setting of a specific mode can be implemented. | {
"pile_set_name": "USPTO Backgrounds"
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1. Field of the Invention
This invention pertains generally to a diplexer, and more particularly to diplexer utilizing composite right/left-handed (CRLH) phase advance/delay lines in combination with a hybrid coupler.
2. Description of Related Art
Modern communication systems often require dual-band operation, and therefore, diplexers are essential elements in transceiver modules for the electromagnetic spectrum. A diplexer is a form of frequency selective demultiplexer having one input and two outputs. One application of a diplexer allows two different devices at different frequencies to share a common communications channel. Diplexers have a wide range of applications for signal transmission in the electromagnetic spectrum. For decades, studies on diplexers attracted industry attention with the results of numerous researchers reported.
However, these diplexers have conventionally comprised two bandpass filters, each of which is responsible for the respective frequencies in dual-band schemes. More recently diplexers have been proposed which comprise waveguide filters. Although low insertion loss and high isolation were obtained from these waveguide filter diplexers, parametric optimization on the three-port junction connecting the filters and the requisite performance tuning are time-consuming processes. In order to suppress higher-order harmonics of filters, stepped-impedance resonators (SIRs) were utilized. In response to this arrangement, the spurious harmonic responses were controlled at the expense of design complexity. Even though channel isolation in diplexer design can perhaps be enhanced, it typically requires interconnection of additional circuit elements, such as tapped open stubs, and λ/4 microstrip lines in front of the filters.
Accordingly, a need exists for an apparatus and method for designing compact diplexers which simplify the design complexity by engineering the dispersion relation of the structure. These needs and others are met within the present invention, which overcomes the deficiencies of previously developed diplexing methods and apparatus. | {
"pile_set_name": "USPTO Backgrounds"
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The present disclosure relates generally to electric power steering system and more particularly to narrow-frequency band feedback control of steering pinion torque associated therewith. It is to be appreciated, however, that the present disclosure may relate to other similar environments and applications.
In today's vehicles, electric power steering (EPS) is utilized to provide steering assistance based on particular vehicle dynamic conditions and maneuvers. In comparison with conventional hydraulic steering systems, an EPS system can provide safety enhancement by providing steering assistance during engine stall and ability to tune steering feel and performance. Further, an EPS system's electric motor is powered by the vehicle's alternator, instead of a hydraulic pump, which is belted into the engine. The efficiency advantage of an EPS system is derived from the fact that it is activated only when needed.
Development efforts have been made to gain favorable steering feel for various steering wheel input conditions in normal steering and handling areas which usually have a frequency range of steering input from zero to 2.5 Hz. External disturbance, which can be from an uneven or rough road surface, an unbalanced mass of tire or wheel, or break torque fluctuation, remains as a source to steering system which can cause unpleasant or annoying steering feel. Existing technologies utilize either a mechanical device to detect the source of steering torque or control logic to stabilize the torque sensor system to define bands of disturbance, which are used for motor current control. However, the frequency bands of common external disturbances to the steering system, such as steering shimmy caused by tire wheel unbalance, brake judder caused by breaking torque fluctuation, and kickback from uneven road surfaces, are much higher than normal steering and handling frequencies (e.g., greater than 2.5 Hz). Furthermore, these kinds of disturbances are all directly sensed by a steering pinion torque sensor and hence the steering signal. Conventional countermeasures to suppress such external disturbances are implemented via chassis sensitivity and receiver attenuation. However, simpler and more cost efficient approaches are desired. | {
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Personal computers are everywhere, yet for most users of database applications it is still not easy to get the information they need and to manipulate that information to get the answers they need. This invention relates generally to database and computational applications and relates particularly to an improved system permitting users to retrieve information from databases and to create programs for manipulation of the data and for performing computations on the data.
One commonly used application is what is generically called a database application. With such an application, the user is able to enter data on a record-by-record basis, edit selected records, browse through the contents of the database, and print reports based on the contents of the database. Some database applications are called "relational", denoting that a field in a selected record of a first database can be a pointer into a second, related database. Some database applications permit the user to write a program in a specialized language peculiar to the application. One commonly used database application is dBase III, published by Ashton-Tate. Another in common contemporary use is Paradox, published by Borland. In dBase III, which is a relational database application, a user can run a program written in the dBase programming language; the conventionally used extension to the DOS filename for the dBase program is the extension of ".PRG". The PRG program is executed by means of the dBase application serving as an interpreter.
Another commonly used application is what is generically called a spreadsheet application. With such an application, the user is able to fill cells in a two-dimensional array by means of keyboard entries. Each cell contains a numerical value, a formula, or a label. A formula is an expression which may include constants, operations, functions, and references to the contents of other cells. A commonly used spreadsheet application is Lotus 1-2-3; another is Excel published by Microsoft. Lotus also permits cells to contain "macros", expressions which contain programming steps interpreted by the Lotus application.
Most database applications have the drawback that programming is quite difficult. It is estimated that well over nine-tenths of the users of dBase, for example, never write any programs in the native dBase programming language, but only perform menu-driven activities such as the aforementioned editing and browsing. Among the many factors making programming difficult are the cumbersome requirements for creating and debugging database programs. The user must typically type in the entirety of a programming line, including the operations, field names, constants, etc. that make up a valid line of program. Syntax and data type mismatch errors are commonplace and cumbersome. Numerical operations such as summing and subtotaling are not easy, nor are operations intended to apply across all records, e.g. to increase the contents of a selected field by a percentage.
With many database applications, one who would write a program is constantly faced with having to try to keep in mind the names of fields in each database that is to be used. If two database files are to be accessed at once, the user will often have the additional complication of a field name turning up in more than one database file, which must also be kept in mind. The user will enter one or more program lines and then execute them. At execution time the user may learn, for the first time, that fields of inconsistent data type are being added, that there is an error in the syntax of the entered lines, or that a nonexistent field has been referred to. The user is thus subjected to a debugging cycle of numerous iterations just to obtain a runnable program, and only after that is the user in a position to check the program for logical correctness and finishing touches.
Most spreadsheet applications are also difficult to program. As with database applications, it is estimated that well over nine-tenths of users of Lotus never create macros to solve problems, but only enter the aforementioned labels, formulas, and constants. While many spreadsheet applications including Lotus have commands and menu choices (including sorting and looking up) intended to permit use of the spreadsheet for database purposes, most users have trouble using them.
When conventional database or spreadsheet applications are employed, a not infrequently encountered task is selecting records for further processing and analysis. In dBase, for example, one does what is called setting a "filter" to cause the display and processing only of records meeting a criterion.
An example will show how selecting records is inconvenient and problematical with present-day applications. A user may be working with a database file having a field for a Zip code, and may wish to arrive at statistics based on the records having a particular Zip code. The user will write a program in which, at the outset a selection step is performed setting a filter so that only records having the particular Zip code are considered for further computation. After executing the program, the user will obtain the desired data, but only, of course, after the usual iterative process of revising the program. After the program is debugged, there could be the unhappy news that there are no records matching the desired Zip code.
It would be helpful to many users of database and spreadsheet applications if there were a way to generate program steps permitting the user to give more attention to the step being generated and less to pesky aspects such as (1) having to remember the fields which can be used in the step, and (2) having to get the syntax and data types right on the first try. It would be additionally helpful to such users if there were a way to find out, and the time of generating the code relating to selecting records, the universe of actual values in the fields being used in the selection process. | {
"pile_set_name": "USPTO Backgrounds"
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Optical bar code scanners typically include a mirrored spinner. An imbalanced spinner can cause excessive wear on bearings and an unacceptable amount of audible noise. It would be desirable to provide an optical scanner having a balanced mirrored spinner. | {
"pile_set_name": "USPTO Backgrounds"
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Bistable latches, such as flip-flops, are capable of assuming either of two stable binary output states. The state of the output depends on the states of a data input and a clock signal. Latching flip-flops used in asynchronous systems, wherein a clock signal and a data input signal are switched asynchronously, are typically subject to a third, or metastable, output state. A metastable output may occur if the data input signal is undergoing a transition in its logic state simultaneously with an active edge of the clock signal. In such a case, the output of the flip-flop may latch at an unstable or metastable state somewhere between a logical high state and a logical low state. Such an invalid logic level cannot be interpreted by subsequent logic stages receiving the output signal from the flip-flop, resulting in system errors.
Typically, the metastable state will resolve itself over time as noise in the system stabilizes the output of the flip-flop by driving the output to either a high or low logical state. If noise does not resolve the metastability problem, however, the output of the flip-flop may be hung in an uncertain logical state until the next active clock cycle occurs. Often, the delay associated with either waiting for the output of the flip-flop to stabilize itself or waiting for the next active clock cycle is sufficiently long to cause subsequent logic circuitry to fail.
A known manner of correcting the metastability problem of flip-flops in asynchronous systems is to arrange two separate flip-flops in a cascaded configuration. U.S. Pat. No. 4,929,850 to Breuninger, for example, discloses two D-type flip-flops which are separately driven by clock pulses which are separated in time by a sufficient duration to nearly negate the possibility of the first latch being in its metastable state when the second latch is clocked. The output of the first flip-flop is permitted to stabilize before data is clocked into the second flip-flop.
U.S. Pat. No. 4,800,296 to Ovens, et al. discloses a metastable resistant flip-flop circuit including a single emitter transistor and a dual emitter transistor. During a metastable condition, each of the transistors conducts current. The second emitter on the dual emitter transistor, however, conducts additional current after a delay provided by a second clock, thereby upsetting the metastable condition of the circuit by drawing sufficient additional current to turn the single emitter transistor off.
Optimal design of flip-flop circuits requires minimal circuitry and minimum of additionally introduced delays for the purpose of eliminating metastability problems. Accordingly, it is an object of the present invention to provide a single flip-flop with improved metastability characteristics, comprising standard electrical components, and having no additional timing delays introduced therein by delayed clocking signals. | {
"pile_set_name": "USPTO Backgrounds"
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In recent years, solar photovoltaic technology has been significantly developed and various solar cells are commercially distributed. The solar photovoltaic power generation of “converts light energy from the sun into electric energy” has such advantages that (1) the energy source is enormous and is not depleted; (2) the energy source is clean and carbon dioxide is not generated during power generation; and (3) it allows energy self-sufficiency, and it is technology that can be used not only outside but also in space. The solar cells are roughly classified into the ones containing a silicon semiconductor (crystalline and amorphous (noncrystalline)) as a material and the ones containing a compound semiconductor as a material and cover more various types including those under development.
However, current solar cells can generate only low electricity despite the high production cost, and result in very low cost effectiveness compared to conventional power generation systems. In addition, solar cells after long-term use are observed to have degradation phenomena such as yellowing, separation, whitening and the like of sealing materials due to sunlight and moisture. Therefore currently the solar cells are required to have a long operating life as well as improved maximum power output.
As one of the currently proposed methods for long operating life of a solar cell, measures for preventing degradation have been confered by adding an ultraviolet absorber, a light stabilizer and an antioxidant to a sealing material.
In order to improve the maximum power output, maximum power point tracking (MPPT) which allows the maximum power output to be obtained by maintaining an optimal operating point according to the variation in the incident light intensity has been widely used (Non-Patent Document 1). | {
"pile_set_name": "USPTO Backgrounds"
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The present invention relates generally to arrangements for preventing the movement of a gear and, more particularly, to gear locking mechanisms having jam prevention structures.
A wide variety of devices have been used to selectively prevent rotational movement of gears and lock against actuation of whatever application is driven by the gears. In general, such arrangements can be referred to as "safelock" systems. However, the environment where the safelock system is employed can restrict the availability of certain prior devices for that purpose.
For example, in an aircraft hydraulic, mechanical and/or electrical power sources can employ gears to transmit power or actuation force to a variety of applications. In addition to the positive lock and safety criterion of ground-based safelock systems, the aircraft environment requires the arrangement to be lightweight, compact in size, highly reliable over long periods of time and unusually rugged with respect to mechanical and thermal stresses. In addition, ease of maintenance and serviceability are important design considerations.
As a specific example, safelock systems have previously been used to prevent inadvertent actuation of weapons access doors on military aircraft. One such safelock system included a gear segment which was selectively rotatable into engagement with the carrier gear of a hydraulic motor. The gear segment was supported for axial movement in either direction (backward or forward with respect to the direction of travel of the gear teeth) along the rotational axis between a plurality of biasing springs by a cam and pin assembly. Such bi-directional axial motion was intended to reduce the incidence of jamming between the gear teeth and the teeth of the gear segment by permitting the gear segment to be self seating between the gear teeth.
To further prevent such jamming, the gear teeth and the teeth of the gear segment were modified to include a taper from the side upon which those teeth first engage. That taper was typically "two dimensional" in that it was directed both inwardly from the side and downwardly from the top of the teeth.
Unfortunately, such prior safelock devices were subject to undesirably high friction upon actuation and, thus, did not always perform optimally. Accordingly, it was previously suggested to replace the cam/pin assembly with a ball bearing assembly. Unfortunately, single or three ball sets proved insufficient to sustain the load requirements, and significantly reduce actuation friction. As a result, a multiple ball array, such as a helical ball spline, was proposed. While such an array permitted significantly lower actuation friction, reliability maintenance for longer periods of time required relubrication of the array, preferably at the interior and outwardly from the longitudinal axis of the array. It was found, however, that acceptable relubrication structures interfered with the use of prior bi-directional spring biasing structures.
Biasing for axial motion of the gear segment forward with respect to the jack gear was still feasible using the prior biasing structure with the relubrication structure, but there was insufficient room for the prior backward motion biasing structure without at least significantly enlarging the size of the safelock assembly and complicating serviceability. In general, the prior biasing structures included helical springs on either side of the gear segment to achieve axially backward and forward biasing. Where only axially forward biasing was used, a helical spring was mounted on one side of the gear segment.
Accordingly, it is an object of this invention to provide an improved safelock system, especially for use in efficiency conscious environments such as aircraft. Further objects include at least providing a safelock system:
A. requiring reduced actuation friction, PA1 B. having a long useful life, PA1 C. with a decreased tendency to jam, PA1 D. of minimal cost and dimension, and PA1 E. which is easy to maintain and service.
These objectives are attained by the provision of a safelock system having a self-seating gear segment rotatably mounted on a helical ball spline for bi-directional axial movement with respect to the gear teeth to be locked. A relubrication structure is provided to service the interior of the ball spline. The interlocking teeth are two-dimensionally tapered from the point of initial engagement. Diverse biasing structures acting on opposing sides of the gear segment are employed to facilitate the axial self-seating reaction of the gear segment after initial engagement with the gear to be locked.
Other objects, advantages and novel features of this invention will become readily apparent from the following drawings and detailed description of preferred embodiments. | {
"pile_set_name": "USPTO Backgrounds"
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The invention relates to a method of demodulating binary data signals and has for its object to provide a method of demodulating a quadphase coded data signal, this data signal comprising words consisting of first, second, third and fourth equally long, consecutive half bit intervals.
The invention further relates to a receiver for carrying out the method.
Quadphase coding is known from the article by U. Appel and K. Trondle titled "Zusammenstellung und Gruppierung verschiedener Codes fur die Uebertragung digitaler Signale" which was published in the Nachrichten-technische Zeitschrift, Volume 1, 1970, pages 11-16, and FIG. 7 in particular. A quadphase coded signal is obtained by dividing the original binary data signal into groups of two bits, denoted dibits, and by placing the first and the second bits, respectively, of the dibit in the first and the second half bit interval, respectively, of the coded word, consisting of two bit intervals, and by placing the inverted value of the first and the second bit, respectively, of the dibit in the third and fourth half bit interval, respectively, of the coded word.
The coding method owes its name "quadphase" to the property that four basic signals can be distinguished, namely 0011, 1001, 0110 and 1100 (allotted to the dibits 00, 10, 01 and 11, respectively). | {
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The present invention relates to a novel 2-O-(9z,12z-octadecadienoyl)-3-O-[xcex1-D-galactopyranosyl-(1xe2x80x3-6xe2x80x2)-O-xcex1-D-galactopyranosyl]glycerol having an excellent effect on arthritis, osteoporosis and ruptured disc, and to a pharmaceutical composition containing the same
At present, it has been known that in Korea patients suffering from various bone diseases are on an increasing tendency annually. However, chemotherapy, operative therapy, etc. which have been currently used for the purpose of treating bone diseases have fail to realize the complete success as yet. Such bone diseases are advanced to chronic and degenerative state due to ageing, and fturther impose a great medical burden on a patient. Therefore, the development of novel materials which can be generally utilized in the clinical field is still urgently required.
It has been known that rheumatoid arthritis and degenerative arthritis known as typical adult diseases and geriatric diseases are an intractable disease (FIG. 2a), and are caused by a mechanism based on the activation of synovial cells in joint and the ageing due to such activation and the autoimmunological factors (FIG. 2b). It is expected that rheumatoid arthritis and degenerative arthritis can be cured by development of a drug which can kill or inhibit arthritic cells or inhibit or repress the expression of cyclooxygenase II (COX-II) as the enzyme produced by such arthritic cells (FIG. 2c).
The constituent drugs contained in the galenic composition developed by the present inventors have been described in xe2x80x9cDongeubogamxe2x80x9d and xe2x80x9cSinnongbonchokyungxe2x80x9d as having various pharmacological activities including hematopoiesis, tonic, diuresis, bone marrow formation, recruitment of vitality and virility, effects on pre- and post-partum joint, lumbago, stomachic, anti-inflammatory, promotion of blood circulation and removal of blood stasis, elimination of nervous disorders, detoxication, hemostasis, effect of alleviating climacteric disorders, emmenagogic effect, nutritive effect, hematic activity, etc. Further, other activities have also been disclosed in prior reference.
Throughout the whole world, the study of bone diseases has been actively conducted, and as a result, according to an increase of a series of immunological knowledge the etiology and mechanism of arthritic invasion have been revealed so that some agents for treatment of osteoporosis have been developed in recent days. Specifically, allendrate, tamoxifen, vitamin D3, parathyroid hormone (PTH) and COX-II inhibitor as an agent for treatment of rheumatoid arthritis have already been successfully commercialized. Further, as an anti-inflammatory agent sulfasalazine (Becker K, Gromer S, Schirmer R H, Muller S., Thioredoxin reductase as a pathophysiological factor and drug target. Eur. J Biochem., 2000 Oct., 15; 267(20):6118-6125) and thioredoxin reductase (a pathophysiological factor and drug target. Eur. J. Biochem., 2000 Oct., 15; 267(20):6118-6125) have been known and are under either clinical trials or research and development. Meanwhile, as an agent for treatment of osteoporosis alendronate, raloxifene, calcitonin (Moraghan T J, Perez E A. Mayo Clin Proc. 2000 Aug.; 75(8):821-9), estradiol (An-dersson T L, Stehle B, Davidsson B, Hoglund P. Maturitas. 2000 Jun. 30; 35(3): 245-52), genistein (Mazurek A P, Polkowski K, Acta Pol Pharm. 2000 Mar-Apr; 57(2):135-55), 1,25-dihydroxyvitamin D3 (Am. J. Physiol. Endocrinol. Metab. 2000 Jul; 279(1):E213-20), patathyroid hormone (Hunziker J, Wronski T J, Miller S C, J. Dent. Res. 2000 Jun; 79(6): 1431-8), alendronate (Kashyap A S, Kashyap S. Postgrad Med J. 2000 Jul; 76(897):417-8), estrogen receptor modulators, calcitonin, and bisphosphonates (Wimal-Awansa SJ. J. Clin. Densitom. 2000 Summer; 3(2):187-201) have been also disclosed.
Thus, in consideration of the problems caused in applying the prior drugs for the clinical purpose and involved in the toxic side effects, the present inventors have obtained the solvent fractions of Cibotii rhizoma (Cibotium barometz J. Smith) as a medicinal plant used in the complex Chinese medicine, and then observed the inhibitory activity of respective fractions against proliferation of synovial cells in joint portion. As a result, we have demonstrated that butanol fraction (CBB fraction) of Cibotii rhizoma is effective.
Cibotii rhizoma is Cibotium barometz J. Smith of which the rhizoma is used for the medicinal purpose and which inhabits a tropical region and is a medicinal plant belonging to Dicksoniaceae. According to the reference relating to Chinese medicines, Cibotii rhizoma has an effect of alleviating the joint pain and strengthening muscles and skeleton and has been disclosed that it has been used as a popular remedy. It has been known that Cibotii rhizoma contains onitin, onitin 4-O-xe2x96xa1-D-allopyranoside, onitin 4-O-xe2x96xa1-di-glucopyranoside and pterosin R (4-deoxy, 4-chloro onitin) and further, onitin has an activity for relaxing smooth muscle [Murakami, Takao; Satake, Toshiko; Ninomiya, Katsumi; Iida, Hideki; Yamauchi, Kazuhiko; Tanaka, Nobotoshi; Saiki, Yasuhisa; Chen, Chiu-Ming, Pterosin-derivate aus der Famile Pteridaceae. Phytochemistry, 19, 1743 1980]. Yang, Meei-Shieu, Studies on the Twian fork medicine VI. Studies on onitin. Planta Medica, p25 (1986)].
The present inventors divided the butanol fraction (CBB fraction) of Cibotii rhizoma into three sub-fractions CBB-10, CBB-20 and CBB-30 by chromatography on Sephadex LH-20 and conducted the animal test using three sub-fractions to identify that all of them are effective. CBB-20 is sugar-containing fraction of which the effective component could not be isolated, and CBB-30 contains polyphenolic compounds so that the effective component could not be isolated. However, from CBB-10 sub-fraction three kinds of a single material, i.e. CBB-11, CBB-12 and CBB-13 could be separated and purified. According to the result of determination on chemical structures, CBB-11 is onitin, CBB-12 is daucosterol as the previously known compound, and CBB-13 is the novel compound which is named chinbarometin. This novel compound has the following structure and its chemical name is 2-O-(9z,12z-octadecadienyl)-3-O-[xcex1-galactopyranosyl-(1xe2x80x3-6xe2x80x2)-O-xcex1-D-galactopyranosyl]glycerol:
The compounds having the similar structure as CBB-13 (shinbarometin) have been separated from Arisaematis rhizoma (Arisaema amurense Max.) and reported [Jung, Jee H.; Lee, Hongkun; Kang, Sam Sik, Diacyglycerylgalactosides from Arisaema amurense. Phytochemistry, 42(2), 447(1996)]. In such reported compounds various saturated fatty acids or unsaturated fatty acids are combined by ester linkage at position 1 and 2 whereas CBB-13 (shinbarometin) is a compound having no ester linkage of saturated or unsaturated fatty acids at position I of glycerol and therefore, is determined as a novel compound.
The present inventors have examined the effect of the compound separated and purified from Cibotii rhizoma on arthritis. As a result thereof, it was demonstrated that CBB-13 (shinbarometin, novel) exhibits the most excellent pharmacological effect and CBB-11 (onitin) has a moderate pharmacological effect.
Therefore, the object of the present invention is to identify that the component having an anti-arthritic effect in Cibotii rgizoma is shinbarometin as the novel compound.
Therefore, the present invention relates to a novel 2-O-(9z,12z-octadecadienoyl)-3-O-[xcex1-D-galactopyranosyl-(1xe2x80x3-6xe2x80x2)-O-xcex1-D-galactopyranosyl]glycerol having excellent effect on arthritis, osteoporosis and ruptured disc, and to a pharmaceutical composition containing said compound as an effective component. | {
"pile_set_name": "USPTO Backgrounds"
} |
1. Field of the Invention
The present invention relates to an adjusting method of button attaching apparatus for attaching a button to a fabric and adjusting jig used in the adjusting method.
2. Description of the Related Art
Conventionally, a button attaching apparatus for automating operation for attaching button etc. such as snap fastener has been utilized (see Japanese Utility Model Publication No. Hei 3-1447).
In such button attaching apparatus, one and the other of a pair of button components (button and backing member) are respectively attached to a pair of dies (first die and second die) sandwiching the fabric, the dies being pressed to caulk and engage the button and the backing member with each other sandwiching the fabric, thereby attaching the button to the fabric.
In the button attaching apparatus, a pair of holders capable of attaching and detaching the respective dies are provided so that a die corresponding to the button to be attached can be selectably used. A drive mechanism is provided on one or both of the respective holders to advance and retract the one or both of the dies in a direction for the dies to be moved toward and away from each other (along an advancement-retraction axis line), so that the respective dies are pressed or separated for attaching the button by caulking.
A cushion structure using spring etc. is provided to a part of the holder or the drive mechanism for absorbing fluctuation of the thickness of the fabric to a degree. In other words, even when the thick fabric is used, the die is pushed against, for instance, biasing force of a spring, so that generation of excessive pressing force between the dies can be prevented. Such cushion mechanism may be provided on either one of the dies or, alternatively, on both of the dies. When the cushion mechanism is provided on one of the dies, either of the advanceable holder and a stationary holder may be provided with the cushion mechanism. Further, various arrangements such as installing the cushion mechanism in the holder, supporting the holder in a cushioning manner against the drive mechanism and disposing the cushion mechanism on a part of the drive mechanism are possible for disposing the cushion mechanism.
Incidentally, when the button is attached by the button attaching apparatus, relatively low pressing force is required for the die in caulking claw portion. However, when rivet-bar type or eyelet type button is caulked, relatively high pressing force is necessary. In order to widely respond to the strong caulking force and weak caulking force, weak spring may be used for supporting one of the dies and strong spring may be used for supporting the other dies.
FIG. 4 shows a button attaching apparatus using the two, i.e. strong and weak springs.
The button attaching apparatus 10 has a metal, approximately box-shaped frame 11, the frame 11 having a recessed work portion 12 at a front side thereof. An upper holder 21 (first holder) for supporting an upper die 20 (first die) is located on the upper side of the work portion 12 and a lower holder 31 (second holder) for supporting a lower die 30 (second die) is located on the lower side thereof.
The lower holder 31 is fixed to the frame 11. On the other hand, the upper holder 21 is vertically advanced and retracted by a drive mechanism 40 installed in the frame 11 for a predetermined stroke. The drive mechanism 40 has a motor 41 as a drive source, which pivotably moves a link mechanism 46 through an arm 42, a rod 43, a crank 44 and a rod 45, the pivot movement vertically moving the upper holder 21.
Accordingly, in the button attaching apparatus 10, the upper holder 21 and the lower holder 31 are moved toward and away from each other by driving the drive mechanism 40, so that upper die 20 and the lower die 30 supported by the respective holders are separated and pressed to caulk the button and the backing member respectively held by the dies.
In the button attaching apparatus 10, the upper holder 21 and the drive mechanism 40 for advancing and retracting the upper holder constitute a first side portion and the lower holder 31 disposed on the frame 11 in a fixed manner constitutes a second side portion. An upper cushion mechanism 22 (a first cushion and a first cushion adjuster) are provided on the upper holder 21 included in the first side portion and a lower cushion mechanism 32 (a second cushion and a second cushion adjuster) are provided on the lower holder as the second side portion.
FIG. 5 shows an upper holder 21.
The upper holder 21 has a cylindrical case 210, the case 210 having a hollow section extending from the lower side of the figure to the upper side thereof, the hollow section accommodating a large number of coned disc springs 211 (first cushion), and an end member 212 is disposed on a free end of the coned disc spring 211.
A sleeve 213 is accommodated around the opening of the hollow section of the case 210, and an upper die 20 is attached to the sleeve 213 to prevent detachment by a setscrew 214. The sleeve 213 is abutted to the end member 212 through an adjusting bolt 215 and receives biasing force toward lower side in the figure by the coned disc spring 211. The movement of the sleeve 213 toward the lower side of the figure is restricted by an engaging member 217 projecting into a side opening 216 of the case 210 at a predetermined position. Accordingly, the sleeve 213 can be moved against the biasing force of the coned disc spring 211 when receiving a force in the upper direction in the figure. The adjusting bolt 215 can be rotated to change projection thereof from the sleeve 213, so that initial load applied to the coned disc spring 211 can be increased and decreased, thereby adjusting the biasing force from the coned disc spring 211 to the sleeve 213 (first cushion adjuster).
FIG. 6 shows a lower holder 31.
The lower holder 31 has a cylindrical case 310, the case 310 integrally clamping and fixing a part of the frame 11 and a base 312 along the backside of the frame 11 by screwing a nut 313 to an external screw formed on the outer circumference thereof. A plurality of tie rods 314 are connected to the base 312. A support plate 315 is inserted to an end of the tie rods 314, where an adjusting nut 316 is screwed. A coil spring 317 (second cushion) is disposed coaxially with the case 310 between the support plate 315 and the case 310.
A support rod 301 and a sleeve 302 are coaxially disposed inside the case 310 in an overlapping manner. A flange 303 is formed at the halfway of the sleeve 302, the flange 303 being supported by an upper end (in the figure) of the coil spring 317 and being held while being pressed to the nut 313 by the biasing force in the upper direction in the figure from the coil spring 317. A lower end (in the figure) of the sleeve 302 extends to a central opening of the support plate 315. An internal thread is formed at a distal end of the sleeve 302. An adjusting bolt 305 is screwed to the internal thread. A rotation-stop lock nut 304 is screwed to the adjusting bolt 305. An upper end (in the figure) of the adjusting bolt 305 is abutted to the lower end (in the figure) of the support rod 301. A lower die 30 is attached to an upper end (in the figure) of the case 310. The rotation of the lower die 30 is restricted by a buried screw 311 screwed from a side of the case 310 but is capable of vertical movement in the figure relative to the case 310. An end of the lower die 30 is abutted to the support rod 301 to support the load applied thereto. Accordingly, when the lock nut 304 is loosened and the adjusting bolt 305 is rotated relative to the sleeve 302, the support rod 301 is elevated and lowered relative to the sleeve 302 or the frame 11, so that the position of the lower die 30 relative to the upper die 20 can be adjusted (die position adjuster).
When a force to the lower side of the figure is applied from the lower die 30, the load is transferred to the sleeve 302 through the support rod 301, the adjusting bolt 305 and the nut 304 to press the coil spring 317. When the load is more than a predetermined value, the lower die or the sleeve 302 are moved to the lower side in the figure. The initial load of the coil spring 317 can be increased and decreased by adjusting the position of the support plate 315 by rotating the adjusting nut 316, so that the biasing force applied from the coil spring 317 to the sleeve 302 can be adjusted (second cushion adjuster).
Incidentally, a guard 308 using a weak coil spring 309 is attached around the lower die 30 for preventing fall-off of the buttons etc. before the die touches the fabric.
In the above button attaching apparatus 10, the upper coned disc spring 211 is normally of relatively weak biasing force and the lower coil spring 317 is normally of relatively strong biasing force. Specifically, the weak biasing force of the upper coned disc spring 211 is set for a button capable of being attached with weak caulking force and the strong biasing force of the lower coil spring 317 is set for a button requiring strong caulking force. Accordingly, the coned disc spring 211 or the coil spring 317 is displaced in accordance with the difference in the thickness of each fabric using the same button attaching apparatus 10 either in a case requiring strong caulking force or in a case capable of displacement with a weak caulking force, thereby appropriately attaching the buttons in accordance with characteristics of the respective fabric.
For instance, when a button capable of being attached with a weak caulking force, the button etc. is held respectively on the upper die 20 and the lower die 30 and the upper die 20 and the lower die 30 are moved toward each other to sandwich the fabric disposed on the halfway thereof. At this time, since the caulking force is weak, the coil spring 317 of the lower holder of which biasing force is set strong is not compressed. On the other hand, the coned disc spring 211 of the upper holder 21 of which biasing force is set weak is appropriately compressed to be displaced in accordance with the fabric, thereby appropriately attaching the button.
For attaching a button requiring strong caulking force, the button etc. is held respectively on the upper die 20 and the lower die 30 and the upper die 20 and the lower die 30 are moved closer to sandwich the fabric disposed on the halfway thereof. At this time, a large-diameter upper die 20 (see dotted line in FIG. 5) is used in the upper holder 21 so that outer circumference 20A is abutted not to the sleeve 213 but to the case 210, so that the coned disc spring 211 of weak biasing force is not compressed, thereby allowing strong caulking force. Accordingly, the coil spring 317 of which biasing force is set strong is compressed in the lower holder 31, thereby conducting displacement in accordance with the fabric for appropriate button attaching.
Incidentally, in order to appropriately attach the button in the above-described button attaching apparatus 10, the biasing force of the coned disc spring 211 and the coil spring 317 has to be set at an appropriate value in the upper holder 21 and the lower holder 31.
Additionally, though the fluctuation in the thickness of the fabric can be appropriately dealt with by the above-described cushion mechanism, appropriate caulking force is influenced by the load required for plastic deformation of the button and the backing member and the rigidity of the frame etc. Since the caulking force required for, for instance, snap fastener, amounts to approximately 1000 to 8000N, not only the flexure of the spring but also the flexure of the frame etc. has to be taken into consideration in attaching the button.
Accordingly, the setting of the button attaching apparatus has to be adjusted at least on the initial stage of installation for each button attaching apparatus and the buttons to be attached.
At present, in order to appropriately attach the buttons, 1) adjustment of relative position (bottom dead center position of advancing and retracting crank mechanism etc.) when the upper die and the lower die are brought the closest, and 2) adjustment of cushion mechanism in accordance with the fabric (adjustment of initial load of the coned disc spring 211 by the adjusting bolt 215 and adjustment of initial load by the coil spring 317 by the adjusting nut 316) are considered necessary.
Conventionally, such adjustment is conducted by actually conducting repeated button attaching while the buttons and the backing members are put into the dies and checking finished condition resulted therefrom.
However, in the above method, repeated setting processes and finish checks are required for adjusting the above die position and respective initial load. Especially, since the buttons are actually attached by putting the buttons and backing members into the dies, totally great amount of work is necessary. Further, since the reference thickness of fabric has to be administered for adjusting the cushion mechanism, handling thereof becomes troublesome. Furthermore, since spring constant of the cushion mechanism and rigidity of the mechanical portion of the frame etc. are greatly deviated, reference value setting is difficult, requiring much time and skill for adjustment and making appropriate adjustment difficult.
A primary object of the present invention is to provide an adjusting method and adjusting jig capable of easily and rapidly conducting adjustment required for a button attaching apparatus.
An adjusting method according to an aspect of the present invention is for a button attaching apparatus which has: a first die capable of receiving one of a pair of button components and located on a predetermined advancement-retraction axis line; a second die capable of receiving the other of the pair of button components and located on the advancement-retraction axis line opposing the first die; a first side portion having a first holder supporting the first die in an attachable and detachable manner and in a manner movable along the advancement-retraction axis line; a second side portion having a second holder supporting the second die in an attachable and detachable manner; a drive mechanism provided at least one of the first side portion or the second side portion for moving the first holder or the second holder toward and away from each other along the predetermined advancement-retraction axis line; a first cushion provided on the first side portion for biasing the first die toward the second die; and a first cushion adjuster for adjusting the biasing force of the first cushion, the method including the steps of: providing a first adjusting jig and a second adjusting jig, at least one of the first adjusting jig and the second adjusting jig being attached with a force gauge; setting the first adjusting jig and the second adjusting jig to the first holder and the second holder instead of the first die and the second die; adjusting a relative position of the first holder and the second holder so that a force measured by the force gauge becomes a predetermined value by mutually pressing the first adjusting jig and the second adjusting jig by bringing the first holder and the second holder closest with each other while the first cushion is disabled; and adjusting the first cushion adjuster so that the force measured by the force gauge becomes a predetermined value by mutually pressing the first adjusting jig and the second adjusting jig by bringing the first holder and the second holder closest with each other while the first cushion is enabled.
According to the above aspect of the present invention, adjustment of the relative position of the first holder and the second holder and adjustment of the first cushion can be conducted by measuring the force applied between the first holder and the second holder, so that reliability and speed of the adjustment can be greatly improved as compared to the conventional adjustment based on repeated trial.
An adjusting method according to another aspect of the present invention is for adjusting a button attaching apparatus which has: a first die capable of receiving one of a pair of button components and located on a predetermined advancement-retraction axis line; a second die capable of receiving the other of the pair of button components and located on the advancement-retraction axis line opposing the first die; a first side portion having a first holder supporting the first die in an attachable and detachable manner and in a manner movable along the advancement-retraction axis line; a second side portion having a second holder supporting the second die in an attachable and detachable manner; a drive mechanism provided at least one of the first side portion or the second side portion for moving the first holder or the second holder toward and away from each other along the predetermined advancement-retraction axis line; a first cushion provided on the first side portion for biasing the first die toward the second die; a first cushion adjuster for adjusting the biasing force of the first cushion; a second cushion being stronger than the first cushion and being provided on the second side portion for biasing the second die toward the first die; and a second cushion adjuster for adjusting the biasing force of the second cushion, the method comprising the steps of: providing a first adjusting jig and a second adjusting jig, at least one of the first adjusting jig and the second adjusting jig being attached with a force gauge; setting the first adjusting jig and the second adjusting jig to the first holder and the second holder instead of the first die and the second die; adjusting a relative position of the first holder and the second holder so that a force measured by the force gauge becomes a predetermined value by mutually pressing the first adjusting jig and the second adjusting jig by bringing the first holder and the second holder closest with each other while both of the first cushion and the second cushion are disabled; adjusting the second cushion adjuster so that the force measured by the force gauge becomes a predetermined value by mutually pressing the first adjusting jig and the second adjusting jig by bringing the first holder and the second holder closest with each other while the second cushion is enabled and the first cushion is disabled; and adjusting the first cushion adjuster so that the force measured by the force gauge becomes a predetermined value by mutually pressing the first adjusting jig and the second adjusting jig by bringing the first holder and the second holder closest with each other while both of the first cushion and the second cushion are enabled.
According to the above aspect of the present invention, adjustment of the relative position of the first holder and the second holder, adjustment of the first cushion and adjustment of the second cushion can be conducted by measuring the force applied between the first holder and the second holder, so that reliability and speed of the adjustment can be greatly improved as compared to the conventional adjustment based on repeated trial.
Especially, though great trouble accompanied in the conventional arrangement when both of the first cushion and the second cushion are provided, the adjustment can be conducted using the same force gauge and the same operations in the present aspect of the present invention.
Incidentally, in the adjusting method of the present invention, the advancement-retraction axis line is not restricted to extend in vertical direction as in the conventional arrangement but may extend in the horizontal direction (right and left). Any drive mechanism can be used as long as the first die and the second die can be moved toward and away with each other, where either one of the first die and the second die may be moved as in the conventional arrangement or, alternatively, both of the first die and the second die may be driven. The first holder on the first side portion may be driven by the drive mechanism or may be provided on the frame in a fixed manner. The second holder of the second side portion may be driven by the drive mechanism or may be provided on the frame in a fixed manner.
The first cushion can be provided on any position of the first side portion. For instance, the first cushion may be provided in the first holder of the first side portion, may be provided in the drive mechanism when the first holder is advanced and retracted, and may be provided between the first holder and the frame when the first holder is not advanced and retracted.
The second cushion may be provided at any position of the second side portion. For instance, the second cushion may be provided in the second holder, may be provided in the drive mechanism when the second holder is advanced and retracted, and may be provided between the second holder and the frame when the second holder is not advanced and retracted.
Further, the application of the present invention is not restricted to the arrangement having both of the first cushion and the second cushion, but may be applied to an arrangement having the cushion only one side.
In the present invention, the measurement of the force by the force gauge can be achieved with use of existing signal processor etc.
In the present invention, disabling the first cushion or the second cushion refers to a condition where the biasing force (resilient repulsive force) of the first cushion or the second cushion is not generated, which can specifically achieved by fixing the portions connected by the first cushion or the second cushion. For instance, the first cushion or the second cushion is deformed to the compression limit thereof by, for instance, tightening the adjusting bolt etc. to the maximum, further deformation is impossible to fix the movement thereof, thereby disabling the cushion. Alternatively, an independent connector may be provided to connect the portions connected by the first cushion or the second cushion to fix the first cushion or the second cushion for disabling the cushion.
In the adjusting method of the present invention, an adjusting jig which is abutted to the first holder so that movement thereof is restricted in the advancement-retraction axis line direction may preferably be used as the first adjusting jig or an adjusting jig which is abutted to the second holder so that movement thereof is restricted in the advancement-retraction axis line direction may preferably be used as the second adjusting jig for disabling the biasing force of the first cushion or the second cushion.
For instance, an adjusting jig having greater diameter than that of the first die or the second die may be used to abut to a stationary portion of the case etc. of the first holder or the second holder, so that the movement of the jig can be easily restricted in the advancement-retraction axis line direction.
According to the present invention, though dedicated jig is necessary, since operation for tightening the spring to the limit thereof etc. is not necessary, rapid operation can be conducted with a simple structure.
In the adjusting method of the present invention, an adjusting jig having a thin portion on a part thereof may preferably be used as either one of the first adjusting jig or the second adjusting jig, and a strain gauge or a piezoelectric gauge may preferably be attached to the thin portion.
The thin portion can magnify the distortion caused by the force applied between the first holder and the second holder, which can be securely and accurately detected by a sensor such as a strain gauge or a piezoelectric gauge.
In the present invention, the first and the second cushion may be a mechanical spring such as coil spring, coned disc spring and plate spring, or may be air cylinder, hydraulic cylinder, air damper or a hydraulic damper. However, considering simpleness of the structure, facilitation of adjustment and durability, mechanical spring may preferably be used.
An adjusting jig according to still another aspect of the present invention is used for adjusting a button attaching apparatus which has: a first die capable of receiving one of a pair of button components and located on a predetermined advancement-retraction axis line; a second die capable of receiving the other of the pair of button components and located on the advancement-retraction axis line opposing the first die; a first side portion having a first holder supporting the first die in an attachable and detachable manner and in a manner movable along the advancement-retraction axis line; a second side portion having a second holder supporting the second die in an attachable and detachable manner; a drive mechanism provided at least one of the first side portion or the second side portion for moving the first holder or the second holder toward and away from each other along the predetermined advancement-retraction axis line; a first cushion provided on the first side portion for biasing the first die toward the second die; and a first cushion adjuster for adjusting the biasing force of the first cushion, in which a position adjustment thickness (T0) required for adjusting relative position of the first holder and the second holder and a first adjustment thickness (T1) required for adjusting the biasing force of the first cushion are selectable.
An adjusting jig according to further aspect of the present invention is used for adjusting a button attaching apparatus which has: a first die capable of receiving one of a pair of button components and located on a predetermined advancement-retraction axis line; a second die capable of receiving the other of the pair of button components and located on the advancement-retraction axis line opposing the first die; a first side portion having a first holder supporting the first die in an attachable and detachable manner and in a manner movable along the advancement-retraction axis line; a second side portion having a second holder supporting the second die in an attachable and detachable manner; a drive mechanism provided at least one of the first side portion or the second side portion for moving the first holder or the second holder toward and away from each other along the predetermined advancement-retraction axis line; a first cushion provided on the first side portion for biasing the first die toward the second die; a first cushion adjuster for adjusting the biasing force of the first cushion; a second cushion being stronger than the first cushion and being provided on the second side portion for biasing the second die toward the first die; and a second cushion adjuster for adjusting the biasing force of the second cushion, in which a position adjustment thickness (T0) required for adjusting relative position of the first holder and the second holder, a first adjustment thickness (T1) required for adjusting the biasing force of the first cushion, and a second adjustment thickness (T2) required for adjusting the biasing force of the second cushion are selectable.
Such jig may be a plurality of jigs of predetermined thickness which is exchanged in use, or may be an assembly jig including a plurality of blocks to be superposed to achieve the predetermined thickness.
With the use of the jig, the above adjusting method including adjustment of the position of the first holder and the second holder, adjustment of the first cushion and adjustment of the second cushion can be securely and rapidly conducted.
The adjusting jig of the present invention may preferably have a base member having a shaft capable of being attached to the first holder or the second holder and a flange formed on an end of the shaft; and an additional member formed in a ring capable of being inserted to the shaft and superposed on the flange may preferably be provided, in which the position adjustment thickness (T0) and the first adjustment thickness (T1) can be formed only with the flange or the superposition of the flange and the additional member.
The adjusting jig of the present invention may preferably have a base member having a shaft capable of being attached to the first holder or the second holder and a flange formed on an end of the shaft; and an additional member formed in a ring capable of being inserted to the shaft and superposed on the flange, in which the position adjustment thickness (T0), the first adjustment thickness (T1) and the first adjustment thickness (T2) can be formed only with the flange or the superposition of the flange and the additional member.
According to the above arrangement, the assembly-type jig using ring-shaped additional member is used so that attachment and detachment can be facilitated and the components can be stably assembled, thereby enhancing usability thereof.
In the adjusting jig of the present invention, any of the additional members may preferably be abutted to the first holder or the second holder so that movement thereof is restricted in the direction of the advancement-retraction axis line in order to disable the biasing force of the first cushion or the second cushion, and the other of the additional members may preferably not interfere with the first holder or the second holder for enabling the biasing force of the first cushion or the second cushion.
According to the above arrangement, either one of the cushion can be disabled in the above adjusting method using the exchangeable additional member of the adjusting jig, so that the operation of the above adjusting method can be further simplified. | {
"pile_set_name": "USPTO Backgrounds"
} |
1. Field of the Invention
The present invention relates to a stylus support assembly for a gauge for a metrological instrument for measuring surface form such as roundness and/or surface finish parameters, such as surface texture or roughness.
2. Discussion of the Background
Metrological instruments are known in which a stylus is mounted on an arm so as to follow the surface form or finish of a workpiece during relative movement of the arm and the workpiece. A transducer outputs a signal in accordance with movement of the stylus relative to the arm. Metrological instruments are normally made so that the stylus is removable and replaceable. This is to allow a different stylus to be fitted to the same machine. This may be necessary to allow the stylus length to be changed or to change the particular stylus tip, in accordance with the workpiece being measured and the accuracy required. However, the constant insertion and removal of different styli means that the gauge must be constantly recalibrated and leads to inaccurate readings from the transducer if recalibration is not carried out.
According to one aspect of the present invention there is provided a stylus support assembly which supports a stylus in a more stable and reliable manner.
According to one aspect of the present invention, there is further provided a stylus support assembly for supporting a stylus for use in a gauge for a metrological instrument, the support assembly comprising two members resiliently connected so as to provide a stylus force in use of the assembly to enable the stylus tip to be pressed against the surface of the body to be measured and keep contact with that surface.
The members may be connected at an angle which is typically within a range of 2xc2x0 to 3xc2x0 from the perpendicular to the gauge axis. The stylus force can be changed by changing the resilience and/or the angle of the connecting means.
In another aspect, the present invention provides a one-piece stylus. A stylus tip can be mounted at the front end. A shaft for holding a core of a transducer ferrite, can be located at the rear end of the stylus.
In one aspect, the invention provides a particular construction of stylus support means to improve stylus stability.
A stylus support assembly embodying the invention is easy to manufacture and assemble. | {
"pile_set_name": "USPTO Backgrounds"
} |
1. Field of the Invention
The present invention relates to telecommunication networks and, more particularly, to a method and system for reporting events to subscribers in telecommunication networks.
2. Background of the Art
Telecommunication networks use various signaling systems for establishing calls between subscribers. At times, however, the networks may detect certain states or events that would prevent the networks from establishing calls between subscribers. These events may include, for example, when a called directory number is out of service, network lines are busy or down, a switching node experiences a problem, etc. In such instances, the networks instead report the detected events to the subscribers by playing prerecorded audible messages.
Specifically, when a subscriber places a call to another subscriber in a network, a switching node local to the calling subscriber receives a call request from the calling subscriber's device. The switching node then sends a route request to a signaling node in the network to determine a route for the call. If the signaling node determines a route, the signaling node returns to the switching node the directory number of the next node in the network through which the call must be routed. Otherwise, if the signaling node detects that the call cannot be established or routed such as when the called subscriber's directory number is out of service, the signaling node returns an error code to the switching node. The switching node then notifies the subscriber that the requested call cannot be established by playing a prerecorded audible message corresponding to the error code.
Although audible messages may be sufficient for reporting events to subscribers who use plain ordinary telephone service (POTS) telephone sets, such messages are not universally recognizable by all subscriber devices. For example, consider a subscriber who uses a telecommunications device for the deaf (TDD) to place calls to other subscribers in the network. When the network plays an audible message to report an event, neither the subscriber nor the TDD device would be able to recognize the message. Similarly, an application running in a desktop computer for dialing into, for example, a local Internet Service Provider (ISP) system cannot recognize audible messages received from the network or present such messages in a form that is recognizable to a subscriber.
In present wireline telecommunications networks, a wireline telephone number or directory number (DN) is associated with a fixed geographic location and is served by a single wireline switch. A wireless DN, however, is associated with multiple geographic locations and is served by any one of a number of wireless switches depending on the specific geographic location of the associated wireless device at the time a call is made. This portability of a wireless DN is one of the basic attributes of wireless telephony.
A home location register and visited location register in a telecommunications network provide seamless roaming when a call is placed to or from a wireless DN. A home location register is associated with a home wireless switch where a wireless DN resides (i.e., the wireless switch to which all incoming calls to the wireless DN are directed). A wireless device is located within its home area when the wireless device can directly communicate with its associated home wireless switch (i.e., located in the area covered by the home wireless switch).
A visitor location register is associated with a wireless switch currently serving a wireless device that is outside of its home area. A wireless device is outside of its home area (or roams) when the wireless device cannot directly communicate with the home wireless switch and instead communicates with another wireless switch, which is referred to as a visited wireless switch.
In telecommunication networks two connections must be established when a call is placed to a wireless DN whose associated wireless device is outside of its home area. In such instances, the telecommunications network first establishes a connection to the home wireless switch associated with the wireless DN. The home wireless switch then establishes a second connection to a visited wireless switch that currently serves the wireless DN. When errors, such as missing information, misrouted query and other process failures are encountered, a numerical error value is returned to the requester representing the reason for the failure.
There are multiple messages used in wireless intelligent networks (WIN) that route call requests from wireless subscribers or from users who use audible devices such as, plain ordinary telephone service (POTS) telephone sets, attempting to communicate with the wireless subscribers. These include, but are not limited to, the LocationRequest, RoutingRequest, OriginationRequest and TerminationRequest messages described in “Interim Standard 41” (IS-41). The IS-41 standard is described in “Radio Telecommunications Intersystem Operations,” ANSI/TIA/EIA/41-D-1997, which is incorporated herein by reference. Although used in different circumstances, each of these messages ultimately requests a Directory Number which to route the call requests.
As an illustration, FIG. 10 shows a block diagram of a conventional Telecommunication network (1000) implementing the LocationRequest, RoutingRequest messages. Telecommunications network 1000 comprises a wireline switch 1020, a home wireless switch 1040, a home location register (HLR) 1050, signal transfer points (STPs) 1060, 1087 and 1057, a visitor location register (VLR)1070, a visited wireless switch 1080, a wireline telephone 1010, antenna 1090, and a wireless device 1095.
Typically, a wireline subscriber using telephone 1010 initiates a call request by dialing the wireless DN associated with wireless device 1095, temporarily located in a visited system controlled by visited wireless switch 1080. The request is sent to wireline switch 1020 over existing connection 1000a, where it examines the DN to determine its status (resident or non-resident). When wireline switch recognizes the non-resident status of the number, it routes the request 1000b to Public switch Telephone Network/Interchange Carrier (PSTN/IXC) 1030 over existing connection 1000b. PSTN/IXC 1030 examines the dialed number and routes it to home wireless switch 1040, using existing connection 1000c.
Home wireless switch 1040 recognizes the DN as one that it is not currently serving, and sends an IS-41 LocationRequest message 1000d to HLR 1050, possibly through STP 1057. HLR 1050 examines its database and determines that the wireless device 1095 is being served by VLR 1070, which is associated with the visited wireless switch 1080. HLR 1050 sends an IS-41 RoutingRequest 1000e to VLR 1070, possibly by way of STP 1060.
VLR 1070 consults its internal database and allocates a Temporary Local Directory Number (TLDN) from a pool of available numbers associated with visited wireless switch 1080 currently serving wireless device 1095. The TLDN is populated into the response to the RoutingRequest 1000e and sent back to HLR 1050 as RoutingRequest response 1000f, possibly by way of STP 1060.
HLR 1050 takes the TLDN from the RoutingRequest response 100 of and populates it into the response to the LocationRequest 1000d from home wireless switch 1040, as LocationRequest response 1000g. Home wireless switch 1040 examines the LocationRequest response 1000g and establishes the route to the TLDN by way of PSTN/IX 1035. The PSTN/IX 1035 establishes a route to the visited wireless switch 1070 and passes the call via connection 1000i. The visited wireless switch 1080 sends a RoutingRequest 1000j to VLR 1070 possibly through STP 1087, and receives a response 1000k containing a mobile identification number (MIN) previously associated with the TLDN populated into RoutingRequest response 1000f. The visited wireless switch 1070 then routes the call to the wireless device 1095 by way of antenna 1090 using internal routing 1000l. Thus, wireline telephone 1010 is connected to wireless device 1095 by a voice path consisting of a subscriber line 1000a, wireline switch 1020, connection 1000b, PSTN/IX 1030, connection 1000c, home wireless switch 1040, connection 1000h, PSTN/IX 1035, connection 1000i, visited wireless switch 1080, internal connection 10001, and antenna 1090.
It should be noted that STPs 1057, 1060 and 1087 may represent one or more STPs that are required to perform the transfer of messages. Furthermore, the communications between VLR 1070 and HLR 1050, visited wireless switch 1080 and VLR 1070, and between home wireless switch 1040 and HLR 1050, may take place without STPs 1060, 1087 and 1057, respectively.
Event reporting (including error handling) occurs whereby an error code is returned in the response to either the RoutingRequest or LocationRequest (depending on the entity encountering the exception condition). This error would propagate back to the original requesting party, the home wireless switch 1040, which would map the event/error to one of the standard recordings already available on the switch. Examples of events that might be reported are Subscriber Not available [No Page Response], No Capacity [Resource Shortage] and Busy.
FIG. 11 shows a block diagram of a conventional Telecommunication network (1100) implementing the OriginationRequest message. Telecommunications network 1100 comprises a wireline switch 1180, a home location register 1160, signal transfer points (STPs) 1150 and 1147, a visitor location register 1140, a visited wireless switch 1130, a wireline telephone 1190, antenna 1120, and a wireless device 1110.
Typically, wireless device 1110 originates a call at visited wireless switch 1130 by way of antenna 1120 and existing internal connectivity 1100a. Visited wireless switch 1130 recognizes parameters previously provided by home location register (HLR) 1160, causing an origination trigger to be invoked, which locates a visited location register (VLR) associated with the visited wireless switch 1130. This results in an OriginationRequest 1100b to be sent to VLR 1140, possibly through STP 1147.
VLR 1140 passes the OriginationRequest 1100b to HLR 1160, possibly by way of STP 1150. HLR consults its internal tables and routing information to determine if the dialed call is allowed, possibly substituting a different destination number into a OriginationRequest response 1100c. The OriginationRequest response 1100c is passed back to the visited wireless switch 1130 by way of VLR 1140 and possibly STPs 1150 and 1147.
It should be noted that STPs 1150 and 1147 may represent one or more STPs that are required to perform the transfer of messages. Furthermore, the communications between VLR 1140 and HLR 1160, and visited wireless switch 1130 and VLR 1140, may take place without STPs 1150 and 1147, respectively.
The visited wireless switch 1130 routes the call to the destination number returned in the OriginationRequest response 1100c by way of existing connection 1100d to PSTN/IX 1170. The call is routed by PSTN/IX 1170 to wireline switch 1180, where the destination number resides, by way of existing connection 1100e. Wireline switch 1180 routes the call to wireline telephone 1190.
The overall differentiation here from an ordinary wireless call is that each call made by the wireless device 1110 is validated by HLR 1160, and the actual destination connected to is that specified by HLR 1160 through the destination number contained in the OriginationRequest response 1100c, which may be the same or different from the number dialed by the wireless device 1110.
Analogous to the description of FIG. 10, event reporting (including error handling) occurs whereby an error code is returned in the response to the OriginationRequest. This error would propagate back to the original requesting party, the visited wireless switch 1130, which would map the event/error to one of the standard recordings already available on the switch. Examples of events that might be reported are No Capacity [Resource Shortage] and Unassigned Directory Number.
FIG. 12 shows a block diagram of a conventional Telecommunication network 1200 implementing the TerminationRequest message. Telecommunications network 1200 comprises a wireline switch 1220, PSTN network 1230, a home wireless switch 1240, a home location register 1250, STP 1257, a wireline telephone 1210, antenna 1260, and a wireless device 1270.
Typically, a wireline telephone 1210 attempts to place a call to wireless device 1270 by utilizing existing connection 1200a to wireline switch 1220. Wireline switch 1220 routes the call through existing connection 1200b to PSTN/IX 1230. PSTN/IX 1230, using existing connection 1200c, passes the call to home wireless switch 1240. Home wireless switch 1240 recognizes parameters previously provided by HLR 1250, causing a termination trigger to be invoked, which locates a HLR associated with the visited wireless switch 1230, in this case HLR 1250. Home wireless switch 1240 subsequently provides a TerminationRequest 1200d to HLR 1250, possibly through STP 1257.
HLR 1250 consults internal tables and routing information to determine if the dialed call is allowed, and possibly substitutes a different phone number into a TerminationRequest response 1200e. The TerminationRequest response 1200e is passed back to the home wireless switch 1240, possibly through STP 1257. The home wireless switch 1240 may then route the call to the wireless device 1270 by way of internal connection 1200f and antenna 1260. The advance described here is the ability of HLR 1250 to examine the call attempt to the wireless device 1270 and specify the actual termination directory number.
It should be noted that STP 1257 may represent one or more STPs that are required to perform the transfer of messages. Furthermore, the communications between home wireless switch 1240 and HLR 1250, may take place without STP 1257.
Similar to the description of FIGS. 10 and 11, event reporting (including error handling) occurs whereby an error code is returned in the response to the TerminationRequest. This error would propagate back to the original requesting party, the home wireless switch 1240, which would map the event/error to one of the standard recordings already available on the switch. Examples of events that might be reported are No Capacity [Resource Shortage] and Unassigned Directory Number.
With reference to the networks described in FIGS. 10-12, problems arise in returning the reason for the failure to the party that originated the call, enabling them to correct their actions, if possible, and retry their call. Current technology provides only for the requester to interpret the error value according to a standard definition and provide their own routing to an audible error message. Because of using only a fixed audible recording technology for the error report, automated and data-only calls may fail to provide usable information to the call originator. For example, an audible message has little value to a hearing impaired user attempting a call using a Telecommunications Device for the Deaf (TDD). Similarly, an application running in a desktop computer for dialing into, for example, a local Internet Service Provider (ISP) system cannot recognize audible messages received from the network or present such messages in a form that is recognizable to the wireless subscriber. With calls in a wireless intelligent network originating from multiple sources and performing requests for routing information from multiple sources, the problem of providing this information in a meaningful format for specific users grows geometrically with the size of the Intelligent Network (IN). Additionally, error sources that are not specific to the IN but may be meaningful to the applications cannot be reported without expanding the standard offering for the IN.
As yet another example, consider subscriber devices used in automotive telemetric or remote reading applications. In such applications, subscriber devices send and receive data from remote systems by automatically placing calls over existing networks. However, since these subscriber devices cannot process the audible messages that are reported by the networks, they cannot provide the subscriber with informative as to the cause of most communication failures. Furthermore, these subscriber devices cannot automatically take corrective actions in response to most communication failures. Corrective actions may include, for example, redialing a directory number when network lines are busy or dialing a different directory number when a previously dialed directory number is temporarily out of service. As the number of subscribers who use these and other devices that cannot process audible messages increases, the need for reporting network events in formats that subscriber devices can process grows accordingly.
Furthermore, even with respect to those users who use audible devices such as, plain ordinary telephone service (POTS) telephone sets, to communicate with wireless subscribers there is a need to provide audible messages in languages that both the users and subscribers can understand. For example, a Spanish speaking subscriber may wish to receive audible messages in Spanish, whereas a French speaking subscriber may wish to receive audible messages in French. The utility of this process recognizes that if a wireless subscriber utilizes a special data type (such as TDD), or language (such as French), for communication, then those who wish to communicate with the wireless subscriber will also be expecting the same format. | {
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The present application relates generally to shower door assemblies, and more specifically, to pivoting, self-closing shower door assemblies.
Conventional pivoting shower door assemblies include a fixed wall member that is coupled to a fixed structure, such as a portion of a shower enclosure, a wall of a building, or another fixed portion of a building. A shower door panel can be pivotably coupled to the fixed wall member via one or more bracket assemblies to enable the door panel to pivot relative to a door opening of, for example, a shower enclosure to thereby allow the ingress and egress of a user from the shower. Typically, the bracket assemblies have fixed mounting points on both the wall member and the pivoting door panel. Thus, once the door panel is pivotably coupled to the fixed wall member, the door panel cannot be adjusted to level or correct for out-of-plumb conditions (i.e., askew positioning of the door) or to adjust a lateral position of the door relative to a door opening. In addition, many shower door assemblies use a separate, external stop mechanism or a latch (e.g., a striker plate, a magnet, etc.) mounted to a portion of, for example, a shower enclosure or a wall of a building to set a rotational position or end point for rotation of the door (i.e., at a fully opened or at a fully closed door position).
Accordingly, it would be advantageous to provide a shower door assembly that includes a pivotable door and also includes independently adjustable door brackets that allow for selective adjustment of the shower door position to level or correct for out-of-plumb conditions and to adjust a horizontal position of the door relative to a door opening. Furthermore, it would be advantageous to have a shower door bracket that includes internal features to set a rotational position/end point for the door, thereby eliminating the need for separate, external stop mechanisms or latches. These and other advantageous features will become apparent to those reviewing the present disclosure and drawings. | {
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Cancer in its different forms is a major cause of death in humans. The most widely used therapeutic treatments of cancer are local therapy, such as surgery and radiation, or chemotherapy. The rapid increase of knowledge in recent years about the molecular and cellular bases of immune regulation, particularly at the level of T-cell responses, provides a new arsenal of immunotherapeutic approaches including the development of tumor vaccines. Tumor vaccine is administered for therapeutic or preventive purposes. This can include administration of immuno-potentiating agents as well as biological response modifiers such as interferons and interleukins, in order to stimulate the immune system.
Vaccination with an antigen molecule, such as a peptide or a protein, generally leads to an antibody response or CD4+ helper T cell response (Raychaudhuri et al., 1993 Immunol Today 14:344). This immune response is initiated by the binding of the antigen to selected major histocompatibility complex (MHC) molecules of either Class I or Class II. The latter molecules are expressed primarily on cells involved in initiating and sustaining immune responses such as T lymphocytes, B lymphocytes and macrophages. Class II molecules are recognized by CD4+ helper T cell and induce their proliferation and the amplification of the immune response to the epitope that is displayed. Class I MHC molecules are found on most nucleated cells and are recognized by cytotoxic T lymphocytes (CTLs) which destroy the antigen bearing cells. The CTL response is a major component of the immune system, active in immune surveillance and destruction of infected or malignant cells and invading organisms expressing foreign antigens on their surface. The ligand of the antigen-specific T lymphocyte receptor is a complex made up of a peptide fragment of a foreign antigen 8 to 10 amino acids in length, presented in the groove of MHC class I molecules. Unlike B cells, T cells do not recognize intact native antigen molecules. In general, cytotoxic T cell activation requires that the antigen be processed endogenously and cleaved into specific peptide fragments which are presented on the surface of antigen processing cells in association with class I MHC molecules.
Accordingly, a successful vaccine for cancer immunotherapy requires the identification of a target antigen and the production of a cytotoxic T cell response. Moreover, identification of cell surface antigens expressed exclusively or preferentially on certain tumors allows the formation of selective treatment strategies.
Numerous disclosures exist concerning immunomodulatory peptides. WO94/20127 discloses means and methods for selecting immunogenic peptides capable of specifically binding HLA-A2.1 allele and inducing T-cell activation. WO95/19783 relates to peptides based on an epitope derived from the product of the tumor associated gene MAGE-3. WO97/11715 discloses a peptide which mimics MUCI or other cancer peptides. WO00/06723 discloses tumor specific antigen peptides and use thereof as anti-tumor vaccines. U.S. Pat. No. 6,406,700 discloses methods for isolating immunogenic complexes by using a cDNA library from cancer cell RNA.
International patent applications WO95/20605 and WO00/58363 which are incorporated herein by reference, describe a novel monoclonal antibody designated BAT-1, also designated herein BAT, which induces lymphocyte proliferation and cytolytic activity against tumor target cells. A single intravenous administration of BAT into mice bearing various tumors resulted in striking anti-tumor effects manifested by regression of tumors and prolongation of survival. BAT also induced regression of human tumor xenografts transplanted into SCID mice that were engrafted with human peripheral blood lymphocytes. The anti-tumor activity of BAT is mediated by its immune stimulatory properties as was evident from adoptive transfer experiments in which splenocytes from BAT treated mice injected to mice bearing tumors induced regression of tumors. The membrane determinant recognized by BAT has not yet been identified or characterized.
Several alternative methods of identifying the peptide epitopes bound by monoclonal antibodies are recognized in the art. These methods include the use of phage display libraries such as disclosed in U.S. Pat. Nos. 5,223,409; 5,403,484; 5,571,698; 5,837,500 and continuations thereto. Phage display involves a selection technique enabling identification and isolation of a protein against a chosen target. The selection procedure is based on DNA molecules, each encoding a protein and a structural signal calling for the display of the protein on the outer surface of a bacteriophage. The protein is expressed and the potential binding domain is displayed on the outer surface of the phage. The cells or viruses bearing the binding domains which recognize the target molecule are isolated, by a repetitive selection process called biopanning, and amplified. The successful binding domains are then characterized.
Epitope libraries can also be screened for epitope sequences which mimic the epitope, i.e., sequences which do not identify a continuous linear native sequence that necessarily occurs within a natural protein sequence. These mimicking peptides are called mimotopes. In most cases mimotopes are short peptides which can be readily synthesized in large amounts. Mimotopes of various binding sites have been found. For example, U.S. Pat. No. 5,877,155 provides an isolated peptide that functionally mimics a binding site for a monoclonal antibody, the monoclonal antibody recognizing an epitope within the human platelet glycoprotein Ib/IX complex.
There is an unmet medical need for peptides capable of eliciting or stimulating an anti-tumor immune response in vivo. | {
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This invention relates to radio communications systems and methods, and in particular to systems and methods for managing the power consumption and performance of analog radio receiver integrated circuits.
The demands placed on the batteries of radio communications devices have increased as such devices incorporate increasingly complex functionality. Increasing power demands pose new challenges for system designers attempting to balance system functionality and power consumption requirements. | {
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1. Field of the Invention
The invention relates to a method and device for improving the printing quality and the repetition accuracy of electrographical printers, in which a latent electric charge pattern of electrical signals is produced by means of an electrode matrix or the like, which opens and closes passages or apertures respectively between electrodes for exposing electrical fields for the attraction of pigment particles against an information carrier. Each electrode of the matrix is arranged on a carrier to completely surround one aperture of the matrix.
2. Description of the Prior Art
International patent application PCT/SE88/00653 discloses a method for developing pictures and text with pigment particles on an information carrier directly from computer generated signals, without the need for these signals to be intermediately stored for temporary conversion to light energy, which is necessary in photo conductive printers, e.g., laser printers. These problems have been solved by bringing the information carrier into electrical cooperation with at least a screen or preferably a lattice-shaped electrode matrix, which through control in accordance with the configuration of the desired pattern, the apertures of the matrix, which is galvanically connected to a voltage source, are at least partly opened and closed. An electric field is exposed through the open apertures for the attraction of the pigment particles against the information carrier.
This method, herein referred to as the EMS concept and as described in the above-mentioned patent application, may result in produced print which does not have high quality, particularly with repeated and continuous use.
The EMS concept refers to electrode matrices in which apertures or meshes in the matrix are defined and separated by simple electrodes, wherein the potential of every single electrode substantially influences the characteristics of the electric field on the pigment particles symmetrically in apertures adjoining the electrodes. This results in the attraction of pigment particles (herein called toner), not only in the mesh, which is surrounded by electrodes and the potential of which is intended to completely or partly open the mesh (herein called "black" voltage), but also in the exposed apertures of adjacent meshes. In electrode matrices with several mesh lines, meshes surrounded by simple electrodes will develop full-dots with intended extension and position, as well as half- and quarter-dots surrounding the full-dots. This results in an unsatisfactory edge definition and in certain cases a "blur" on the printed page. It is possible to change the potential of the adjacent electrodes, which are intended to close the apertures in the adjacent meshes (called "white" voltage) and reduce the problem of the undesired half- and quarter-dots, by skew setting the abovementioned symmetrical influence on the electrical field. This, however, leads to a potential difference between electrodes with "white" voltage and electrodes with "black" voltage (herein called contrast voltage), which in turn increases the manufacturing costs for the control electronics, as well as the electrode matrix.
The problems stated above are not limited to the EMS concept, but are also present wholly or partially in several electrographic printer concepts, where passage of toner is created in an electrical manner.
Common to all problems described here, another drawback of the known technique is that the printing quality, and thereby the readability, is influenced negatively resulting in reduced competitiveness and lower consumer value. | {
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The following abbreviations are herewith defined, at least some of which are referred to within the following description of the prior art and the present invention. AFC Automatic Frequency Control ATC Automatic Time Control BA BCCH Allocation BCCH Broadcast Control Channel BS-PA-MFRMS Base Station Paging Multiframes BSIC Base Station Identification Code CCCH Common Control Channel CRC Cyclic Redundancy Check DRX Discontinuous Reception E-UTRA Evolved-Universal Terrestrial Radio Access FCCH Frequency Correction Channel GSM Global System for Mobile Communications HLR Home Location Register LA Location Area MS Mobile Station MTC Machine Type Communication NAS Non Access Stratum RA Routing Area RSSI Received Signal Strength Indicator SCH Synchronization Channel TSC Training Sequence Code UTRA Universal Terrestrial Radio Access
In a Global System for Mobile Communications (GSM) network today, each registered mobile station (MS) must monitor its own paging group on the paging channel periodically with a periodicity which varies between 0.47 and 2.12 seconds and is set by the parameter BS-PA-MFRMS (see 3GPP TS 44.018 V11.3.0 (2012-11)'s chapter 10.5.2.11—the contents of which are incorporated by reference herein). The length of the paging cycle is set to achieve a balance between the acceptable responsiveness for mobile terminated call set-up procedures and the MS battery lifetime. Today, the MS uses a significant amount of power decoding and processing received information which is not intended for it when it periodically checks for incoming paging messages and performs other idle mode activities. This leads to significant overhead which quickly drains the MS battery especially for MSs which are characterized as machine type communication (MTC) devices. | {
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Optical films, including polymeric single layer optical films, polymeric multilayer optical films and polymeric optical films including disperse and continuous phases, are widely used for various purposes. Exemplary applications of polymeric optical films include display devices, such as liquid crystal displays (LCDs) placed in mobile telephones, personal data assistants, computers, televisions and other devices. Well known polymeric optical films include reflective polarizer films, such as Vikuiti™ Dual Brightness Enhancement Film (DBEF) and Vikuiti™ Diffuse Reflective Polarizer Film (DRPF), both available from 3M Company. Other well known polymeric optical films include reflectors, such as Vikuiti™ Enhanced Specular Reflector (ESR), also available from 3M Company.
Polymeric multilayer optical films used as polarizers or mirrors, usually include one or more first optical layers and one or more second optical layers. In addition to the first and second optical layers, some traditional multilayer films include one or more non-optical layers, such as one or more protective boundary layers located over or between packets of optical layers. The non-optical layers are usually integrated into the polymeric multilayer optical films so that at least a portion of the light to be transmitted, polarized, or reflected by the first and second optical layers also travels through these non-optical layers. Such non-optical layers can protect the optical layers from damage, aid in coextrusion processing and/or enhance post-processing mechanical properties of the optical films. Thus, in such traditional optical films, it is usually important that the non-optical layers do not substantially affect the reflective properties of the optical films over the wavelength region of interest. | {
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Ski bindings for use in cross-country skiing can already be obtained in the marketplace (see European Patent Office publication No. 0088673). The bearing block and receiving part are, in the known and comparable ski binding, two separate structural parts, namely a part which is secured to the ski by screws and a part which is hinged to the bearing block and on which the hook element is releasably secured. All together four structural parts must be manufactured for the known and comparable ski binding.
Other known ski bindings for use in cross-country skiing (see German OS No. 29 42 806 which corresponds to U.S. Pat. No. 4,309,833 and German Pat. No. 30 02 874 which corresponds to U.S. Pat. No. 4,382,611) have the disadvantage that the locking element is constructed as a hand lever, which both during a stepping of a skier into the binding and also during a stepping out of the binding can be pivoted only by a complete bending over of the skier. This, however, takes much effort, and in particular older persons at times have difficulty in bending over after long periods of cross-country skiing.
Finally, Austrian Pat. No. 371 016 (which corresponds partly to U.S. Pat. No. 4,303,259) describes a ski binding for use in cross-country skiing, in which the hook element is formed by the extended sole of the shoe. The ski binding has the disadvantage that the ski shoe must be guided in longitudinal direction of the ski into the bearing block which is secured on the ski, which can cause a sliding away of the ski during the stepping-in procedure.
The purpose of the invention is to overcome the disadvantages of all known designs and to provide a ski binding, in particular for use in cross-country skiing, in which the number of structural parts is reduced, in which not the receiving part, but the hook element makes possible the pivotal movement of the ski shoe needed for cross-country skiing.
The purpose is inventively attained by providing an elastic member between the ski shoe and a receiving part on a bearing block fastened to the ski. A separate receiving part and thus also a separate joint for same is no longer needed in this construction. Thus, not only the number of the structural parts is limited, but the entire design of the ski binding is simplified.
The hook element could actually--viewed from the side--have a rectangular form. For reasons of sturdiness, however, it has proven to be inventively advantageous to construct the hook element approximately O-shaped when viewed in a side view, and with the lower web member being connected to the shoe sole and the upper web member being connected to the tip of the shoe.
The possibility exists that at least the lower web member is constructed in one piece with the sole of the shoe. This makes a gluing of the lower web member to the shoe sole unnecessary, and the manufacture of the ski binding is thereby simplified.
Various possibilities are offered for the design of the locking element. A preferred embodiment is distinguished by the locking element being constructed approximately Z-shaped, with one leg of the Z being held by the bearing block, the intermediate web portion thereof having a locking protuberance thereon and the other leg functioning as an opening lever. It has been proven to be advantageous, when the elastic portion of the locking element extends between the leg which is secured to the bearing block and the intermediate web portion. This characteristic may make it possible to do without a separate spring for urging the locking element into the locking position.
In another embodiment, the locking element is constructed as a two-arm lever, one lever arm of which has the locking protuberance thereon and the other lever arm of which engages the spring. The locking element is supported on the bearing block. In this embodiment, the locking element can have a spur which grips beneath the shoe sole. This enables both a stepping into the binding and also a stepping out of the binding to be made easier. | {
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Of interest is commonly owned copending application Ser. No. 821,511 entitled "X-ray Apparatus" filed Jan. 15, 1992 in the name of G. Harding et al.
Such an arrangement is known from EP-OS 360 347 corresponding to U.S. Pat. No. 5,008,911 incorporated by reference herein. It can be used for luggage control in order to identify, for example, explosives or drugs. In fact it has been found that these substances show on account of their crystalline structure a spectrum produced by diffraction and having distinctly pronounced peaks, which is characteristic of these substances and can be clearly distinguished from the spectra of other substances, which are generally taken along in pieces of luggage.
In the known arrangement, in which the diaphragm arrangement has a circular opening, so that the primary beam of radiation in the examination region generates the surface of a circular cone, the second diaphragm arrangement comprises several tubes, which are arranged concentrically to each other and through which the detector arrangement comprising several annular detector elements is struck by scattered radiation. As a result, the examination region is subdivided into a number of sections (in the form of parallel disks) corresponding to the number of the detector elements; each detector element detects the scattered radiation for one of these sections. | {
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1. Field of the Invention
This invention relates to a device for transverse sizing of printed products such as in a rotary offset press, and for a corresponding process for sizing the printed products.
2. The Prior Art
In the prior art, there are roller transverse sizing units with a perforated plate, in which the holes are mechanically opened in a sizing position by a common seal. This system has the disadvantage that it can get dirty very easily and requires a great deal of servicing due to the common seal for all of the holes. Furthermore, this system is complex and expensive. In addition, the sizing is simply pressed out of the holes with this system, which also causes a great deal of soiling. Moreover, the sizing is always applied over the entire length of the set of holes.
Other prior art devices include electronically-controlled nozzle transverse sizing units with individual seals of a sizing application device. These nozzle transverse sizing units are static in relation to the moving printed product, so that a satisfactory pattern can be applied only up to certain speeds due to the mechanical and electrical tolerances of the application devices and the tear-off behavior of the sizing dots.
It is therefore an object of the present invention to provide a device and a process for transverse sizing of printed products that is easy to service and produces sizing of a high quality.
These and other objects of the invention are accomplished by a device for transversely sizing printed products that uses individual application devices that are provided on a roller. The method includes moving individual application devices in at least one sizing position where the relative speed between the application devices and printed product is held at essentially zero.
In the present context, xe2x80x9cindividual application devicesxe2x80x9d comprise each component of an application device that contacts the sizing and can be removed individually from a roller for servicing, and which can be attached to the roller independent of other application devices. In particular, these can be individual nozzles or nozzle heads or parts.
To make servicing easier, at least one exchangeable holder is provided on the roller for at least one applicator. There can also be several applicators in the holder. An exchangeable module can be provided in the roller that has at least two holders. With this arrangement, cleaning is made easier and one can adapt to changed conditions. The down time required for such jobs is reduced and the machine time is thus increased.
The flexibility of the arrangement according to the invention can be increased when the applicators are individually controllable or controlled. Without constructional measures, the manner in which the sizing is applied by the individual applicators and the length of the sizing path can be adapted. In particular, the individual control of the applicators allows the applicators to be supplied with sizing by a common feed without abandoning the advantages of the invention.
Depending on the requirements, the individual applicators can be controlled in groups or blocks to reduce the complexity of the controlling. Simple and flexible control is achieved by electrically controlling at least one of the applicators.
The risk of soiling can be further reduced if the applicators spray the sizing onto the printed product. This is best achieved by nozzles. If the nozzles are electrically controlled, the applied sizing can be easily and precisely dosed. The nozzles can also have a pump that transports the sizing in response to an electrical control. This can provide particularly fine and finely adjusted dosing.
To reduce impurities, the nozzles apply the sizing without contacting the printed product. Alternatively, application with contact is also possible.
To prevent the nozzles from drying out or to reduce drying when the device is not used, a gate is provided for covering the nozzles. A gate can be used for all or some of the nozzles and is actuated by a pneumatic actuator.
The sizing is applied evenly when the applicator is moved synchronous with the movement of the printed product. This can be guaranteed when the roller with the applicators is rotated at a corresponding speed.
The device and process are particularly simple when the roller is designed to retain the format of the printed product, i.e., when the perimeter of the roller is a non-fractional multiple of the length of the printed product, or the length of the printed product corresponds to a non-fractional multiple of the roller perimeter. Preferably, the perimeter of the roller identically corresponds to the format of the printed product. | {
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A growing number of electrical devices, which may be ICs or embedded cores within ICs, are being tested using test compression architectures (TCA), such as Mentor's TestKompress™ embedded deterministic test technology, incorporated herein by reference. Fundamentally a TCA consists of three elements, a decompressor circuit, a parallel scan path arrangement, and a compactor circuit. The decompressor circuit receives compressed input data from one or more inputs from a tester, decompresses the compressed input data into parallel stimulus patterns that are input to parallel scan paths. The compactor circuit receives parallel response patterns that are output from the parallel scan paths, compacts the response patterns down to one or more compressed data outputs that are input to the tester. A first advantage of TCAs is that they allow a large number of shorter length parallel scan paths to be accessed using only a small number of compressed data inputs and compressed data outputs. A second advantage of TCAs is that they reduce the amount of test data that needs to be transmitted between the tester and device under test, since the test data is compressed. The present disclosure provides methods and apparatuses for enabling a device TCA to be accessed for testing using either a parallel bus of compressed input and compressed output test signals or a serial bus of a compressed input and compressed output test signals.
FIG. 1 illustrates an example of device 100 containing a test compression architecture (TCA) 102. The TCA 102 is interfaced to an external tester via a parallel bus of N compressed data input (CI) signals, a parallel bus of N compressed data output (CO) signals, a scan clock (SC) input, and a scan enable (SE) input. While TCAs may use only a single CI input and a single CO output, it is more common in a device manufacturing test environment to use a bus of parallel CI inputs and a bus of parallel CO outputs, since this reduces device test time. The TCA 102 comprises a decompressor 104, a compactor 106, and parallel scan paths 108. The TCA 102 may also include a clock selector (CS) 110 to allow the parallel scan paths to be clocked by the devices functional clock (FC) at times when the parallel scan paths are capturing response data. The decompressor has inputs coupled to the CI, SC and SE inputs and outputs coupled to the scan inputs (SI) of the parallel scan paths 108. The compactor has inputs coupled to the scan outputs (SO) of parallel scan paths 108 and an output coupled to the CO output. The parallel scan paths 108, in addition to the SI inputs and SO outputs, have inputs coupled to the SC and SE inputs, inputs coupled to response outputs from combinational logic, and outputs coupled to stimulus inputs to combinational logic, as shown in FIG. 3. If the CS 110 is used, the SE input will control it to pass the SC signal to the parallel scan paths 108 during shift operations and to pass the FC signal to the parallel scan paths 108 during capture operations.
FIG. 2 illustrates the operational states 202 and 204 of the TCA during test. In state 202 when the SE input is low and an SC input occurs the parallel scan paths capture response data from the combinational logic and the decompressor is reset to a known state. If CS 110 is used, the logic low on SE will select the FC signal to clock the parallel scan paths in state 202. In state 204 when the SE input is high and SC inputs occur the decompressor 104 decompresses the data input on CI inputs into parallel scan inputs (SI) that are shifted into the parallel scan paths, and the compactor 106 inputs and compacts the parallel scan outputs (SO) from the parallel scan paths into compressed outputs that are output on the CO outputs. If CS 110 is used, the logic high on SE will select the SC signal to clock the parallel scan paths in state 204. The TCA will remain in state 204 until the compressed input to the parallel scan paths and the compressed output from the scan paths is complete. As can be seen the capture and shift operation states of the TCA is similar to the capture and shift operation states of conventional scan paths, with the exception that the TCA includes the additional operations of decompressing the data input on the CI inputs to produce the scan inputs (SI) to the parallel scan paths and compressing the scan outputs (SO) from the parallel scan paths into a compressed form that can be output on the CO outputs.
While the example of FIG. 2 shows SE being low in state 202 and high in state 204, the logic levels of SE for these states could be reversed if desire.
Most known decompressors 104 utilize a linear feedback state machine (LFSM) in conjunction with a phase shifter circuit to produce the output patterns that are applied to the SI inputs of the parallel scan paths 108. In the referenced Mentor TestKompress™ technology, the LFSM is referred to as a ring generator which is a particular type of linear feedback shift register. The ring generator receives the CI input data and, in response, produces pseudo random input patterns to the phase shifter. The phase shifter responds to the pseudo random input patterns to output stimulus input (SI) patterns to the parallel scan paths. The CI input data modifies the output patterns from the ring generator to allow the phase shifter to produce the desired stimulus pattern input to the parallel scan paths.
Most known compactors 106 utilize XOR gating trees that input the scan outputs (SO) from the parallel scan paths and compress them, via XOR gating, into compacted signals that can be output on the CO outputs. While simple compactors may only use XOR gating trees, more sophisticated compactors, such as the compactor used the reference Mentor TestKompress™ technology, may use XOR gating trees in combination with masking circuitry to allow masking off unknown scan outputs (SO) from the parallel scan path scan to prevent the unknown scan outputs from corrupting the compacted signals output on the CO outputs. If the compactor contains masking circuitry it can receive masking data (MD) from the decompressor 104 and control from SC and SE to load the masking data, as shown in dotted line in FIG. 1.
FIG. 4 illustrates an example of a device 402 with a TCA 102 being connected to an external parallel tester 404 via parallel CI (PCI), parallel CO (PCO), SC, and SE interface signals to allow TCA test patterns to be applied to the device. This example is typical of how the device manufacturer would test the device.
FIG. 5 illustrates the tester 404 of FIG. 4 operating the SC and SE signals to perform a TCA scan cycle. The scan cycle includes a capture operation 502 that Captures response data and Resets the decompressor to a starting seed state, i.e. state 202 of FIG. 2, followed by a shift operation 504, whereby the tester inputs PCI data to the TCA decompressor 104 and receives PCO data from the TCA compactor 106, i.e. state 204 of FIG. 2. The response capture and decompressor reset operation is indicated in this and following timing diagrams as CR. The shift operation 504 continues until the parallel scan paths are filled with stimulus data and emptied of response data. The scan cycle of FIG. 5 repeats 508 until all the TCA test patterns have been applied and the TCA test is complete.
FIGS. 4 and 5 have illustrated an example of how a tester 404 can access a device's TCA 102 for testing when a connection can be made between the tester and the device's TCA interface. As seen in FIG. 4 the connection between the tester and device TCA requires a direct connection for the PCI signals, a direct connection for the SC signal, a direct connection for the SE signal and a direct connection for the PCO signal.
The present disclosure, as will described in detail below, identifies how to modify a TCA to allow the TCA to be selectively accessed using parallel CI and parallel CO signals coupled to high cost parallel testers as shown in regard to FIG. 4 or using serial CI (SCI) and serial CO (SCO) signals coupled to low cost serial testers. Additionally, the disclosure identifies how to test a device TCA using low cost JTAG controllers. | {
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Golf clubs may be fitted to an individual based on the type of golf club, the individual's physical characteristics and/or the individual's play style. Depending on the individual's physical characteristics and play style, a golf club having a certain lie angle and loft angle may be selected to provide optimum performance for the individual. Accordingly, each individual may require a golf club having a certain lie and loft to fit the physical characteristics and the play style of the individual. | {
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One image-forming device well known in the art is a color laser printer having a plurality of cartridges arranged parallel to one another and juxtaposed in a prescribed direction, and a support member for supporting the plurality of cartridges. In this color laser printer, the support member can be pulled out of the printer body. Once the support member has been pulled out of the body, cartridges can be mounted in or removed from the support member. | {
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1. FIELD OF THE INVENTION
The present invention relates to foodstuffs having improved taste quality, more particularly, after taste quality. The present invention also relates to the use of sclareolde having the structure: ##STR1## in enhancing the effect of sodium chloride or in debittering potassium chloride used as a substitute for a sodium chloride in such foods as soups. The present invention also relates to the enhancement of food flavors using sclareolide having the structure: ##STR2## as a flavor enhancer.
The present invention also relates to the use of sclareolide having the structure: ##STR3## as at least a partial fat replacer to be used in dairy products such as ice cream, sour cream and whipped toppings. The present invention also relates to the use of sclareolide having the structure: ##STR4## as a modulator to reduce or elmininate the aftertaste of artificial sweeteners such as aspartame.
2. DESCRIPTION OF THE PRIOR ART AND DISCUSSION OF THE BACKGROUND
Taste qualities of foodstuffs change depending on the composition of taste components contained therein. When foodstuffs have miscellaneous tastes or an unpleasant taste, various improvements can be made by adjusting the composition. Among low calorie sweeteners, the use of which has been rapidly growing recently, for example, aspartame is characterized as a sweetener free from a bitter or astringent taste or an irritating taste and having a refreshing sweetness. However, aspartame is somewhat insufficient in rich tasteness in terms of sweet quality. Further, aspartame has a tendency to impart a sweet aftertaste, as is characteristically noted with sweeteners having a high titer. To improve such a sweet quality of aspartame, various proposals have been made (Published Unexamined Japanese Patent Application Nos. 90667/77, 148255/81, 63068/82, 141760/83, etc.).
However, the purpose of improving sweet quality of aspartame and imparting satisfaction comparable to that of sugar have not been sufficiently achieved. Further the method of using these various taste components in combination requires the component used in combination in a weight almost the same as or larger than that of aspartame, in most cases. From an aspect of rendering a low calorie or general purpose use, a further improvement has been desired.
In addition, tastes such as an astringent taste of the like, especially a different flavor or miscellaneous flavors left on the tongue as an aftertaste tend to adversely affect the taste quality of foodstuffs as a whole. In such a case, even though a beforetaste, etc., is of good quality, the taste quality tends to be lowered as a whole due to the unpleasant aftertaste and it becomes necessary to improve the whole taste from the beforetaste to aftertaste.
It is well known that the combination of monosodium L-glutamate (MSG) and a flavor inducing 5'-nucleotide, such as disodium inosine-5'-monophosphate (IMP), disodium guanosine-5'-monophosphate(GMP), or mixtures thereof, exhibit a synergistic flavoring activity. Moreover, mixtures comprising MSG and a flavor inducing 5'-nucleotide having long been widely used as economical flavoring agents or seasoning agents for various foods and beverages.
U.S. Pat. No. 4,258,072 issued on Mar. 24, 1981 discloses a mixed seasoning comprising 100 parts by weight monosodium glutamate; 0.05 to 25 parts by weight of a flavor inducing 5'-nucleotide; 5.0 to 38.0 parts by weight of sodium chloride; 0.1 to 0.87 parts by weight succinic acid and/or sodium succinate; and 0.5 to 10.0 parts by weight of at least one alkali metal salt of an organic acid which may be sodium fumarate, sodium citrate, sodium or calcium lactate, sodium maleate, sodium tartrate, sodium ascorbate or sodium aspartate.
U.S. Pat. No. 4,216,244 issued on Aug. 5, 1980 discloses a low sodium seasoning which includes potassium chloride as its major ingredient together with other non-sodium compounds masking the bitterness of the potassium chloride so that the seasoning can be substituted for sodium chloride seasonings.
U.S. Pat. No. 4,216,244 specifically discloses a low sodium salt seasoning consisting by weight of a mixture of about 90 percent low sodium salt base and about 10 percent low sodium diluent, with the base consisting by weight of a mixture of about 92 percent potassium chloride, about 3 percent L-glutamic acid and about 1 percent each of monopotassium glutamate, potassium citrate and potassium phosphate.
U.S. Pat. No. 4,066,793 issued on Jan. 3, 1978 discloses seasoning compositions, and processes for their production, which have an improved and enhanced meat-like flavor, and comprise mixtures containing extracts of yeast autolysates, 5'-nucleotides, sodium chloride and potassium salts; the potassium ion concentration being more than 0.5 times the sodium ion concentration.
Yamada in German Offenlegungsschrift No. 3144-166, French Patent No. 2,493,681 and Japan Published Application No. J57-079860 discloses a seasoning composition which may be either:
______________________________________ Weight Percent ______________________________________ (i) 15-21 magnesium chloride; 3-10 magnesium sulfate; 2-4 potassium chloride; 0.2-0.5 magnesium bromide; and 2-7 sodium chloride; or (ii) 15-21 magnesium chloride; 6-9 magnesium sulfate; 2-4 potassium chloride; 0.2-0.4 magnesium bromide; 2.6 sodium chloride; and 0.1-21 calcium salt. ______________________________________
The Yamada patents and patent applications indicate that when the salt composition is diluted, it does not give bitterness but gives a round taste and gives rise to intensity of the saltiness of common salt.
Issued Japanese Patent No. J82-022311 discloses a synergistic seasoning composition containing monosodium glutamate, a nucleic acid type tasting compound, sodium chloride, succinic acid salt and at least one othr sodium salt. The seasoning is composed of:
(i) monosodium glutamate; PA0 (ii) nucleic acid-type tasting substance such as disodium inosine-5'-monophosphate and/or disodium guanosine-5'-monophosphate; PA0 (iii) sodium chloride; PA0 (iv) succinic acid and/or sodium succinate; and PA0 (v) at least one salt selected from the group consisting of monosodium furmarate, tri-sodium citrate, monosodium lactate, calcium lactate, disodium malate, disodium tartarate, sodium ascorbate and monosodium aspartate. PA0 (a) emulsifying meat or meat by-products; PA0 (b) admixing a salt, with the emulsified meat or meat by-products, in a weight-persent proportion of 1.5-3% based on the weight of the fabricated product, the salt being present in a proportion sufficient to extract salt soluble protein from the emulsified meat or meat by-products, the salt being selected from the group consisting of sodium chloride, potassium chloride, sodium phosphate, potassium phosphate, sodium polyphosphates and potassium polyphosphates; PA0 (c) extracting the salt soluble protein from the meat and meat by-products; PA0 (d) admixing texturized soy with the emulsified meat or meat by-products, extracted protein and salt; PA0 (e) forming the mixture into a desired shape; PA0 (f) blanching the shaped mixture in a temperature range of 170.degree.-210.degree. F.; and PA0 (g) thereafter maintaining the moisture content of the fabricated meat and meat by-product in the range of up to about 70%, PA0 (i) processed cheese; PA0 (ii) cheese spread; PA0 (iii) cheese dip; PA0 (iv) cheese analogues and imitation cheese analogues; PA0 (i) dog foods; PA0 (ii) cat foods; PA0 (i) extruded snacks; PA0 (ii) crackers, pretzels, potato chips and the like; PA0 (iii) meat sauces, white sauces and gravies; PA0 (iv) casseroles; PA0 (v) cheese sauces; PA0 (vi) soups (instant and finished) PA0 (vii) prepared meats and meat spreads; PA0 (viii) meat and poultry analogues and extenders and the like; PA0 (ix) margarine; PA0 (x) salad dressings PA0 (xi) condiments; PA0 (xii) seasonings and flavorings; PA0 (xiii) meat and poultry (processed); and PA0 (xiv) breading and stuffing. PA0 (a) from about 0.25 up to about 0.80 mole percent (herein and hereinafter to be understood as meaning a percentage based on total moles of cations, anions, and substantially non-ionized organic acids) on a dry basis of a lactic acid/lactate species mixture having the structures: ##STR15## (b) from 0 up to about 0.09 mole percent on a dry basis of glycollic acid/glycollate ion species mixture having the structure: ##STR16## (c) from 0 up to about 10.0 mole percent on a dry basis of magnesium ion; (d) from about 6 mole percent up to about 50 mole percent on a dry basis of a phosphate/monoacid phosphate/diacid phosphate/phosphoric acid species mixture having the formula: EQU [PO.sub.4.sup.= ]+HPO.sub.4.sup.= ]+H.sub.2 PO.sub.4.sup.- ]+H.sub.3 PO.sub.4 PA0 (e) from 0 mole percent up to about 40 mole percent on a dry basis of sodium ion; PA0 (f) from about 8 mole percent up to about 50 mole percent on a dry basis of potassium ion; PA0 (g) from about 0.3 mole percent up to about 16 mole percent on a dry basis of chloride ion; PA0 (h) from 0 mole percent up to 30 mole percent on a dry basis of carbonate/bicarbonate/carbonic acid species mixture having the formula: EQU [CO.sub.3.sup.= ]+[HCO.sub.3.sup.-]+H.sub.2 CO.sub.3 PA0 (i) from 0 mole up to about 2.0 mole percent on a dry basis of monobasic glutamate/dibasic glutamate/glutamic acid species having the formulae: ##STR17## (j) from 0 up to about 0.6 mole percent on a dry basis of calcium ion; and (k) from about 0.1 up to about 0.6 mole percent on a dry basis of sclareolide having the structure: ##STR18## PA0 (a) from about 2.times.10.sup.-4 up to about 7.times.10.sup.-4 moles per liter of the lactic acid/lactate ion species defined according to the structures: ##STR19## (b) from 0 up to about 9.times.10.sup.-5 moles per liter of the species glycollic acid/glycollate ion defined according to the structures: ##STR20## (c) from 0 moles per liter up to about 1.5.times.10.sup.-3 moles per liter of the ion/acid species, glutamic acid/monobasic glutamate/dibasic glutamate defined according to the structures: ##STR21## (d) from about 3.times.10.sup.-4 up to about 1.6.times.10.sup.-2 moles per liter of the chloride ion species; PA0 (e) from about 3.times.10.sup.-3 up to about 1.times.10 moles per liter of the acid/ion species, phosphoris acid/ion species, phosphoric acid/monoacid phosphate/diacid phosphate/phosphate having the formula: EQU [PO.sub.4.sup.5 ]+[HPO.sub.4.sup.= ]+[H.sub.2 PO.sub.4.sup.- ]+H.sub.3 PO.sub.4 PA0 (f) from 0 up to about 2.times.10.sup.-3 moles per liter of the ion/acid species carbonate/bicarbonate/carbonic acid having the formula: EQU [CO.sub.3.sup.= ]+[HCO.sub.3.sup.- ]+H.sub.2 CO.sub.3 PA0 (g) from 0 up to about 4.times.10.sup.-2 moles per liter of the sodium ion species; PA0 (h) from about 4.times.10.sup.-3 up to about 9.times.10.sup.-2 moles per liter of the potassium ion species; PA0 (i) from about 0 up to about 1.times.10.sup.-2 moles per liter of the magnesium ion species; PA0 (j) from about 0 up to about 6.times.10.sup.-4 of the calcium ion species; and PA0 (k) from about 1.times.10.sup.-3 about 6.times.10.sup.-3 of the sclareolide having the structure: ##STR22## with the provisos: (i) that the mole ratio of metal cation:total acid and ion is from about 0.4 up to about 0.7; PA0 (ii) that the concentration of ions and acids is from about 0.04 up to about 0.25 moles per liter; and PA0 (iii) that the range of concentration of metal cations is from about 0.02 up to about 0.15 moles per liter. PA0 (i) from about 60 weight percent up to about 96 weight percent on a dry basis of a substance selected from the group consisting of (a) KH.sub.2 PO.sub.4 or (b) K.sub.2 HPO.sub.4 or (c) a mixture of Mg.sub.3 (PO.sub.4). (4H.sub.2 O and K.sub.2 CO.sub.3 ; PA0 (ii) from about 0.4 up to about 3.5 weight percent on a dry basis of lactic acid; PA0 (iii) from about 0.4 up to about 17.0 weight percent on a dry basis of a compound selected from the group consisting of sodium chloride, postassium chloride and calcium chloride; and PA0 (iv) from about 1.75 up to about 3.25 weight percent on a dry basis of monosodium glutamate or monopotassium glutamate of a mixture of same (with the proviso that the sum total of the ingredients cannot be greater than 100%). PA0 (i) from about 60 weight percent up to about 96 weight percent on a dry basis of a substance selected from the group consisting of (a) KH.sub.2 PO.sub.4 or (b) K.sub.2 HPO.sub.4 or (c) a mixture of Mg.sub.3 (PO.sub.4).4H.sub.2 O and K.sub.2 CO.sub.3 ; PA0 (ii) from about 0.4 up to about 3.5 weight percent on a dry basis of lactic acid; PA0 (iii) from about 0.4 up to about 17.0 weight percent on a dry basis of a compound selected from the group consisting of sodium chloride, potassium chloride and calcium chloride; PA0 (iv) from about 1.75 up to about 3.25 weight percent on a dry basis of monosodium glutamate or monopotassium glutamate or a mixture of same; and, in addition PA0 (v) from about 4.0 weight percent up to about 25.0 weight percent of a compound selected from the group consisting of MgCo.sub.3 KHCO.sub.3 and NaHCO.sub.3 (with the proviso that the sum total of the ingredients cannot be greater than 100%). PA0 (i) on a dry basis from about 0.5% up to about 25%; and PA0 (ii) on a wet basis from about 0.02% up to about 1.5%.
The abstract of Japanese Patent No. J8/2022311 is as follows:
Derwent Abstracts ("FOODOC"/January, 1983)
"Synergistic seasoning compsn.-contains monosodium glutamate, nucleic acid type tasting cpd., sodium chloride succinic acid salt and at least one other sodium salt. The seasoning is composed of (1) monosodium glutamate, (2) nucleic acid-type tasting substance (e.g., disodium inosine-5'-monophosphate and/or disodium guanoisine-5'-monophosphate), (3) sodium chloride, (4) succinic acid and/or sodium succinate and (5) at least 1 salt selected from monosodium fumarate, trisodium citrate, monosodium lactate, calcium lactate, disodium malate, disodium tartarate, sodium ascorbate and monosodium aspartate. The ratio (1):(2)=1:0.0005-0.25, esp. 1:0.001-0.15; (1)+(2):(3)=1:0.05-3, esp. 0.07-0.25 (1)+(2):(4) =1:0.0010-0.0070, esp. 1:0.0015:0.0055. (1)+(2):(5)=1:0.005-0.080, esp 1:0.010-0.070 (4) and (5) are expressed as the free acid. "By combining sodium chloride (4) and (5) the tasting strength of the seasoning can be increased and its taste made similar to that of monosodium glutamate."
U.S. Pat. No. 3,821,368 issued on June 28, 1974 discloses a therapeutic composition of an aqueous medium containing about 75-150 moles sodium ions; 5-50 moles potassium ion; 5-50 moles bicarbonate ions; 75-150 moles chloride ion and preferably containing about 1-30 moles magnesium ion and about 1-30 moles of HPO.sub.4 =and/or SO.sub.4 =ion with a solution having a pH of about 5.95-8.4 and an osmolality of about 170-460.
Japanese Patent No. J82/00777 issued on Jan. 7, 1982 and abstracted at Chem.Abstracts, Volume 96:161168h discloses a salt composition for sea food preservation containing 0.15-1% sodium chloride and a mixture of magnesium sulfate and calcium sulfate (1:1) weight ratio. It is indicated the magnesium sulfate and calcium sulfate marketedly improved the flavor of the food product.
U.S. Pat. No. 4,332,823 discloses a process for preparing a fabricated meat comprising the sequential steps of:
the weight-percent proportions of the ingredients being: meat and meat by-products: 77-92% and texturized soy: 8-20%.
U.S. Pat. No. 4,340,614 issued on July 20, 1982 discloses a stringently sodium-restricted dietetic salt in its preparation which consists of a mixture of from 60-85 weight percent potassium chloride; 10-30 weight percent potassium adipate; 2-5 weight percent potassium tartrate; 0.5-2 weight percent potassium glutamate; 0.5-2 weight percent adipic acid; and from 0.004 up to 0.06 weight percent of potassium inosinate and/or potassium guanylate.
Furthermore, the use of certain materials for enhancing the flavor of foodstuffs is well recognized in the art. One of the first materials widely utilized for this purpose was monosodium glutamate. More recently, 5'-nucleotides, particularly inosinates and guanylates, have been similarly utilized as flavor enhancers. These nucleotides have particularly been used with meat and fish materials.
It has been recognized that certain pyrazines are present in coffee and other beverages. The use of acetylpyrazines to impart popcorn-like flavors has been suggested. The use of tetramethylpyrazine, preferably with vanillin, to improve the flavor of cocoa and chocolate material is also known. In these instances the pyrazines are said to have actively imparted a particular flavor character or specific aroma note to a foodstuff or other product.
Nothing in the prior art discloses that sclareolide having the structure: ##STR5## is useful as a fat replacer in ice cream whereby the mouthfeel affect caused by fat may be created using sclareolide as opposed to the fact in the ice cream.
Nothing in the prior art discloses that sclareolide having the structure: ##STR6## has a salt sparing effect whereby traces of sclareolide enchance traces of sodium chloride and also reduce the bittering affect of sodium chloride substitutes such as potassium chloride.
Nothing in the prior art discloses the use of sclareolide having the structure: ##STR7## for accentuation or enhancement of flavor such as cheese flavors in snack applications particularly where the snacks are relatively low in fat content.
Nothing in the prior art discloses the use of sclareolide having the structure: ##STR8## as an aspartame modulator particularly where the aspartame aftertaste is reduced or eliminated.
Fernandez, et al (PhytoChemistry, Volume 24, No. 1, pp. 188-189, 1985, (abstracted at Chemical Abstracts, Vol. 102:128829u) discloses the occurrence of sclareolide having the structure: ##STR9## in Sideritis nutans.
Kaneko in Agr.Biol.Chem., Volume 35, No. 9, pages 1461-1462, 1971 (The Aroma of Cigar Tobacco, Part II/Isolation of Norambreinolide from Cigar Tobacco)(abstracted at Chemical Abstracts Volume 76, 1972, 56811b) discloses the isolation of sclareolide having the structure: ##STR10## from cigar tobacco.
Wahlberg, et al, Acta Chemica Scandinavica B 33 (1979) pages 541-543 (title: "Tobacco Chemistry.49.*New Labdanic Diterpenoids Isolated from Tobacco", (abstract at Chemical Abstracts, Volume 92:19004a) discloses the occurrence of sclareolide having the structure: ##STR11## in tobacco.
Teresa, et al, An. Quim. 1979, 75(5), 335-40 (abstracted at Chemical Abstracts Volume 91:137149d) discloses the isolation of sclareolide having the structure: ##STR12## from the neutral part of the C. ladaniferus gum. | {
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The present invention concerns a portable object, in particular a timepiece, including a case with which is associated an electronic module intended to allow contactless and wireless communication between the portable object and an external terminal provided for this purpose.
The present invention is intended for a multitude of situations or places where for example it is checked whether or not a person has a right of access, the latter being either upon payment or free of charge.
The invention is particularly intended for systems for controlling access to industrial sites (research and development laboratories, production units, etc.) and to public buildings (stadiums, museums, cinemas or suchlike) in which the portable object is presented by the holder thereof to a control device which only authorises access to the site or to the building if the data stored in the object worn by the person corresponds to an access authorisation, the payment of a sufficient sum or even a suitable expiry date.
Access control systems, which use cards provided with a magnetic card able to be inserted into the slot of an access control terminal inside which the data carried by the magnetic strip are read, are known. When this data is recognised, access authorisation is issued and new data can be written on the magnetic strip.
Magnetic strip access control systems are, however, sometimes difficult to use, in particular because of the narrowness of the slot into which the card has to be inserted for accurate reading of its content. Thus, when a magnetic card access control system is used on certain equipment such as, for example, skilifts in winter sports resorts, handling of the magnetic card by users whose hands are not free proves particularly slow and awkward. Moreover, the repeated insertion of the card into the slot of the terminal causes wear of the magnetic strip on which the useful data is stored.
In order to overcome this drawback, there has been proposed an automatic control and identification system for objects in which a portable object encloses, in a case, an electronic module including in particular a memory for storing useful data such as an identification code, a transceiver device for radio transmitted signals, and an antenna electrically connected to the transceiver device. In this object control system, when coupled to an external terminal provided for this purpose, the transceiver device, is capable of transmitting radio signals corresponding to the reading of the data stored in the memory circuit and, if necessary, receiving radio signals for writing new useful data into such memory circuit. Thus, when the external circuit transmits an interrogation signal, the detection of this signal by the portable object causes the transmission, for example of an identification code for this object, which then allows the terminal to identify this object and consequently to check the identity of the wearer thereof.
The above automatic object identification system has numerous advantages.
Access control, whether upon payment or free of charge, is made easier and quicker. The necessary identification or other data are written into and read from a memory in a contactless and wireless manner. Thus, for example, the mechanical insertion of a card into the slot of a reading device, often made difficult by circumstances, is omitted. Moreover, this system is entirely passive, i.e. it does not require any power source of its own. The power necessary for the operation thereof is provided by the electromagnetic waves transmitted by the object identification terminal.
At the present time, however, the different manufacturers in the market propose contactless object control systems which differ from each other, in particular as regards the structure of the electronic modules used in the objects to be checked, which makes these systems totally incompatible with each other. The user thus finds himself obliged to purchase, for each required service, for example for the skilifts of several ski resorts, as well as opening the door of a hotel room and for payments at the bar thereof, the object which corresponds thereto. It will easily be understood that such a situation is not very convenient for the user. It multiplies the number of portable objects, increases the risk of theft, loss or forgetting such objects, and involves a considerable increase in cost.
An object of the present invention is to overcome the problems and drawbacks described hereinbefore by proposing a portable object, in particular a wristwatch, which allows a plurality of different services to be selected personally and simultaneously.
The invention therefore concerns a portable object for contactless access control systems, including a case with which at least one antenna is associated, characterised in that the case includes at least two different electronic modules, each electronic module allowing access to a particular service, the portable object also including means for selecting and activating one of said electronic modules as a function of the service desired by the user.
As a result of the features of the present invention, the user can have access, simultaneously and with great ease, to a plurality of different services, for example access to the skilifts of several winter sports resorts, opening the door of a hotel room, payment of a cinema ticket and others, using a single portable object. The risks of loss, theft or forgetting the object are minimised, and the costs reduced.
According to an advantageous feature of the invention, the selection and activation means control the movement of an electric contact member to connect the electronic module which corresponds to the service required by the user.
Other features and advantages of the present invention will appear more clearly upon reading the following description of an embodiment of the invention, given purely by way of non-limiting illustration, this description being made in conjunction with the annexed drawings. | {
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1. Field of the Invention
The present invention relates generally to establishing computer-based user communities, and more particularly to establishing computer user communities based on user activities on the Web.
2. Description of the Related Art
The World Wide Web and other information repositories such as online databases afford quick access to a large amount of information. Users typically interact only with the information, however, and generally do not share a sense of community with other users who might nevertheless be interested in the same topics. In other words, most social interactions using the Web are asynchronous (e.g., a user reads what another user has written sometime earlier), and lack the richness of ordinary communication. The present invention understands that Web users as well as content providers would benefit from creating a sense of community in cyberspace, for many of the same economic and psychic reasons that physical markets such as shopping malls benefit both store owners and shoppers by creating a sense of personalized community.
Isolated social places currently exist on the Web, but they suffer inadequacies with respect to effectively promoting meaningful social interaction. One type of social place is centered on a single document, such as a chat room. Users access the document and by means of xe2x80x9cchatxe2x80x9d technology converse with each using their computers. The drawback with single-document social places, however, is two-fold. Under some circumstances, there may be few if any companion users in, e.g., a chat room who would be appropriate social partners for a person wishing to engage in social activity. Indeed, although present in the chat room with each other, users might very well share little if any commonality with each other. Currently, there is no way to account for this fact. On the other hand, many thousands of users might be clustered around a single document. It will readily be appreciated, however, that social interactions in a crowded place can be as difficult to strike up as in an empty place.
A second type of Web community is one that is based on a predefined grouping (i.e., a xe2x80x9cbuddy listxe2x80x9d). Examples of such communities are set forth in U.S. Pat. Nos. 5,796,393 and 5,727,950. In these systems, communication is established between members of a predefined group, e.g., users of America Online (AOL)(copyright), or students that are pre-grouped by an instructor. In any case, these systems do not use indicia that can be expected to be related to user preferences, but rather rely on arbitrary groupings of a disparate collection of users who might in fact share little or no social interests with each other.
As understood by the present invention, a good gauge of a user""s social preferences and/or characteristics can be had from the user""s computer-based activities. As an example, suppose that children of various ages access a Web page related to dinosaurs. The present invention postulates that fifth graders might use similar paths as each other to arrive at the Web page, whereas ninth graders might, on the whole, take a different path to arrive at the page, and that this information can be used to place the fifth graders in communication with each other, with whom they are more likely to share common interests than with ninth graders.
As recognized by the present invention, U.S. Pat. Nos. 5,796,952 and 5,727,129, both of which are incorporated herein by reference, provide methods for monitoring and storing activities of users of networked information. The referenced methods do so for reasons other than for promoting social interaction, however, and thus do not consider or recognize that such user activity-based information might be advantageously used to facilitate social interactions on computer networks, such as the Web.
The present invention has carefully considered the above problems and has provided the solution set forth herein.
A computer-implemented method is disclosed for establishing at least one communication grouping that includes at least first and second client computers based on user activity with respect to an information repository, such as the World Wide Web. The method includes storing respective first and second histories of user activities undertaken with the first and second client computers with respect to the information repository. As intended by the present invention, the user activities can include accessing at least two documents in the repository, inputting at least one query, and establishing a pattern of document access. The communication grouping is established based on the first and second histories of user activities. In a preferred embodiment, the communication grouping is established when the activities of the first client computer match the activities of the second client computer in accordance with predefined criteria.
Preferably, a chat room is established between computers in a grouping. Also, communication windows including chat windows are displayed on respective monitors associated with the client computers. In a particularly preferred embodiment, the communication windows display icons that represent client computers in the communication grouping.
In another aspect, a computer system includes at least two client computers communicating with the World Wide Web. Each client computer is associated with a client proxy, and the client proxy accesses, for each client computer, user activity information that represents at least one of: a group of Web pages accessed by the client computer, a pattern of Web page access established by the client computer, and query terms input to the client computer. A place server receives the user activity information and based thereon determines whether to establish a communication grouping among the client computers.
In still another aspect, a computer program storage device establishes a client proxy that includes a program of instructions. In turn, the program of instructions includes structure to undertake the following method. For at least one client computer, a history of user activities undertaken with the client computer with respect to an information repository such as the World Wide Web is stored. The user activities are among the group of activities consisting of: accessing at least two documents in the repository, inputting at least one query, and establishing a pattern of document access. The history is communicated to a place server module, and a window is displayed that represents companion client computers in a communication grouping based on the histories of the client computers.
In yet another aspect, a computer program storage device establishes a place server including a program of instructions that in turn includes structure to undertake the following method. From each of plural client computers, a respective history of user activities undertaken with the client computer with respect to an information repository such as the World Wide Web is received. The user activities are among the group of activities consisting of: accessing at least two documents in the repository, inputting at least one query, and establishing a pattern of document access. The method also includes, for client computers having histories that match each other in accordance with predefined criteria, establishing a communication grouping.
The details of the present invention, both as to its structure and operation, can best be understood in reference to the accompanying drawings, in which like reference numerals refer to like parts, and in which: | {
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This invention relates to a pedestal for mounting a seat in a vehicle. More particularly, the invention relates to a pedestal which is adapted to be anchored to the floor of the vehicle and which is adapted to mount the seat for turning about an upright axis so that the seat may be swivelled between different positions. Swivel seats are commonly used in trucks, vans, recreational vehicles and the like.
Pedestals for swivel seats usually comprise a base adapted to be anchored to the vehicle floor and adapted to rotatably support a member which serves a mounting platform for the seat. The safety harness for strapping the occupant in the seat is attached to the swivel platform and is adapted to swivel with the seat.
Existing federal safety regulations require that the pedestal be able to withstand a very severe pull test which simulates the upward and forward force imposed on the pedestal by the safety harness during impact. In order for the pedestal to pass the test, the base must remain anchored to the vehicle floor when subjected to the specified force and, in addition, the swivel platform must not pull upwardly and forwardly from the base by more than a designated distance. To meet the safety regulations, prior pedestals have been made from heavy materials and by expensive manufacturing procedures. As a result, such pedestals are both high in cost and high in weight. | {
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The present invention relates to an improved catalyst support and catalyst and, more particularly, a catalyst support and catalyst for use in a process for upgrading hydrocarbon feedstocks.
The prior art is replete with catalysts for use in processes for upgrading hydrocarbons to higher value products. Most of the aforesaid processes are carried out at elevated temperatures under controlled conditions. The processes tend to be expensive as a result of the high energy input required to carry out the processes at elevated temperatures and pressures. Catalysts are employed in the processes for various reasons, including, but not limited to, reducing the temperatures and pressures at which the hydrocarbon conversion reaction takes place.
Naturally, it would be highly desirable to provide improved catalyst supports and catalysts for use in hydrocarbon conversion processes which would allow for the hydrocarbon conversion to take place at significantly lower temperatures and pressures than heretofore attainable.
Accordingly, it is the principle object of the present invention to provide an improved catalyst support and catalyst for use in hydrocarbon conversion processes for the conversion of hydrocarbons to products of higher value.
It is a further object of the present invention to provide a process, catalyst and catalyst support which allows for the hydrocarbon conversion processes to be carried out under more favorable conditions of temperature and pressure.
It is another object of the present invention to provide a catalyst and catalyst support which is useful in combination with microwave energy to convert hydrocarbon feeds to higher quality products.
Further objects and advantages of the present invention will appear hereinbelow. | {
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The present invention relates to a method and system of monitoring and controlling deflection of a wafer during a plasma etching process.
When processing wafer substrates for use in electronic and optoelectronic applications there is a need to ensure the wafer surfaces are very smooth and clean. Once the bulk wafer has been prepared various grinding, polishing and etching steps are required to produce smooth uniform surfaces. However, it is found that there can be a build up of stress near the surface of the wafer, largely as a consequence of the mechanical abrasion steps. A stress imbalance between a front and rear of the wafer can result in wafer bow, which in turn, can have adverse consequences for future process steps. To minimise the stress imbalance, various methods can be employed, such as wet chemical etching, chemical mechanical polishing or plasma etching, or a combination of these processes.
When using plasma etching to relieve stress or to produce a surface texture on a wafer substrate the key requirements are the uniform removal of material from the surface, without producing wafer damage, at as high a rate as possible. Inherent in this plasma etch process is a change in stress in the wafer that can result in wafer deformation. Excessive deformation can result in wafer breakage which is very undesirable, since the etch chamber must then typically be vented to remove the debris. This is turn results in costly downtime for the plasma etch tool.
In conventional plasma etching, the substrate is retained in position using mechanical or electrostatic clamps, and cooled through the use of a coolant, such as helium, for example. However, when the entire surface of the wafer needs to be etched, mechanical clamping cannot be used as the areas of the wafer where the clamp makes wafer contact, and thus covers the wafer, will receive a different etch rate to the exposed or uncovered areas of the wafer. Furthermore, when the substrate is an insulator such as sapphire or glass for example, an electrostatic clamp or chuck cannot be used. | {
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The invention relates to a thermal regulating composition that can be used, for example, as a catalyst system in a fuel processor for a fuel cell system.
Fuel cells are an increasingly popular power generation technology, where chemical reactions are utilized to produce electricity. The reactants are typically hydrogen and oxygen. Along with the electricity generated, the sole reaction product is water. Hydrogen for such fuel cells may be supplied by chemically converting a fuel such as natural gas, propane, gasoline, diesel, methanol, etc., into a hydrogen-rich stream. This process is typically referred to as fuel processing, and the hydrogen-rich stream is typically referred to as reformate.
The catalyst systems used in fuel processors generally include a dispersion of small catalyst particles on a support material. It is generally desirable to minimize the size of the catalyst particles that are used in order to maximize the surface area of catalyst that is provided to promote a given reaction. However, small metal particles, such as those typically used as catalysts, may tend to be pyrophoric, meaning that they will spontaneously and rapidly oxidize when exposed to oxygen or air. Oxidation is exothermic, meaning that the reaction releases heat energy. Pyrophoricity tends to increase as smaller particles are used, and some metals (e.g., non-precious metals such as iron and copper) may tend to be more pyrophoric than others. In some cases, the heat generated by this oxidation may pose a fire or other safety hazard, or may damage the catalyst configuration itself.
Catalysts subject to such concerns are typically pre-reacted with oxygen in a controlled environment before they are handled. For example, a catalyst may be oxidized slowly in a dilute oxygen atmosphere to avoid overheating, and may then be shipped in a relatively non-reactive oxidized state (referred to as the oxidized state). Since catalysts in an oxidized state generally have diminished catalytic effectiveness or no effectiveness at all, they are typically reduced or activated before they can be used (referred to as the reduced, or active state). This generally involves flowing hydrogen or another reducing agent across the catalyst at an elevated temperature (e.g., over 200xc2x0 C.), in order to react away the oxidation layer. This reduction (activation) step is also exothermic, and may need to be controlled (e.g., by using diluted hydrogen) to avoid overheating.
One reason why catalyst overheating can be a problem, and thus why catalyst temperature control is important, is because some catalysts will lose their catalytic effectiveness if they are overheated. For example, when copper-based catalyst particles are heated to over 400xc2x0 C., the particles may tend to sinter (also referred to as densification), meaning that small particles will tend to combine into larger particles. Thus, this temperature may be referred to as the sintering temperature of this material. Such sintering can reduce the surface area of the catalyst, thereby reducing its effectiveness. As known in the art, other catalyst materials are subject to similar concerns at other sintering temperatures.
The invention relates to a thermal regulating composition that can be used, for example, as a catalyst system in a fuel processor for a fuel cell system.
In general, in one aspect, the invention provides a composition including a first material capable of catalyzing or undergoing an exothermic chemical reaction, and a second material capable of sorbing and desorbing a heat transfer material. The second material is present in an amount sufficient to sorb an amount of the heat transfer material sufficient to remove heat from the first material when heat from the exothermic reaction causes the heat transfer material to desorb from the second material. The first material and the second material may form a mixture.
In certain embodiments, the second material can be a desiccant, such as a zeolite, silicon oxide, aluminum oxide, or a clay. In such embodiments, the heat transfer material is water. The first material can be a fuel processor catalyst, such as a material or compound including copper, nickel, iron, chromium, zinc, cobalt, platinum, palladium, rhodium, ruthenium, or iridium. Fuel processor catalysts can be classified, for example, as catalytic partial oxidation catalysts, high temperature water-gas shift catalysts (also generally referred to as the shift reaction), low temperature water-gas shift catalysts (also generally referred to as the shift reaction), and preferential oxidation catalysts.
An advantage is that this configuration reduces the pyrophoricity of the composition such that in some embodiments the composition can be exposed to air without hazard to safety or damage to the catalyst configuration. The finely-divided catalyst material, consequently, can have a high surface area and oxidize, for example, when air accidentally enters into the reformer, without damage to the catalyst. Thus, in some embodiments, the invention provides a catalyst material that is easier and safer to handle, and can be oxidized (as for shipping) or activated more easily, safely and conveniently than catalyst systems not of the invention. Another advantage is that this temperature quenching capability of the composition allows superior temperature control of the composition during reaction. For example, compositions under the invention are less prone to rapid temperature excursions from runaway reactions than compositions not of the invention. The temperature of compositions under the invention have improved controllability through heat exchange methods and reactant control (such as cutting off or reducing reactants), as examples.
In general, some embodiments of the invention provide a catalyst that includes a sufficient amount of a desiccant to sorb and desorb water to substantially quench the temperature of the catalyst when the catalyst is exposed to an exothermic reaction. Under normal operating conditions, the desiccant sorbs water from the reformate stream. However, when the catalyst is exposed to an exothermic oxidizing or reducing condition, the heat generated causes the water in the desiccant to desorb as vapor into the reformate, thereby cooling the catalyst and making the system more temperature controllable. The desorbed, vaporized water also permeates throughout the catalyst tending to further cool the catalyst. As an example, some desiccants, such as zeolites, can desorb up to about 50-100 L of steam per one liter of desiccant. Thus, the risk of the catalyst overheating and/or igniting is minimized with the desorption/evaporative cooling capacity of this water, thereby lessening the risk of damage to the catalyst material and other components in the reformer.
The water sorption by the desiccant may also temporarily enhance the performance of the catalyst by allowing the desiccant to supply more water to the catalyst material. More water generally enhances the water-gas shift reaction by shifting the reaction to an equilibrium favoring the production of hydrogen and carbon dioxide, thereby producing more hydrogen while reducing CO.
In certain embodiments, the first material (generally the catalyst) and the second material (generally the desiccant) are present in a range of weight ratios from about 1:1 to about 1:10, respectively. In other embodiments, a narrower range may be desired, such as from about 1:1 to about 1:5. The first and second materials may also be present in approximately equal amounts. In yet other embodiments, it may be desired to have more of the first material than second material, or to have even more of the second material present than described above, such as a ratio of over 1:10.
In certain embodiments, the first and second materials are formed into granules. The granules may have spherical, cylindrical, or other shapes. The granules can also be pellets and agglomerated particles. The first and second materials may also be coated onto a support structure, such as a ceramic monolith. In some embodiments, the first material may be coated onto the second material. In other embodiments, the first material may be disposed on a third material. The third material may include, as examples, an aluminum oxide, zinc oxide, zirconium oxide, or an iron oxide. As examples, it may be desired to have the first material disposed on the third material with a load between about 5% and about 30% by weight, or a load between about 10% and about 20% by weight. It may also be desired for the first and third materials to form a catalytic composite containing less than about 20% by weight of the third material, such as about 5% to about 15% by weight of the third material.
In still other embodiments, it may be desired for the catalytic composite to contain a fourth material such as zinc oxide, zirconium oxide, and iron oxide. It may be desired for the catalytic composite comprises less than about 50% by weight of the fourth material, such as between about 20% and about 30% by weight of the fourth material. The composition can also include a fifth material capable of sorbing hydrogen and forming hydrogen atoms, such as platinum, nickel, palladium, rhodium, or ruthenium.
In general, in another aspect, the first material can have a reduced state and an oxidized state, and the second material can be present in an amount sufficient to prevent the composition from sintering when the first material is in the reduced state and is exposed to air. The second material can also be present in an amount sufficient to prevent the composition from reaching a sintering temperature of the first material when the first material has a starting temperature of less than 100xc2x0 C. and is in the reduced state and is exposed to a flow of 4 liters per minute of air. The second material can also be present in an amount sufficient to prevent the composition from reaching a sintering temperature of the first material when the first material has a starting temperature of less than 100xc2x0 C. and is in the oxidized state and is exposed to a flow of 100 standard liters per minute of hydrogen.
In general, in another aspect, the invention can include a fuel processor for a fuel system that includes a catalyst composite containing a first material capable of catalyzing an exothermic reaction and a second material capable of sorbing and desorbing water. The catalyst composite can be disposed within the fuel processor. In some embodiments, the fuel processor can be devoid of a high-temperature shift catalyst.
In general, in another aspect, the invention provides a low temperature water-gas shift reaction catalyst that can have one or more of the following features: it can be present in granules (such as pellets); it can include a copper based catalyst; it can include a zinc based catalyst or component; and it can include a desiccant material such as a zeolite in a weight percent equal to or greater than a combined first and second amounts of CuO and ZnO. As previously discussed, the granules can be present in multiple shapes and sizes. In general, a granule""s largest cross-sectional dimension is referred to as a cross-sectional dimension. For example, this would refer to the diameter of a spherical granule, or to the larger of the length and diameter of a cylindrical granule. In certain embodiments, the granules can have a cross-sectional dimension of about xe2x85x9 inch (this dimension can be larger as desired), and the desiccant can be present in an amount such that when about 20 kg of the granules are at a temperature less than 100xc2x0 C., and are exposed to a water-saturated flow of 100 standard liters per minute of hydrogen at a temperature less than 300xc2x0 C., the granules are limited to a temperature below about 400xc2x0 C. as the granules are subject to reduction from the hydrogen. In some embodiments the desiccant can be present in an amount such that when about 20 kg of the granules are saturated with water at a temperature less than 100xc2x0 C., and are exposed to a dry flow of 100 standard liters per minute of hydrogen at a temperature less than 300xc2x0 C., the granules are limited to a temperature below about 400xc2x0 C. as the granules are subject to reduction from the hydrogen. In some embodiments, the desiccant can contain water and be present in an amount such that the granules are limited to a temperature below about 400xc2x0 C. as the granules are exposed to air. In some embodiments, this exposure to air can include an air flow of about 4 liters per minute.
Many other embodiments are possible. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims. All percents and ratios described are by weight. | {
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A typical apparatus for dispensing a heated liquid, such as hot melt adhesive, generally includes a dispensing gun or module having a valve element that opens and closes a dispensing outlet. The valve element is positioned within a passage supplied with pressurized liquid and contacts a valve seat to prevent the heated liquid from flowing to the outlet. To dispense the heated liquid, an actuator, such as an electrically and/or pneumatically operated actuator, causes the valve element to move away from the valve seat and allows the heated liquid to flow from the passage to the outlet. A biasing mechanism, such as a spring, or the same actuator may then cause the valve element to move back toward the valve seat to close the outlet.
The dispensing module typically receives the heated liquid from a liquid supply component, such as a manifold. For example, a manifold may be coupled to both a source of the liquid adhesive and an inlet of the dispensing module. The heated liquid flows through various internal passageways within the manifold before reaching the inlet of the dispensing module. Because the dispensing module and manifold are separate components, they must typically be coupled together in a secure manner to prevent leakage.
One method for coupling the dispensing module to the manifold uses conventional fasteners. For example, one or more screws may be inserted through the dispensing module to engage threaded holes tapped into the manifold. The screws are tightened (i.e., placed in tension) until the dispensing module is pressed against the manifold with sufficient force to maintain a seal between an outlet of the manifold and the inlet of the dispensing module.
In some liquid dispensers, several factors can make the use of screws and other conventional fasteners challenging. For example, a heater within the manifold typically creates an environment of relatively high temperatures. The forces required to effectively couple the dispensing module to the manifold may exceed the pullout strength of the screws at such relatively high temperatures. As a result, tightening the screws to secure the dispensing module may lead to failure of the screw threads, failure of the threads in the tapped hole of the manifold, or both.
Another factor that can make the use of screws and other conventional fasteners challenging relates to the space required to accommodate the screws. Both the dispensing module and manifold include internal passages for the heated liquid that should be avoided by the screws. Because of the limited space available for the screws, the size of the screws themselves is typically limited. Smaller screws have lower resistance to failure than larger screws. As a result, a greater number of smaller screws may be required to press the dispensing module against the manifold with the same amount of force that would be applied if larger screws were used. Finding the space to accommodate more screws can be difficult due to the space limitations discussed above.
Moreover, in some liquid dispensers, the manifold further includes a piston or piston assembly that actuates a pivot arm connected the valve element within the dispensing module. Examples of such heated liquid dispensers assigned to the assignee of the present invention are described in U.S. Patent Application Publication Nos. 2005/0236438 and 2006/0097010 and U.S. Provisional Patent Application Serial No. 60/865,886, the disclosures of which are fully incorporated herein by reference. The additional passages needed to accommodate the piston and pivot arm, along with the relatively small thicknesses associated with these dispensers, may make it even more difficult to accommodate screws or other conventional fasteners.
Therefore, new devices and methods for coupling a dispensing module to a liquid supply component, such as a manifold, are highly desirable. | {
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The present invention relates to polymeric opacifying agents used in the production of paints, paper coatings, and films and, more particularly, to opacifying agents having a core/sheath structure.
The steady increase in the price of titanium dioxide (TiO.sub.2) as well as the steady decrease in its availability have created a demand for products capable of replacing at least a part of the TiO.sub.2 needed to opacify paints and other coating compositions. In TiO.sub.2 and other naturally white products, such as snow, a multiplicity of irregular surfaces and/or microvoids randomly scatter light within these products to create the appearance of whiteness. Microvoid-containing polymer particles perform in a similar manner. When incorporated into a paint or paper coating composition, the microvoid-containing polymer particles cause a significant increase in the resulting composition's whiteness or opacity.
Recently, a number of approaches to incorporating microvoid-containing polymer particles into paint and paper coating formulations has been disclosed. (See "Air and Polymer Extended Paints," Chalmers et al., European Supplement to Polymer Paint Colour Journal, Oct. 5, 1983, pp. 94-102.) One approach entails the use of solid and/or vesiculated (hollow) polyester/styrene copolymer beads having a size in the range of 3 to 50 microns and marketed under the tradename "Spindrift." These particles are formulated to contain both air and TiO.sub.2 within their interior. A major use of these particles has been to formulate matte paints with good polish resistance. However, unpigmented beads act as windows in the film and are generally used only for highly saturated colors. For cost effectiveness, the vesiculated beads have been generally used as a partial replacement for TiO.sub.2.
In a second approach, aggregates of fine particles are formed by a process of addition polymerization under conditions of high shear in an aqueous medium. This process produces irregular shaped particles (sold under the name "Microblock"). The irregular shaped particles allegedly produce higher film strengths than produced by spherical beads. Unlike the vesiculated beads, described above, internal pigmentation with TiO.sub.2 has not been found to be effective. Accordingly, the irregular shaped particles are usually combined with external TiO.sub.2 and a film extender to produce high pigment value content (pvc) paints which are very flat.
In a third approach, fine particle size, non-film-forming, polystyrene hollow beads are used. These beads have a particle size range of the same order of magnitude as that of latex particles normally used in emulsion paints, namely 100 to 600 nm. Typically, the beads are blended with the latex particles in a 1:1 by weight ratio. These particles are sold under the tradename of "Plastic Pigment."
A fourth approach involves a suspension of non-film-forming hollow styrene/acrylic copolymer beads (typically 38% by weight, 52% by volume). The processes for manufacturing these microvoid particles are described in U.S. Pat. No. 4,427,836 (Kowalski et al. I), U.S. Pat. No. 4,469,825 (Kowalski et al. II) and U.S. Pat. No. 4,594,363 (Blankenship et al.). Kowalski et al. I and Blankenship et al. disclose the production and use of water insoluble particles made by sequential emulsion polymerization to form a swellable "core"z=0 of polymeric acid. The core is then at least partially encased with a "sheath" or "shell" polymer permeable to a volatile base such as ammonia or an organic amine. Sheath permeability is necessary to allow the base to contact the core. Kowalski et al. II differs from Kowalski et al. I and Blankenship et al. in that in Kowalski et al. II the core comprises a polymeric base and the sheath polymer is permeable to an acid, e.g., acetic acid. When any of these particles are neutralized, the core swells and causes the entire particle to swell up. When a paint film containing these particles dries, water is lost from the beads' interior voids and replaced by air. The resulting empty "microvoids" act as light scattering sources, thus increasing the hiding power of the dried film. In addition to opacifying by scattering incident light, it has been postulated that these particles also contribute to hiding power by uniformly spacing TiO.sub.2 particles and, thus, help prevent TiO.sub.2 clumping. Accordingly, these particles supplement or replace a part of the pigmentary medium or extenders that would otherwise be required to achieve equivalent hiding power. For example, literature articles concerning these products indicate that these particles can replace up to about 25% of the TiO.sub.2 content in a paint formulation. In particular, four parts by volume of these opaque polymers are approximately equal in hiding power to one part by volume of TiO.sub.2. | {
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1. Field of the Invention
The present invention relates to a pressure-sensitive adhesive composition required to have durability and light leakage preventive ability for an optical film and to a pressure-sensitive adhesive optical film including an optical film and a pressure-sensitive adhesive layer that is made from the pressure-sensitive adhesive composition on at least one side of the optical film. The invention also relates to an image display such as a liquid crystal display and an organic electroluminescence (EL) display, using the pressure-sensitive adhesive optical film. The optical film may be a polarizing plate, a retardation plate, an optical compensation film, a brightness enhancement film, a laminate thereof, or the like.
2. Description of the Related Art
The image-forming mode of liquid crystal displays or the like essentially requires polarizing elements to be placed on both sides of a liquid crystal cell, and generally polarizing plates are attached thereto. Besides polarizing plates, a variety of optical elements have been used for liquid crystal panels to improve display quality. For example, there are used retardation plates for prevention of discoloration, viewing angle expansion films for improvement of the viewing angle of liquid crystal displays, and brightness enhancement films for enhancement of the contrast of displays. These films are generically called optical films.
When optical members such as the optical films are attached to a liquid crystal cell, pressure-sensitive adhesives are generally used. Bonding between an optical film and a liquid crystal cell or between optical films is generally performed with a pressure-sensitive adhesive in order to reduce optical loss. In such a case, a pressure-sensitive adhesive optical film including an optical film and a pressure-sensitive adhesive layer previously formed on one side of the optical film is generally used, because it has some advantages such as no need for a drying process to fix the optical film.
The pressure-sensitive adhesive is required to have some characteristics. In some cases, for example, if in the process of bonding an optical film to a liquid crystal cell, they are misaligned or foreign matter is caught on the bonding surface, the optical film should be separated from the liquid crystal panel so that the liquid crystal cell can be recycled. For this separation process, the pressure-sensitive adhesive should have re-peelability (reworkability) such that the optical film can be easily peeled from the liquid crystal panel with no adhesive residue. Particularly in recent years, thin liquid crystal panels using chemically-etched glass plates are frequently used together with conventional panel manufacturing processes, and it has become difficult to subject optical films from the thin liquid crystal panels to reworking or processing. The pressure-sensitive adhesive is also required to have processability such that it can be processed without causing adhesive stain or dropout after it is formed. In addition, the pressure-sensitive adhesive is required not to cause any defect in durability tests by heating, moistening and so on, which are generally performed as accelerated environmental tests. Also, the pressure-sensitive adhesive is required to prevent light leakage caused by dimensional change generated in the pressure sensitive adhesive layer in the film.
A conventionally proposed method to solve the problems with the reworkability of liquid crystal panels includes adding a plasticizer or an oligomer component to an acrylic polymer used as a base polymer for an acrylic pressure-sensitive adhesive (see Japanese Patent Application Laid-Open (JP-A) No. 2003-329837). However, such an acrylic pressure-sensitive adhesive cannot provide satisfactory reworkability or processability for the thin liquid crystal panels.
Other than the above, proposed acrylic pressure-sensitive adhesives for optical films include an acrylic pressure-sensitive adhesive including an acrylic polymer produced using alkyl (meth)acrylate, a monomer having a hydroxyl group in the molecule and a monomer having a functional group such as a carboxyl, amide or amino group in the molecule as monomer components (see JP-A No. 2004-091499 and JP-A No. 2004-091500); and a pressure-sensitive adhesive including an acrylic polymer produced using aromatic ring-containing monomer (see Publication of Examined Application No. 62-23287). However, none of these acrylic pressure-sensitive adhesives disclosed in the patent literatures can provide satisfactory reworkability or processability, although they can provide improved durability and adhesiveness.
On the other hands, a pressure-sensitive adhesive composition including plasticizer or oligomers is proposed to prevent light leakage of an image display that is prepared with the use of an optical film (Japanese Patent No. 3594206 and Japanese Patent No. 3533589). However, such a pressure-sensitive adhesive composition cannot provide satisfactory workability and durability.
A pressure-sensitive adhesive composition for improvements in durability and reworkability and remediation of light leakage is proposed, which includes a copolymer of an acrylate eater, an aromatic ring-containing monomer, and a hydroxyl group-containing monomer as a base (see JP-A No. 2007-138057 and JP-A No. 2007-1380560). However, such a copolymer does not have satisfactory durability, because of its low molecular weight and high degree of dispersion. Such a pressure-sensitive adhesive composition is intended to reduce staining or adhesive residue during re-peeling, but it is not easily peelable and therefore not practically satisfactory. Patent Document 1: Japanese Patent Application Laid-Open (JP-A) No. 2003-329837 Patent Document 2: JP-A No. 2004-091499 Patent Document 3: JP-A No. 2004-091500 Patent Document 4: Publication of Examined Application No. 62-23287 Patent Document 5: Japanese Patent No. 3594206 Patent Document 6: Japanese Patent No. 3533589 Patent Document 7: JP-A No. 2007-138057 Patent Document 8: JP-A No. 2007-138056 | {
"pile_set_name": "USPTO Backgrounds"
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On such a farm machine that is now known, the tongue comprises at its front part a sort of prismatic cavity determined by three walls, two side walls and a front wall. The upper part of the transmission housing extends inside the prismatic cavity between the three walls and is fastened there by a number of bolts.
In practice, it has been found that this mode of fastening the transmission housing can be liable to loosening of the assembly bolts, in particular the assembly bolts that fasten the transmission housing to the side walls of the prismatic cavity.
This loosening phenomenon is due both to the production tolerances of the upper part of the transmission housing and, especially, to the production tolerances of the prismatic cavity, particularly the tolerances on the inside distance separating the two side walls.
Since the tongue is a mechanically welded part, the production tolerances must be relatively broad. Thus, during tightening of the side assembly bolts, the side walls are first deformed a certain amount before they come in contact with the upper part of the transmission housing. It is then found that an elastic assembly instead of a solid assembly is obtained, due to the elastic deformation of the side walls.
In addition, the assembly bolts which fasten the transmission housing to the side walls are subject to shear stress.
It is then understood, considering the facts:
(1) that the entire tractive force needed to draw the machine goes through the assembly bolts;
(2) that the resulting assembly is generally an elastic assembly; and
(3) that the side bolts are subjected to shear stress, that the vibrations produced by the configuration of the ground on which the machine travels during work causes loosening of the side bolts--which, of course, is not desirable.
Moreover, the known assembly mode does not allow a fast and easy mounting. This is because, during the entire operation of introducing and tightening the bolts, it is necessary to hold the transmission housing by positioning it exactly so that the bolts can be introduced into the corresponding threaded holes. Therefore, it will be understood, considering the relatively heavy weight of the transmission housing, that its mounting is long and expensive. | {
"pile_set_name": "USPTO Backgrounds"
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1. Field of the Invention
The present invention relates to a sound and flash suppressor for a firearm, and more particularly to reduce the noise caused by the firing of a firearm comprising a silencer muffler which attenuates explosive sounds generated by firearms and which have a straight-through passage for the projectile and silencing chambers for the explosive exhaust.
2. Background of the Invention
Sound suppressors for firearms are well known in the prior art, and many have been patented over a hundred years.
Many different techniques have been created and patented, chambers, gas passages and baffles of varying designs have been extensively used. The purpose of a sound and flash suppressor, regardless of the technique used, is to reduce the exit pressure and velocity of the propellant gases from the firearm's barrel so that the resulting sound level and flash is significantly reduced.
In addition, most prior art firearm suppressors do not significantly reduce muzzle flash. Also, some prior suppressor inventions require many different internal parts that are difficult to assemble and require constant replacement.
U.S. Pat. No. 3,385,164 (Walther et al) discloses the use of conical baffles that includes a plurality of shoulders on the interior surface of a conical baffle. Also disclosed is the use of these annular shoulders on the exterior and interior surfaces of a conical baffle. However, the use of these shoulders with annular shoulders was used together with other methods and these conical baffles were located only in the area of the exit of the bullet from the suppressor.
U.S. Pat. No. 6,575,074 (Gaddini) features several baffles that have an integral reduced diameter coaxial spacers that are vented in a specific manner, dependent upon the caliber of the firearm in use.
U.S. Pat. No. 4,588,043 (Finn) and U.S. Pat. No. 5,164,535 (Leasure) are indicative of the complex baffles that use slanted sidewalls or asymmetric cuts into the bore of the baffles.
International Publication Number WO 99/39147 (Lapwood et al) discloses a gun silencer that compromises of a single baffle free gas expansion chamber. This single chamber is easier to maintain and to clean. | {
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Differential signaling, wherein both positive and negative versions of a signal are used to represent values being carried on the signal, is popular due to its high degree of immunity to noise and its large voltage margin. High speed electronic equipment and their interfaces, such as double data rate (DDR) and double data rate two (DDR2) memory interfaces, take advantage of differential signals to help ensure signal integrity. These signals typically have very sharp edges and very short transitions, referred to as signal crossover. Therefore, a typical automated test equipment (ATE) will lack instrumentation that is capable of measuring signal crossovers.
The Nyquist Sampling Theorem states that to accurately represent a signal, it is necessary to sample the signal at twice the signal's frequency. Therefore, one way to capture the signal crossovers is to sample the signal at a sampling rate that is twice the frequency of the signal crossover.
Another commonly used technique to enable the capture of very high frequency signals that is being generated by a device under test (DUT) is to configure the DUT so that it is producing the event that is to be tested at a specified frequency. Then, the ATE can sample the signal being produced by the DUT at a sampling frequency that is slightly different from the frequency of the event's occurrence on the signal. By sampling the signal produced by the DUT for an extended amount of time, the ATE can effectively and accurately capture the signal and the event. While the sampling frequency can either be greater than or less than the frequency of the signal, typically, the sampling frequency is less than the frequency of the signal, and hence the name, undersampling.
One disadvantage of the prior art is that in many cases, the signal crossovers can sometimes last only a few nano-seconds or less. Therefore, to sample the signal at twice this frequency may not be possible. Furthermore, if the sampling at such a sampling rate were possible, the amount of sample data produced may be very large, which could increase the complexity of the test equipment and the testing process.
A second disadvantage of the prior art is that even though the use of undersampling can enable the capture of the signal crossover, it is not capable of determining if both signals in the differential signal are within a specified voltage threshold. The undersampling of the signal can only indicate if one of the two signals (or both signals) in the differential signal is within the specified threshold, it cannot differentiate between both signals being within the specified threshold (a passing case) and only one signal being within the specified threshold (a failing case).
A third disadvantage of the prior art is that the use of undersampling cannot provide additional information about the signal crossover, such as if the signal crossover is occurring in the middle of the voltage swing of the differential signal, an approximate location of the signal crossover in the voltage swing, and so forth. | {
"pile_set_name": "USPTO Backgrounds"
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Forming and shaping of thermoplastic materials, such as polyvinyl chloride (PVC) resin, generally requires heating a mass of the thermoplastic material to a temperature at which it can undergo plastic flow. Depending on the type of formation techniques used, this heated mass will be generally subject to shear stresses that form the mass into the desired shaped. In extrusion operations, for example, the heated mass is subsequently forced through a plate containing one or more orifice openings, sometimes referred to as a die plate, to impart a profile shape to the emerging extrudate. The extrudate is then cooled until it becomes sufficiently rigid to retain the profile shape. In calendering, the heated mass is forced into the nip between a roll and another object, such as a knife blade or other roll, and thereby sheeted into the desired shape and thickness.
In general a shaping feedstock composition is prepared by combining a thermoplastic polymer, such as PVC resin, with one or more adjuvants, such as lubricants. For example, extrudable PVC compositions are described in Handbook of Plastic Materials and Technology, Ed. I. Rubin, Wiley-Interscience, John Wiley & Sons, Inc. New York, 1990 and Plastics Additives and Modifiers Handbook, Ed. J. Edenbaum, Van Nostrand Reinhold, New York 1992, Chapter 3, each of which is incorporated herein by reference. Examples of additional components include filler, for example calcium carbonate, processing aids, for example acrylic copolymers, and stabilizer which imparts heat stability to the composition during the extrusion process, for example, a tin based stabilizer such as TM281® from Rohm & Haas. The composition is commonly then “fused”, that is, subjected to heating and blending, for example in a two mill roll, until it forms a plastic composition which is substantially homogeneous. The various additives and the amounts of the additives used influence the properties of the feedstock composition both during the fusion process and after it has been “fused.” The properties of the composition in turn affect the performance, such as processability, of the material during shaping, such as in extrusion and/or calendering or in follow-on processes, in which the feedstock material is employed. Of the various components comprising typical PVC feedstock compositions, the lubricant included in the composition can have an important influence on one or more of the properties related to processability, as well as on the quality of a the shaped article.
Dimensional stability is an important characteristic affecting the commercial value of a shaped product and hence of the processes and the components used to make the extruded product. Dimensional stability is assessed by observing the amount by which a shaped article expands during solidification after it emerges from the shaping apparatus or tool, such as the die plate in an extrusion operation or the calendaring nip in a calendering operation. The amount of expansion is sometimes referred to as swell or die swell.
For a given shapable feedstock composition, it is generally possible to increase the rate at which material is shaped. However, such shaping rate increases have practical limitations. For example, it is possible to obtain extrusion rate increases by operating the extruder at a higher temperature and/or at a higher head pressure. However, at some point of increasing extruder temperature the extrudable composition will generally begin to scorch, and the surface and structural qualities of the extrudate will begin to degrade. Similar effects occur in other shaping operations. Furthermore, as the amount of force used to shape the mass is increased, such as increasing the head pressure or extruder torque, a point is generally reached at which the dimensional stability and/or surface condition of the shaped material is unacceptable. These process limitations have created practical limits on the rate at which prior compositions could be extruded, calendered and the like.
Another mechanism that is at least theoretically available to achieve higher shaping rates is to increase the amount and/or type of lubricant incorporated into the formable feedstock composition. However, it is also possible that increasing the amount of the lubricant or changing the type of lubricant can have deleterious effects on the shaped product and/or on other aspects of the shaping process. For example, increasing the amounts of certain lubricants known as internal lubricant may compromise one or more the inherent physical properties of a shaped article, such an improvement in deflection temperature under load (DTUL) of the shaped article. Also, increased amounts of external lubricant may negatively impact not only the strength of the shaped product, but may also increase the fusion time, which increases the overall processing time.
It has been suggested that certain combinations of materials may be used as a lubricant in extrudable PVC compositions. For example, European Patent Application No. 79302422.5 discloses a PVC composition which incorporates as an alkaline earth metal or zinc soap as a stabilizer and mixed glycerides as a lubricant. The patent also indicates that sucrose mono- and di-esters may optionally included in the lubricant, in amounts ranging from about 20% to about 35% by weight of the composition. The patent does not disclose the acids from which the sucrose ester is formed, except to imply that they result from transesterification of sucrose with triglycerides. While it may be possible that some measure of success can be achieved in accordance with the teachings of European Patent Application No. 79302422.5, applicants have discovered that certain types of sucrose esters are highly undesirable from a performance standpoint, from a cost standpoint, or both.
Applicants have thus come to recognize the need for formable or shapable compositions, particularly PVC-based compositions, having one or more of those desirable shaping characteristics associated with high levels of lubricant while reducing or substantially eliminating one or more or the adverse effects that would otherwise be associated with a high level of lubricant. The present methods, feedstock compositions and shaped articles meet this and other needs. | {
"pile_set_name": "USPTO Backgrounds"
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Wireless communication systems, such as cellular telephone systems, have proved to be very popular. Such systems typically include numerous mobile units (e.g., cellular telephones), a plurality of base stations at fixed locations, and one or more switching centers connecting the wireless communication systems to other communications systems, such as the land line public switched telephone network.
It is common for such systems to employ a large number of discrete communication channels for communicating voice and data from one location to another and for controlling system functions. It is also common for there to be multiple communications service providers in competition with each other for each type of communication service. As such, within a given geographical area it is typical for the various communication channels to be allocated to the different competitors such that only one service provider is responsible for providing service on any given channel.
To facilitate communications channel allocation, the spectrum of channels may be divided into several channel bands, each containing a plurality of communications channels. Thereafter, an entire channel band may be allocated to a particular service provider for a given geographic region. Thus, in a certain region, service provider Alpha may be allocated channel bands A and C, while service provider Beta may be allocated channel band B, and service provider Gamma all other channel bands. The particular details of the channel band allocations are well known in the industry. Further, because it is desirable for a subscriber of service provider Alpha to use service provider Alpha's communications channels, it is common for mobile units subscribing to Alpha's service to maintain a listing of the channel bands allocated to Alpha. This list is then used to preferentially select which channels are used for communications.
During use, it is common for the mobile unit to be switched from one channel to another, an event which can be triggered by a wide variety of reasons. For example, in a cellular phone call release procedure, a cellular base station can provide a channel pointer that will direct a mobile cellular phone to switch to a new control channel to await future paging signals. As another example, a mobile unit may receive a channel pointer as part of a redirection procedure to alleviate overload conditions when a base station is handling too many communications sessions. In any event, because it is very desirable for channel switching to be transparent to the user, this channel switching must happen as quickly as possible. In addition, because the channel switching utilizes system resources including mobile unit power, the switching procedure should be as efficient as possible. | {
"pile_set_name": "USPTO Backgrounds"
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This invention relates to elastic gloves, and more particularly to protective elastic gloves used in medical related procedures and facilities. | {
"pile_set_name": "USPTO Backgrounds"
} |
This invention relates to prostaglandin agonists, pharmaceutical compositions containing such agonists and the use of such agonists to prevent bone loss or restore or augment bone mass including the treatment of conditions which present with low bone mass in mammals, including humans.
Osteoporosis is a systemic skeletal disease, characterized by low bone mass and deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture. In the U.S., the condition affects more than 25 million people and causes more than 1.3 million fractures each year, including 500,000 spine, 250,000 hip and 240,000 wrist fractures annually. Hip fractures are the most serious consequence of osteoporosis, with 5-20% of patients dying within one year, and over 50% of survivors being incapacitated.
The elderly are at greatest risk of osteoporosis, and the problem is therefore predicted to increase significantly with the aging of the population. Worldwide fracture incidence is forecasted to increase three-fold over the next 60 years, and one study estimated that there will be 4.5 million hip fractures worldwide in 2050.
Women are at greater risk of osteoporosis than men. Women experience a sharp acceleration of bone loss during the five years following menopause. Other factors that increase the risk include smoking, alcohol abuse, a sedentary lifestyle and low calcium intake.
There are currently two main types of pharmaceutical therapy for the treatment of osteoporosis. The first is the use of anti-resorptive compounds to reduce the resorption of bone tissue.
Estrogen is an example of an anti-resorptive agent. It is known that estrogen reduces fractures. In addition, Black, et al. in EP 0605193A1 report that estrogen, particularly when taken orally, lowers plasma levels of LDL and raises those of the beneficial high density lipoproteins (HDL""s). However, estrogen failed to restore bone back to young adult levels in the established osteoporotic skeleton. Furthermore, long-term estrogen therapy, however, has been implicated in a variety of disorders, including an increase in the risk of uterine cancer, endometrial cancer and possibly breast cancer, causing many women to avoid this treatment. The significant undesirable effects associated with estrogen therapy support the need to develop alternative therapies for osteoporosis that have the desirable effect on serum LDL but do not cause undesirable effects.
A second type of pharmaceutical therapy for the treatment of osteoporosis is the use of anabolic agents to promote bone formation and increase bone mass. This class of agents is expected to restore bone to the established osteoporotic skeleton.
U.S. Pat. No. 3,932,389, incorporated herein by reference, discloses certain tetrazolyl prostaglandin derivatives as vasodilators, bronchodilators, antiulcer and antisecretory agents.
U.S. Pat. No. 4,097,601, incorporated herein by reference, discloses selected compounds from U.S. Pat. No. 3,932,389 as having utility in the treatment of bone disorders.
British patent number GB 1 521 688 discloses certain cyclopentanones for the production of hypotension, bronchodilation, inhibition of gastric acid secretion, healing of gastric ulcers, luteolysis and the stimulation of uterine contraction.
U.S. Pat. No. 3,980,700, incorporated herein by reference, discloses certain cyclopentanones as antibacterial agents.
U.S. Pat. No. 4,197,407, incorporated herein by reference, discloses certain cyclopentanones as smooth muscle stimulants, arterial blood pressure lowering agents and antagonists of epinephrine-induced mobilization of free fatty acid.
In addition to osteoporosis, approximately 20-25 million women and an increasing number of men have detectable vertebral fractures as a consequence of reduced bone mass, with an additional 250,000 hip fractures reported yearly in America alone. The latter case is associated with a 12% mortality rate within the first two years and with a 30% rate of patients requiring nursing home care after the fracture. While this is already significant, the economic and medical consequences of convalescence due to slow or imperfect healing of these bone fractures is expected to increase, due to the aging of the general population. While there are several promising therapies (bis-phosphonates, etc.) in development to prevent bone loss with age and thus reduce the probability of incurring debilitating fractures, these therapies are not indicated for restoration of bone mass once the fracture has occurred.
Estrogens have been shown (Bolander et al., 38th Annual Meeting Orthopedic Research Society, 1992) to improve the quality of the healing of appendicular fractures. Therefore, estrogen replacement therapy might appear to be a method for the treatment of fracture repair. However, patient compliance with estrogen therapy is relatively poor due to its side effects, including the resumption of menses, mastodynia, an increased risk of uterine cancer, an increased perceived risk of breast cancer, and the concomitant use of progestins. In addition, men are likely to object to the use of estrogen treatment. Clearly the need exists for a therapy which would be beneficial to patients who have suffered debilitating bone fractures and which would increase patient compliance.
Although there are a variety of osteoporosis therapies there is a continuing need and a continuing search in this field of art for alternative osteoporosis therapies. In addition, there is a need for bone fracture healing therapies.
This invention is directed to compounds of Formula I
prodrugs thereof and pharmaceutically acceptable salts of said compounds and prodrugs wherein
A is hydrogen or hydroxy;
B is propylene, propenylene or propynylene;
Q is propylene, xe2x80x94CH2OCH2xe2x80x94, thiazolyl, pyridyl, phenyl or thienyl;
Z is carboxyl, (C1-C6)alkoxycarbonyl, tetrazolyl, 1,2,4-oxadiazolyl or 5-oxo-1,2,4-oxadiazolyl;
K is ethylene or ethenylene;
L is a bond or xe2x80x94COxe2x80x94;
M is xe2x80x94Ar, xe2x80x94Ar1xe2x80x94Vxe2x80x94Ar2, xe2x80x94Ar1xe2x80x94Sxe2x80x94Ar2 or xe2x80x94Ar1xe2x80x94Oxe2x80x94Ar2 wherein
Ar and Ar1 are either (1) each independently a fully unsaturated five to eight membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated five and/or six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen, or a tricyclic ring consisting of three fused partially saturated, fully saturated or fully unsaturated five and/or six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen, any of said partially saturated or fully saturated rings optionally having one or more oxo groups substituted on carbon, or
(2) each independently a fully saturated five to eight membered ring;
Ar2 is a partially saturated, fully saturated or fully unsaturated five to eight membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated five and/or six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen, or a tricyclic ring consisting of three fused partially saturated, fully saturated or fully unsaturated five and/or six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen, any of said partially saturated or fully saturated rings optionally having one or more oxo groups substituted on carbon;
said Ar and Ar1 moieties, when a fully unsaturated five to eight membered ring, a bicyclic ring or a tricyclic ring, and said Ar2 moieties are each independently optionally substituted on carbon, on one ring if the moiety is monocyclic, on one or both rings if the moiety is bicyclic, or on one, two or three rings if the moiety is tricyclic, with up to three substituents selected from R1, R2 and R3 wherein R1, R2 and R3 are independently hydroxy, nitro, halo, (C1-C7)alkoxy, (C1-C4)alkoxy(C1-C4)alkyl, (C1-C4)alkoxycarbonyl, (C1-C7)alkyl, (C2-C7)alkenyl, (C2-C7)alkynyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C4)alkyl, (C3-C7)cycloalkyl(C1-C4)alkanoyl, formyl, (C1-C8)alkanoyl, (C1-C6)alkanoyl(C1-C6)alkyl, aminocarbonylamino or mono-N-, di-N,N-, di-N,Nxe2x80x2- or tri-N,N,Nxe2x80x2-(C1-C4)alkyl substituted aminocarbonylamino, (C1-C4)alkanoylamino, (C1-C4)alkoxycarbonylamino, sulfonamido, hydroxysulfonyl, (C1-C4)alkylsulfonamido, amino, mono-N- or di-N,Nxe2x80x94(C1-C4)alkylamino, carbamoyl, mono-N- or di-N,Nxe2x80x94(C1-C4)alkylcarbamoyl, cyano, thiol, (C1-C6)alkylthio, (C1-C6)alkylsulfinyl, (C1-C4)alkylsulfonyl or mono-N- or di-N,Nxe2x80x94(C1-C4)alkylaminosulfinyl;
R1, R2 and R3, when containing an alkyl, alkenyl, alkylene or alkenylene moiety, are optionally straight or branched and are optionally mono-, di- or tri-substituted on carbon independently with halo or hydroxy; and
V is a bond, xe2x80x94COxe2x80x94 or (C1-C3)alkylene optionally mono- or di-substituted independently with hydroxy or fluoro,
provided that (1) when L is xe2x80x94COxe2x80x94, A is hydroxyl; (2) when L is a bond and M is phenyl, said phenyl is substituted with one to three substitutes selected from R1, R2 and R3; and (3) when M is monosubstituted phenyl, M is not methylphenyl.
A preferred group of compounds, designated the A Group, contains those compounds having the Formula I as shown above, and pharmaceutically acceptable salts thereof, wherein L is absent, B and Q are each n-propylene and Z is carboxy, (C1-C3)alkoxycarbonyl or tetrazolyl.
A group of compounds which is preferred within the A Group, designated the B Group, contains those compounds, and pharmaceutically acceptable salts thereof, wherein A is OH.
A group of compounds which is preferred within the B Group, designated the C Group, contains those compounds, and pharmaceutically acceptable salts thereof, wherein M is thiazolyl or pyridyl optionally substituted with up to three substituents independently selected from R1, R2 and R3; or M is phenyl substituted with one to three substituents independently selected from R1, R2 and R3.
A group of compounds which is preferred within the C Group, designated the D Group, contains those compounds, and pharmaceutically acceptable salts thereof, wherein K is ethenylene.
A group of compounds which is preferred within the D group, designated the E Group, contains those compounds, and pharmaceutically acceptable salts thereof, wherein M is phenyl substituted with one to three groups selected from R1, R2 and R3, wherein R1, R2 and R3 are independently selected from (C1-C7) alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, halo and (C1-C6) alkyl.
A group of compounds which is preferred within the E group designated the F Group, contains those compounds, and pharmaceutically acceptable salts thereof, wherein R1, R2 and R3 are independently chloro and Z is carboxy, ethoxycarbonyl or tetrazolyl.
Especially preferred compounds within the F Group are those compounds, and pharmaceutically acceptable salts thereof, wherein said phenyl group is substituted with 3-chloro or 3,5-dichloro.
Another group of preferred compounds within the A Group, designated the G Group, contains those compounds, and pharmaceutically acceptable salts thereof, wherein A is H.
A group of compounds which is preferred within the G Group, designated the H Group, contains those compounds, and pharmaceutically acceptable salts thereof, wherein M is thiazolyl or pyridyl optionally substituted with up to three substituents independently selected from R1, R2 and R3; or M is phenyl substituted with one to three substituents independently selected from R1, R2 and R3.
A group of compounds which is preferred within the H Group, designated the J Group, contains those compounds, and pharmaceutically acceptable salts thereof, wherein K is ethenylene.
A group of compounds which is preferred within the J Group, designated the K Group, contains those compounds, and pharmaceutically acceptable salts thereof, wherein M is phenyl substituted with one to three groups selected from R1, R2 and R3, wherein R1, R2 and R3 are independently selected from (C1-C7) alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, halo and (C1-C6) alkyl.
A group of compounds which is preferred within the K Group, designated the L Group, contains those compounds, and pharmaceutically acceptable salts thereof, wherein R1, R2 and R3 are independently chloro, fluoro or trifluoromethyl and Z is carboxy, ethoxycarbonyl or tetrazolyl.
Especially preferred compounds within the K Group are trans-7-(2-(2-(3,5-bis-trifluoromethyl-phenyl)-vinyl)-5-oxo-cyclopentyl)-heptanoic acid; trans-7-(2-(2-(4-chloro-3-trifluoromethyl-phenyl)-vinyl)-5-oxo-cyclopentyl)-heptanoic acid; trans-7-(2-(2-(3,5-dichlorophenyl)-vinyl)-5-oxo-cyclopentyl)-heptanoic acid; trans-7-(2-(2-(3-chlorophenyl)-vinyl)-5-oxo-cyclopentyl)-heptanoic acid; trans-7-(2-oxo-5-(2-(3-trifluoromethyl-phenyl)-vinyl)-cyclopentyl)-heptanoic acid; and trans-7-(2-(2-(4-fluoro-phenyl)-vinyl)-5-oxo-cyclopentyl)-heptanoic acid; and pharmaceutically acceptable salts thereof.
Another group of compounds which is preferred within the L Group, designated the M Group, contains those compounds, and pharmaceutically acceptable salts thereof, wherein Z is carboxy.
An especially preferred compound within the M Group is the compound wherein M is 3,5-bis-trifluoromethylphenyl.
Another especially preferred compound within the M Group is the compound wherein M is 4-chloro-3-trifluoromethylphenyl.
Another especially preferred compound within the M Group is the compound wherein M is 3,5-dichlorophenyl.
Another especially preferred compound within the M Group is the compound wherein M is 3-chlorophenyl.
Another especially preferred compound within the M Group is the compound wherein M is 3-trifluoromethylphenyl.
Another especially preferred compound within the M Group is the compound wherein M is 4-fluorophenyl.
Other especially preferred compounds within the K Group are ethyl trans-7-(2-(2-(3,5-bis-trifluoromethyl-phenyl)-vinyl)-5-oxo-cyclopentyl)-heptanoate; ethyl trans-7-(2-(2-(4-chloro-3-trifluoromethyl-phenyl)-vinyl)-5-oxo-cyclopentyl)-heptanoate; ethyl trans-7-(2-(2-(3,5-dichlorophenyl)-vinyl)-5-oxo-cyclopentyl)-heptanoate; ethyl trans-7-(2-(2-(3-chlorophenyl)-vinyl)-5-oxo-cyclopentyl)-heptanoate; ethyl trans-7-(2-oxo-5-(2-(3-trifluoromethyl-phenyl)-vinyl)-cyclopentyl)-heptanoate; and ethyl trans-7-(2-(2-(4-fluoro-phenyl)-vinyl)-5-oxo-cyclopentyl)-heptanoate; and pharmaceutically acceptable salts thereof.
Another group of compounds which is preferred within the L Group, designated the N Group, contains those compounds, and pharmaceutically acceptable salts thereof, wherein Z is ethoxycarbonyl.
An especially preferred compound within the N Group is the compound wherein M is 3,5-bis-trifluoromethylphenyl.
Another especially preferred compound within the N Group is the compound wherein M is 4-chloro-3-trifluoromethylphenyl.
Another especially preferred compound within the N Group is the compound wherein M is 3,5-dichlorophenyl.
Another especially preferred compound within the N Group is the compound wherein M is 3-chlorophenyl.
Another especially preferred compound within the N Group is the compound wherein M is 3-trifluoromethylphenyl.
Another especially preferred compound within the N Group is the compound wherein M is 4-fluorophenyl.
Other especially preferred compounds within the K Group are trans-3-(2-(3,5-bis-trifluoromethyl-phenyl)-vinyl)-2-(6-(2-H-tetrazol-5-yl)-hexyl)-cyclopentanone; trans-3-(2-(4-chloro-3-trifluoromethylphenyl)-vinyl)-2-(6-(2H-tetrazol-5-yl)-cyclopentanone; trans-3-(2-(3,5-dichloro-phenyl)-vinyl)-2-(6-(2H-tetrazol-5-yl)-hexyl)-cyclopentanone; trans-3-(2-(3-chloro-phenyl)-vinyl)-2-(6-(2H-tetrazol-5-yl)-hexyl)-cyclopentanone; trans-3-(2-(3-trifluoromethyl-phenyl)-vinyl)-2-(6-(2H-tetrazol-5-yl)-hexyl)-cyclopentanone; and trans-3-(2-(4-fluoro-phenyl)-vinyl)-2-(6-(2H-tetrazol-5-yl)-hexyl)-cyclopentanone; and pharmaceutically acceptable salts thereof.
Another group of compounds which is preferred within the L Group, designated the P Group, contains those compounds wherein Z is tetrazolyl.
An especially preferred compound within the P Group is the compound wherein M is 3,5-bis-trifluoromethylphenyl.
Another especially preferred compound within the P Group is the compound wherein M is 4-chloro-3-trifluoromethylphenyl.
Another especially preferred compound within the P Group is the compound wherein M is 3,5-dichlorophenyl.
Another especially preferred compound within the P Group is the compound wherein M is 5-chlorophenyl.
Another especially preferred compound within the P Group is the compound wherein M is 3-trifluoromethylphenyl.
Another especially preferred compound within the P Group is the compound wherein M is 4-fluorophenyl.
Another preferred group of compounds of Formula I, designated the Q Group, contains those compounds, and pharmaceutically acceptable salts thereof, having the Formula I as shown above wherein L is xe2x80x94COxe2x80x94, B and Q are each n-propylene and Z is carboxy, (C1-C3)alkoxycarbonyl or tetrazolyl.
A group of compounds which is preferred within the Q Group, designated the S Group, contains those compounds, and pharmaceutically acceptable salts thereof, wherein A is OH.
A group of compounds which is preferred within the S Group, designated the T Group, contains those compounds, and pharmaceutically acceptable salts thereof, wherein M is thiazolyl or pyridyl optionally substituted with up to three substituents independently selected from R1, R2 and R3; or M is phenyl substituted with one to three substituents independently selected from R1, R2 and R3.
A group of compounds which is preferred within the T Group, designated the U Group, contains those compounds, and pharmaceutically acceptable salts thereof, wherein K is ethenylene.
A group of compounds which is preferred within the U Group, designated the V Group, contains those compounds, and pharmaceutically acceptable salts thereof, wherein M is phenyl substituted with one to three groups selected from R1, R2 and R3, wherein R1, R2 and R3 are independently selected from (C1-C7) alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, halo and (C1-C6) alkyl.
A group of compounds which is preferred within the V Group, designated the X Group, contains those compounds, and pharmaceutically acceptable salts thereof, wherein R1, R2 and R3 are independently chloro and Z is carboxy, ethoxycarbonyl or tetrazolyl.
Especially preferred compounds within the X Group are those compounds, and pharmaceutically acceptable salts thereof, wherein said phenyl group is substituted with 3-chloro or 3,5-dichloro.
This invention is also directed to methods for augmenting and maintaining bone mass and preventing further bone loss in vertebrate, e.g., a mammal, comprising administering to a mammal a therapeutically effective amount of a compound of Formula IA
prodrugs thereof or pharmaceutically acceptable salts of said compounds or said prodrugs wherein
A is hydrogen or hydroxy;
B is propylene, propenylene or propynylene;
Q is propylene, xe2x80x94CH2OCH2xe2x80x94, thiazolyl, pyridyl, phenyl or thienyl;
Z is carboxyl, (C1-C6)alkoxycarbonyl, tetrazolyl, 1,2,4-oxadiazolyl or 5-oxo-1,2,4-oxadiazolyl;
K is ethylene or ethenylene;
L is a bond or xe2x80x94COxe2x80x94;
M is xe2x80x94Ar, xe2x80x94Ar1xe2x80x94Vxe2x80x94Ar2, xe2x80x94Ar1xe2x80x94Sxe2x80x94Ar2 or xe2x80x94Ar1xe2x80x94Oxe2x80x94Ar2 wherein
Ar, Ar1 and Ar2 are each independently a fully saturated, partially unsaturated or fully unsaturated five to eight membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or, a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated five and/or six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen, or, a tricyclic ring consisting of three fused partially saturated, fully saturated or fully unsaturated five and/or six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen, any of said partially saturated or fully saturated rings optionally having one or more oxo groups substituted on carbon,
said Ar, Ar1 and Ar2 moieties are each independently optionally substituted on carbon, on one ring if the moiety is monocyclic, on one or both rings if the moiety is bicyclic, or on one, two or three rings is the moiety is tricyclic, with up to three substituents independently selected from R1, R2 and R3 wherein R1, R2 and R3 are hydroxy, nitro, halo, (C1-C7)alkoxy, (C1-C4)alkoxy(C1-C4)alkyl, (C1-C4)alkoxycarbonyl, (C1-C7)alkyl, (C2-C7)alkenyl, (C2-C7)alkynyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C4)alkyl, (C3-C7)cycloalkyl(C1-C4)alkanoyl, formyl, (C1-C8)alkanoyl, (C1-C6)alkanoyl(C1-C6)alkyl, aminocarbonylamino or mono-N-, di-N,N-, di-N,Nxe2x80x2- or tri-N,N,Nxe2x80x2xe2x80x94(C1-C4)alkyl substituted aminocarbonylamino, (C1-C4)alkanoylamino, (C1-C4)alkoxycarbonylamino, sulfonamido, hydroxysulfonyl, (C1-C4)alkylsulfonamido, amino, mono-N- or di-N,Nxe2x80x94(C1-C4)alkylamino, carbamoyl, mono-N- or di-N,Nxe2x80x94(C1-C4)alkylcarbamoyl, cyano, thiol, (C1-C5)alkylthio, (C1-C6)alkylsulfinyl, (C1-C4)alkylsulfonyl or mono-N- or di-N,Nxe2x80x94(C1-C4)alkylaminosulfinyl;
R1, R2 and R3, when containing an alkyl, alkenyl, alkylene or alkenylene moiety, are optionally straight or branched and are optionally mono-, di- or tri-substituted on carbon independently with halo or hydroxy; and
V is a bond, xe2x80x94COxe2x80x94 or (C1-C3)alkylene optionally mono- or di-substituted independently with hydroxy or fluoro.
This invention also directed to methods for treating vertebrates, e.g., a mammal, having a condition which presents with low bone mass comprising administering to vertebrate, e.g., a mammal, having a condition which presents with low bone mass a therapeutically effective amount of a compound of Formula IA above or a pharmaceutically acceptable salt or prodrug thereof. Preferably post-menopausal women and men over the age of 60 are treated. Also included are individuals regardless of age who have significantly reduced bone mass, i.e., greater than or equal to 1.5 standard deviations below young normal levels.
Yet another aspect of this invention is directed to methods for treating osteoporosis, bone fractures, osteotomy, bone loss associated with periodontitis, or prosthetic ingrowth in vertebrate, e.g., a mammal (including a human being), comprising administering to vertebrate, e.g., a mammal suffering from osteoporosis, bone fracture, osteotomy, bone loss associated with periodontitis, or prosthetic ingrowth an osteoporosis, bone fracture, osteotomy, bone loss associated with periodontitis, or prosthetic ingrowth treating amount of a Formula IA compound or a pharmaceutically acceptable salt or prodrug thereof.
Yet another aspect of this invention is directed to methods for treating osteoporosis in vertebrate, e.g., a mammal (including a human being), by comprising administering to vertebrate, e.g., a mammal suffering from osteoporosis an osteoporosis treating amount of a Formula IA compound or a pharmaceutically acceptable salt or prodrug thereof.
Yet another aspect of this invention is directed to method for treating osteotomy bone loss in vertebrate, e.g., a mammal (including a human being), comprising administering to vertebrate, e.g. a mammal suffering from an osteotomy bone loss an osteotomy bone loss treating amount of a Formula IA compound or a pharmaceutically acceptable salt or prodrug thereof. In one aspect the Formula IA compound is applied locally to a site of osteotomy.
Yet another aspect of this invention is directed to methods for treating alveolar bone loss in vertebrate, e.g., a mammal (including a human being), comprising administering to vertebrate, e.g., a mammal suffering from an alveolar bone loss an alveolar bone loss treating amount of a Formula IA compound or a pharmaceutically acceptable salt or prodrug thereof.
Yet another aspect of this invention is directed to methods for treating bone loss associated with periodontitis in vertebrate, e.g., a mammal (including a human being), comprising administering to vertebrate, e.g., mammal suffering from bone loss associated with periodontitis a bone loss associated with periodontitis treating amount of a Formula IA compound or a pharmaceutically acceptable salt or prodrug thereof.
Yet another aspect of this invention is directed to methods for treating childhood idiopathic bone loss in vertebrate, e.g., a mammal comprising administering to a child suffering from childhood idiopathic bone loss a childhood idiopathic bone loss treating amount of a Formula IA compound or a pharmaceutically acceptable salt or prodrug thereof.
Yet another aspect of this invention is directed to methods for treating xe2x80x9csecondary osteoporosisxe2x80x9d, which includes glucocorticoid-induced osteoporosis, hyperthyroidism-induced osteoporosis, immobilization-induced osteoporosis, heparin-induced osteoporosis or immunosuppressive-induced osteoporosis in vertebrate, e.g., a mammal (including a human being), by administering to vertebrate, e.g., a mammal suffering from xe2x80x9csecondary osteoporosisxe2x80x9d a xe2x80x9csecondary osteoporosisxe2x80x9d treating amount of a Formula IA compound or a pharmaceutically acceptable salt or prodrug thereof.
Yet another aspect of this invention is directed to methods for treating glucocorticoid-induced osteoporosis in vertebrate, e.g., a mammal (including a human being), comprising administering to vertebrate, e.g., a mammal suffering from glucocorticoid-induced osteoporosis a glucocorticoid-induced osteoporosis treating amount of a Formula IA compound or a pharmaceutically acceptable salt or prodrug thereof.
Yet another aspect of this invention is directed to methods for treating hyperthyroidism-induced osteoporosis in vertebrate, e.g., a mammal (including a human being), comprising administering to vertebrate, e.g., a mammal suffering from hyperthyroidism-induced osteoporosis a hyperthyroidism-induced osteoporosis treating amount of a Formula IA compound or a pharmaceutically acceptable salt or prodrug thereof.
Yet another aspect of this invention is directed to methods for treating immobilization-induced osteoporosis in vertebrate, e.g., a mammal (including a human being), comprising administering to vertebrate, e.g., a mammal suffering from immobilization-induced osteoporosis a immobilization-induced osteoporosis treating amount of a Formula IA compound or a pharmaceutically acceptable salt or prodrug thereof.
Yet another aspect of this invention is directed to methods for treating heparin-induced osteoporosis in vertebrate, e.g., a mammal (including a human being), comprising administering to vertebrate, e.g., a mammal suffering from heparin-induced osteoporosis a heparin-induced osteoporosis treating amount of a Formula IA compound or a pharmaceutically acceptable salt or prodrug thereof.
Yet another aspect of this invention is directed to methods for treating immunosuppressive-induced osteoporosis in vertebrate, e.g., a mammal (including a human being), comprising administering to vertebrate, e.g., a mammal suffering from immunosuppressive-induced osteoporosis an immunosuppressive-induced osteoporosis treating amount of a Formula IA compound or a pharmaceutically acceptable salt or prodrug thereof.
Yet another aspect of this invention is directed to methods for treating a bone fracture in vertebrate, e.g., a mammal (including a human being), comprising administering to vertebrate, e.g., a mammal suffering from a bone fracture a bone fracture treating amount of a Formula IA compound or a pharmaceutically acceptable salt or prodrug thereof. In one aspect of this invention for treating a bone fracture the Formula IA compound or a pharmaceutically acceptable salt or prodrug thereof is applied locally to the site of bone fracture. In another aspect of this invention the Formula IA compound or a pharmaceutically acceptable salt or prodrug thereof is administered systemically.
Yet another aspect of this invention is directed to methods for enhancing bone healing following facial reconstruction or maxillary reconstruction or mandibular reconstruction in vertebrate, e.g., a mammal (including a human being), comprising administering to vertebrate, e.g., a mammal which has undergone facial reconstruction or maxillary reconstruction or mandibular reconstruction a bone enhancing amount of a Formula IA compound or a pharmaceutically acceptable salt or prodrug thereof. In one aspect of this method the Formula IA compound or a pharmaceutically acceptable salt or prodrug thereof is applied locally to the site of bone reconstruction.
Yet another aspect of this invention is directed to methods for treating prosthetic ingrowth in vertebrate, e.g., a mammal (including a human being), comprising administering to vertebrate, e.g., a mammal suffering from prosthetic ingrowth a prosthetic ingrowth treating amount of a Formula IA compound or a pharmaceutically acceptable salt or prodrug thereof.
Yet another aspect of this invention is directed to methods for inducing vertebral synostosis in vertebrate, e.g., a mammal (including a human being), comprising administering to vertebrate, e.g., a mammal undergoing surgery for vertebral synostosis a therapeutically effective amount of a Formula IA compound or a pharmaceutically acceptable salt or prodrug thereof.
Yet another aspect of this invention is directed to methods for enhancing long bone extension in vertebrate, e.g., a mammal (including a human being), comprising administering to vertebrate, e.g., a mammal suffering from an insufficiently sized long bone a long bone enhancing amount of a Formula IA compound or a pharmaceutically acceptable salt or prodrug thereof.
Yet another aspect of this invention is directed to methods for strengthening a bone graft in vertebrate, e.g., a mammal including a human being), comprising administering to vertebrate, e.g., a mammal in receipt of a bone graft a bone graft strengthening amount of a Formula IA compound or a pharmaceutically acceptable salt or prodrug thereof. In one aspect of this method the Formula IA compound or a pharmaceutically acceptable salt or prodrug thereof is applied locally to the site of the bone graft.
A preferred dosage is about 0.001 to 100 mg/kg/day of the Formula IA compound or a pharmaceutically acceptable salt or prodrug thereof. An especially preferred dosage is about 0.01 to 10 mg/kg/day of the Formula IA compound or a pharmaceutically acceptable salt or prodrug thereof.
This invention is also directed to pharmaceutical compositions which comprise a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier.
This invention is also directed to pharmaceutical compositions for the augmentation of bone mass which comprise a bone mass augmenting amount of a compound of Formula I above or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier.
This invention is also directed to pharmaceutical compositions for the treatment of a condition which presents with low bone mass in vertebrate, e.g., a mammal (including a human being), which comprise a low bone mass condition treating amount of a compound of Formula I above or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier.
This invention is also directed to pharmaceutical compositions for the treatment of osteoporosis, bone fractures, osteotomy bone loss, bone loss associated with periodontitis, or prosthetic ingrowth in vertebrate, e.g., a mammal (including a human being), which comprises a therapeutically effective amount of a compound of Formula I above or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier.
This invention is also directed to pharmaceutical compositions for the treatment of xe2x80x9csecondary osteoporosisxe2x80x9d, which includes glucocorticoid-induced osteoporosis, hyperthyroidism-induced osteoporosis, immobilization-induced osteoporosis, heparin-induced osteoporosis or immunosuppressive-induced osteoporosis in vertebrate, e.g., a mammal (including a human being), which comprise a xe2x80x9csecondary osteoporosisxe2x80x9d treating amount of a compound of Formula I above or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier.
This invention is also directed to pharmaceutical compositions for the treatment of osteoporosis in vertebrate, e.g., a mammal (including a human being), which comprise an osteoporosis treating amount of a compound of the Formula I above or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier.
This invention is also directed to pharmaceutical compositions for enhancing bone fracture healing in vertebrate, e.g., a mammal (including a human being), which comprise a bone fracture treating amount of a compound of the Formula I above or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier.
This invention is also directed to pharmaceutical compositions for the treatment of osteotomy bone loss in vertebrate, e.g., a mammal (including a human being), which comprise an osteotomy bone loss treating amount of a compound of the Formula I above or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier.
This invention is also directed to pharmaceutical compositions for the treatment of alveolar bone loss in vertebrate, e.g., a mammal (including a human being), which comprise an alveolar bone loss treating amount of a compound of the Formula I above or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier.
This invention is also directed to pharmaceutical compositions for the treatment of childhood idiopathic bone loss in a child which comprises a childhood idiopathic bone loss treating amount of a compound of the Formula I above or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier.
This invention is also directed to pharmaceutical compositions for the augmentation of bone healing following facial reconstruction or maxillary reconstruction or mandibular reconstruction in vertebrate, e.g., a mammal (including a human being), which comprise a bone healing amount of a compound of the Formula I above or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier.
This invention is also directed to pharmaceutical compositions for the treatment of bone loss associated with periodontitis in vertebrate, e.g., a mammal (including a human being), which comprise a bone loss associated with periodontitis treating amount of a compound of the Formula I above or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier.
This invention is also directed to pharmaceutical compositions for the treatment of prosthetic ingrowth in vertebrate, e.g., a mammal (including a human being), which comprise a prosthetic ingrowth treating amount of a compound of the Formula I above or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier.
This invention is also directed to pharmaceutical compositions for inducing vertebral synostosis in vertebrate, e.g., a mammal (including a human being), which comprise a therapeutically effective amount of a compound of the Formula I above or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier.
This invention is also directed to pharmaceutical compositions for the augmentation of long bone extension in vertebrate, e.g., a mammal (including a human being), which comprise bone mass augmentation treating amount of a compound of the Formula I above or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier.
This invention is also directed to pharmaceutical compositions for the treatment of glucocorticoid-induced osteoporosis in vertebrate, e.g., a mammal (including a human being), which comprise a glucocorticoid-induced osteoporosis treating amount of a compound of the Formula I above or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier.
This invention is also directed to pharmaceutical compositions for the treatment of hyperthyroidism-induced osteoporosis in vertebrate, e.g., a mammal (including a human being), which comprise a hyperthyroidism-induced osteoporosis treating amount of a compound of the Formula I above or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier.
This invention is also directed to pharmaceutical compositions for the treatment of immobilization-induced osteoporosis in vertebrate, e.g., a mammal (including a human being), which comprise an immobilization-induced osteoporosis treating amount of a compound of the Formula I above or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier.
This invention is also directed to pharmaceutical compositions for the treatment of heparin-induced osteoporosis in vertebrate, e.g., a mammal (including a human being) which comprise a heparin-induced osteoporosis treating amount of a compound of the Formula I above or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier.
This invention is also directed to pharmaceutical compositions for the treatment of immunosuppressive-induced osteoporosis in vertebrate, e.g., a mammal (including a human being) which comprise an immunosuppressive-induced osteoporosis treating amount of a compound of the Formula I above or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier.
Yet another aspect of this invention are combinations of the Formula I compounds or a pharmaceutically acceptable salt or prodrug thereof and other compounds as described below.
Yet another aspect of this invention is directed to pharmaceutical compositions comprising a compound of Formula I above or a pharmaceutically acceptable salt or prodrug thereof and an anti-resorptive agent and for the use of such compositions for the treatment or prevention of conditions which present with low bone mass, including osteoporosis in vertebrates, e.g., mammals (e.g., humans, particularly women) or the use of such compositions for other bone mass augmenting uses.
The combinations of this invention comprise a therapeutically effective amount of a first compound, said first compound being a Formula I compound or a pharmaceutically acceptable salt or prodrug thereof; and a therapeutically effective amount of a second compound, said second compound being an anti-resorptive agent such as an estrogen agonist/antagonist or a bisphosphonate.
Another aspect of this invention are methods for treating vertebrates, e.g., mammals which present with low bone mass comprising administering to vertebrate, e.g., a mammal having a condition which presents with low bone mass
a. an amount of a first compound, said first compound being a Formula IA compound or a pharmaceutically acceptable salt or prodrug thereof; and
b. an amount of a second compound, said second compound being an anti-resorptive agent such as an estrogen agonist/antagonist or a bisphosphonate.
Such compositions and methods may also be used for other bone mass augmenting uses.
A preferred aspect of this method is wherein the condition which presents with low bone mass is osteoporosis.
Another preferred aspect of this method is wherein the first compound and the second compound are administered substantially simultaneously.
Another preferred aspect of this method is wherein the first compound is administered for a period of from about three months to about three years.
Optionally the administration of the first compound is followed by administration of the second compound wherein the second compound is an estrogen agonist/antagonist for a period of from about three months to about three years without the administration of the first compound during the second period of from about three months to about three years.
Alternatively, the administration of the first compound is followed by administration of the second compound wherein the second compound is an estrogen agonist/antagonist for a period greater than about three years without the administration of the first compound during the greater than about three year period.
Another aspect of this invention is a kit comprising:
a. an amount of a Formula IA compound or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier in a first unit dosage form;
b. an amount of an anti-resorptive agent such as an estrogen agonist/antagonist or a bisphosphonate and a pharmaceutically acceptable carrier in a second unit dosage form; and
c. container means for containing said first and second dosage forms.
Yet another aspect of this invention is directed to pharmaceutical compositions including a compound of Formula IA above or a pharmaceutically acceptable salt or prodrug thereof and another bone anabolic agent (although the other bone anabolic agent may be a different Formula I compound) and for the use of such compositions for the treatment of conditions which present with low bone mass, including osteoporosis in vertebrates, e.g., mammals (e.g., humans, particularly women) or the use of such compositions for other bone mass augmenting uses.
The combination comprises a therapeutically effective amount of a first compound, said first compound being a Formula IA compound or a pharmaceutically acceptable salt or prodrug thereof; and a therapeutically effective amount of a second compound, said second compound being another bone anabolic agent.
Another aspect of this invention are methods for treating vertebrates, e.g., mammals which present with low bone mass comprising administering to vertebrate, e.g., a mammal having a condition which presents with low bone mass
a. an amount of a first compound, said first compound being a Formula IA compound or a pharmaceutically acceptable salt or prodrug therof; and
b. an amount of a second compound, said second compound being another bone anabolic agent other than the Formula IA compound.
Such compositions and methods may also be used for other bone mass augmenting uses.
A preferred aspect of this method is wherein the condition which presents with low bone mass is osteoporosis.
Another preferred aspect of this method is wherein the first compound and the second compound are administered substantially simultaneously.
Another aspect of this invention is a kit comprising:
a. an amount of a Formula I compound or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier in a first unit dosage form;
b. an amount of a second compound, said second compound being a bone anabolic agent other than the Formula I compound of part a above; and
c. container means for containing said first and second dosage forms.
Where used in any of the above methods, kits and compositions, certain bone anabolic agents, estrogen agonists/antagonists and bisphosphonates are preferred or especially preferred.
Preferred bone anabolic agents include IGF-1, prostaglandin, prostaglandin agonist/antagonist, sodium fluoride, parathyroid hormone (PTH), active fragments of parathyroid hormone, parathyroid hormone related peptides and active fragments and analogues of parathyroid hormone related peptides, growth hormone or growth hormone secretagogues and the pharmaceutically acceptable salts thereof.
Preferred estrogen agonist/antagonists include droloxifene, raloxifene, tamoxifen; 4-hydroxy-tamoxifen; toremifene; centchroman; levormeloxifene; idoxifene; 6-(4-hydroxy-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-naphthalen-2-ol; {4-[2-(2-aza-bicyclo[2.2.1]hept-2-yl)-ethoxy]-phenyl}-[6-hydroxy-2-(4-hydroxy-phenyl)-benzo[b]thiophen-3-yl]-methanone;
cis-6-(4-fluoro-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;
(xe2x88x92)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;
cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;
cis-1-[6xe2x80x2-pyrrolodinoethoxy-3xe2x80x2-pyridyl]-2-phenyl-6-hydroxy-1,2,3,4-tetrahydronaphthalene;
1-(4xe2x80x2-pyrrolidinoethoxyphenyl)-2-(4xe2x80x3-fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydroisoquinoline;
cis-6-(4-hydroxyphenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol; and
1-(4xe2x80x2-pyrrolidinolethoxyphenyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline and the pharmaceutically acceptable salts thereof.
Especially preferred estrogen agonist/antagonists include droloxifene;
cis-6-(4-fluoro-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;
(xe2x88x92)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;
cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;
cis-1-[6xe2x80x2-pyrrolodinoethoxy-3xe2x80x2-pyridyl]-2-phenyl-6-hydroxy-1,2,3,4-tetrahydronaphthalene;
1-(4xe2x80x2-pyrrolidinoethoxyphenyl)-2-(4xe2x80x3-fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydroisoquinoline;
cis-6-(4-hydroxyphenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;
1-(4xe2x80x2-Pyrrolidinolethoxyphenyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline; and the pharmaceutically acceptable salts thereof.
Preferred bisphosphonates include, tiludronic acid, alendronic acid, ibandronic acid, risedronic acid, etidronic acid, clodronic acid, and pamidronic acid and their pharmaceutically acceptable salts.
The phrase xe2x80x9ccondition(s) which presents with low bone massxe2x80x9d refers to a condition where the level of bone mass is below the age specific normal as defined in standards by the World Health Organization xe2x80x9cAssessment of Fracture Risk and its Application to Screening for Postmenopausal Osteoporosis (1994). Report of a World Health Organization Study Group. World Health Organization Technical Series 843xe2x80x9d. Included in xe2x80x9ccondition(s) which presents with low bone massxe2x80x9d are primary and secondary osteoporosis. Secondary osteoporosis includes glucocorticoid-induced osteoporosis, hyperthyroidism-induced osteoporosis, immobilization-induced osteoporosis, heparin-induced osteoporosis and immunosuppressive-induced osteoporosis. Also included is periodontal disease, alveolar bone loss, osteotomy bone loss and childhood idiopathic bone loss. The phrase xe2x80x9ccondition(s) which presents with low bone massxe2x80x9d also includes long term complications of osteoporosis such as curvature of the spine, loss of height and prosthetic surgery.
The phrase xe2x80x9ccondition which presents with low bone massxe2x80x9d also refers to vertebrate, e.g., a mammal known to have a significantly higher than average chance of developing such diseases as are described above including osteoporosis (e.g., post-menopausal women, men over the age of 60).
Other bone mass augmenting or enhancing uses include increasing the bone fracture healing rate, enhancing the rate of successful bone grafts, bone healing following facial reconstruction or maxillary reconstruction or mandibular reconstruction, prosthetic ingrowth, vertebral synostosis or long bone extension.
Those skilled in the art will recognize that the term bone mass actually refers to bone mass per unit area which is sometimes (although not strictly correctly) referred to as bone mineral density.
The term xe2x80x9ctreatingxe2x80x9d, xe2x80x9ctreatxe2x80x9d or xe2x80x9ctreatmentxe2x80x9d as used herein includes preventative (e.g., prophylactic) and palliative treatment.
By xe2x80x9cpharmaceutically acceptablexe2x80x9d it is meant the carrier, diluent, excipients, and/or salt must be compatible with the other ingredients of the formulation, and not deleterious to the recipient thereof.
The expression xe2x80x9cprodrugxe2x80x9d refers to compounds that are drug precursors which following administration, release the drug in vivo via some chemical or physiological process (e.g., a prodrug on being brought to the physiological pH or through enzyme action is converted to the desired drug form). Exemplary prodrugs upon cleavage release the corresponding free acid, and such hydrolyzable ester-forming residues of the Formula I compounds include but are not limited to substituents wherein the Z moiety is independently carboxyl and the free hydrogen is replaced by (C1-C4)alkyl, (C2-C7)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N,Nxe2x80x94(C1-C2)alkylamino(C2-C3)alkyl (such as b-dimethylaminoethyl), carbamoyl-(C1-C2)alkyl, N,N-di(C1-C2)alkylcarbamoyl-(C1-C2)alkyl and piperidino-, pyrrolidino- or morpholino(C2-C3)alkyl.
Exemplary five to six membered aromatic rings optionally having one or two heteroatoms selected independently from oxygen, nitrogen and sulfur (i.e., X rings) are phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridiazinyl, pyrimidinyl and pyrazinyl.
Exemplary partially saturated, fully saturated or fully unsaturated five to eight membered rings optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen (i.e., Ar, Ar1 and Ar2) are cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and phenyl. Further exemplary five membered rings are furyl, thienyl, 2H-pyrrolyl, 3H-pyrrolyl, pyrrolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 1,3-dioxolanyl, oxazolyl, thiazolyl, imidazolyl, 2H-imidazolyl, 2-imidazolinyl, imidazolidinyl, pyrazolyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2-dithiolyl, 1,3-dithiolyl, 3H-1,2-oxathiolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-thiadiazolyl, 1,2,3,4-oxatriazolyl, 1,2,3,5-oxatriazolyl, 3H-1,2,3-dioxazolyl, 1,2,4-dioxazolyl, 1,3,2-dioxazolyl, 1,3,4-dioxazolyl, 5H-1,2,5-oxathiazolyl and 1,3-oxathiolyl.
Further exemplary six membered rings are 2H-pyranyl, 4H-pyranyl, pyridyl, piperidinyl, 1,2-dioxinyl, 1,3-dioxinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, 1,3,5-trithianyl, 4H-1,2-oxazinyl, 2H-1,3-oxazinyl, 6H-1,3-oxazinyl, 6H-1,2-oxazinyl, 1,4-oxazinyl, 2H-1,2-oxazinyl, 4H-1,4-oxazinyl, 1,2,5-oxathiazinyl, 1,4-oxazinyl, o-isoxazinyl, p-isoxazinyl, 1,2,5-oxathiazinyl, 1,2,6-oxathiazinyl, 1,4,2-oxadiazinyl and 1,3,5,2-oxadiazinyl.
Further exemplary seven membered rings are azepinyl, oxepinyl, thiepinyl and 1,2,4-diazepinyl.
Further exemplary eight membered rings are cyclooctyl, cyclooctenyl and cyclooctadienyl.
Exemplary bicyclic rings consisting of two fused partially saturated, fully saturated or fully unsaturated five and/or six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen are indolizinyl, indolyl, isoindolyl, 3H-indolyl, 1H-isoindolyl, indolinyl, cyclopenta(b)pyridinyl, pyrano(3,4-b)pyrrolyl, benzofuryl, isobenzofuryl, benzo(b)thienyl, benzo(c)thienyl, 1H-indazolyl, indoxazinyl, benzoxazolyl, anthranilyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinoiizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, indenyl, isoindenyl, naphthyl, tetralinyl, decalinyl, 2H-1-benzopyranyl, pyrido(3,4-b)-pyridinyl, pyrido(3,2-b)-pyridinyl, pyrido(4,3-b)pyridinyl, 2H-1,3-benzoxazinyl, 2H-1,4-benzoxazinyl, 1H-2,3-benzoxazinyl, 4H-3,1-benzoxazinyl, 2H-1,2-benzoxazinyl and 4H-1,4-benzoxazinyl.
Exemplary tricyclic rings consisting of three fused partially saturated, fully saturated or fully unsaturated five and/or six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen are indacenyl, biphenylenyl, acenaphthylenyl, fluorenyl, phenalenyl, phenanthrenyl, anthracenyl, naphthothienyl, thianthrenyl, xanthenyl, phenoxathiinyl, carbazolyl, carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyi, phenazinyl, phenothiazinyl and phenoxazinyl. It will be understood that the fully saturated and all parially unsaturated forms of these rings are within the scope of this invention. Further, it will be understood that the heteroatom or heteroatoms in the heterocyclic rings can be substituted at any non-bridgehead position within said ring.
By alkylene is meant saturated hydrocarbon (straight chain or branched) wherein a hydrogen atom is removed from each of the terminal carbons. Exemplary of such groups (assuming the designated length encompases the particular example) are methylene, ethylene, propylene, butylene, pentylene, hexylene and heptylene.
By alkenylene is meant a hydrocarbon containing monounsaturation in the form of one double bond wherein said hydrocarbon is straight chain or branched and wherein a hydrogen atom is removed from each of the terminal carbons. Exemplary of such groups (assuming the designated length encompasses the particular example) are ethenylene (or vinylene), propenylene, butenylene, pentenylene, hexenylene and heptenylene.
By alkynylene is meant a hydrocarbon containing di-unsaturation in the form of one triple bond wherein said hydrocarbon is straight chain or branched and wherein a hydrogen atom is removed from each of the terminal carbons. Exemplary of such groups (assuming the designated length encompasses the particular example) are ethynylene, propynylene, butynylene, pentynylene, hexynylene and heptynylene.
By halo is meant chloro, bromo, iodo, or fluoro.
By alkyl is meant straight chain saturated hydrocarbon or branched saturated hydrocarbon. Exemplary of such alkyl groups (assuming the designated length encompasses the particular example) are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tertiary butyl, pentyl, isopentyl, neopentyl, tertiary pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, hexyl, isohexyl, heptyl and octyl.
By alkoxy is meant straight chain saturated alkyl or branched saturated alkyl bonded through an oxy. Exemplary of such alkoxy groups (assuming the designated length encompasses the particular example) are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, neopentoxy, tertiary pentoxy, hexoxy, isohexoxy, heptoxy and octoxy.
As used herein the term mono-N- or di-N,Nxe2x80x94(C1-Cx)alkyl . . . refers to the (C1-Cx)alkyl moiety taken independently when it is di-N,Nxe2x80x94(C1-Cx)alkyl . . . (x refers to integers and is taken independently when two (C1-Cx)alkyl groups are present, e.g., methylethylamino is within the scope of di-N,Nxe2x80x94(C1-Cx)alkyl).
Unless otherwise stated the xe2x80x9cMxe2x80x9d moieties defined above are optionally substituted (e.g., the mere listing of a substituent such as R1 in a subgenus or dependent claim does not mean that M is always substituted with the R1 moiety unless it is stated that the M moiety is substituted with R1). However, in the compounds of Formula I, when L is a bond and M is phenyl, said phenyl group is substituted with one to three substituents. Additionally, in the compounds of Formula I, when Ar or Ar1 is a fully saturated five to eight membered ring, said ring is unsubstituted.
It is to be understood that if a carbocyclic or heterocyclic moiety may be bonded or otherwise attached to a designated substrate, through differing ring atoms without denoting a specific point of attachment, then all possible points are intended, whether through a carbon atom or, for example, a trivalent nitrogen atom. For example, the term xe2x80x9cpyridylxe2x80x9d means 2-, 3-, or 4-pyridyl, the term xe2x80x9cthienylxe2x80x9d means 2-, or 3-thienyl, and so forth.
The expression xe2x80x9cpharmaceutically acceptable saltxe2x80x9d refers to nontoxic anionic salts containing anions such as (but not limited to) chloride, bromide, iodide, sulfate, bisulfate, phosphate, acetate, maleate, fumarate, oxalate, lactate, tartrate, citrate, gluconate, methanesulfonate and 4-toluene-sulfonate. The expression also refers to nontoxic cationic salts such as (but not limited to) sodium, potassium, calcium, magnesium, ammonium or protonated benzathine (N,Nxe2x80x2-dibenzylethylenediamine), choline, ethanolamine, diethanolamine, ethylenediamine, meglamine (N-methyl-glucamine), benethamine (N-benzylphenethylamine), piperazine or tromethamine (2-amino2-hydroxymethyl-1,3-propanediol).
As used herein, the expressions xe2x80x9creaction inert solventxe2x80x9d and xe2x80x9cinert solventxe2x80x9d refers to a solvent which does not interact with starting materials, reagents, intermediates or products in a manner which adversely affects the yield of the desired product.
The chemist of ordinary skill will recognize that certain compounds of this invention will contain one or more atoms which may be in a particular stereochemical or geometric configuration, giving rise to stereoisomers and configurational isomers. All such isomers and mixtures thereof are included in this invention.
The oxocyclopentane derivatives of Formulas I and IA, substituted at the xcex1- and xcex2-positions (see structures below) of the ring relative to the carbonyl group by Bxe2x80x94Qxe2x80x94Z and Kxe2x80x94Lxe2x80x94M, respectively, can exist as either the cis or the trans isomer. xe2x80x9cCisxe2x80x9d forms of the oxocyclopentane compounds of Formulas I and IA are those compounds wherein the substituents at the xcex1- and xcex2-positions of said ring are both directed either above the ring or below the ring. The term xe2x80x9ctransxe2x80x9d indicates a stereochemistry wherein one of the substituents is directed above the ring and the other substituent is directed below the ring. Both the cis and the trans forms of the compounds of Formulas I and IA are within the scope of this invention. The trans forms are generally more preferred due to the propensity to epimerize demonstrated by the cis forms. The most preferred compounds of the invention are those compounds wherein the xcex1 substituent is directed below the ring and the xcex2 substituent is directed above the ring. Furthermore, wherein the compounds of the invention are xcex3-hydroxy substituted, xcex1-substituted with Bxe2x80x94Qxe2x80x94Z and xcex2-substituted with Kxe2x80x94Lxe2x80x94M, the skilled person will recognize that there are three stereocenters. In that case, the compounds wherein the hydroxy group is directed down, the xcex1-substituent is directed down and the xcex2-substituent is directed up are the most preferred isomers.
Hydrates of the compounds of this invention are also included.
DTT means dithiothreitol. DMSO means dimethyl sulfoxide. EDTA means ethylenediamine tetraacetic acid.
The methods and compounds of this invention result in bone formation resulting in decreased fracture rates. This invention makes a significant contribution to the art by providing compounds and methods that increase bone formation resulting in prevention, retardation, and/or regression of osteoporosis and related bone disorders.
Other features and advantages will be apparent from the specification and claims which describe the invention.
In general the compounds of this invention can be made by processes which include processes known in the chemical arts, particularly in light of the description contained herein. Certain processes for the manufacture of the compounds of this invention are provided as further features of the invention and are illustrated by the following reaction schemes. Other processes may be described in the examples.
Some substituents (e.g., carboxyl) may best be prepared through conversion of another functional group (for carboxyl, examples are hydroxyl or carboxaldehyde) at a point later in the synthetic sequence.
In the schemes set forth hereinbelow, the compounds of this invention are depicted in the most preferred form, having the general stereochemical substitution pattern:
when A is OH and
when A is H.
It will be understood by those skilled in the art that other isomeric forms, including, when A is OH, the other trans-trans form, and either of the cis-trans forms, and, when A is H, the other trans form and the cis form, can be prepared by the methods set forth in those schemes or by methods generally known to those skilled in the art. All of the possible stereoisomeric forms are included within the scope of this invention. Further, in the schemes set forth hereinbelow, the xe2x80x9cRxe2x80x9d substituent, where it appears, is (C1-C6)alkyl; the xe2x80x9cnxe2x80x9d substituent, where it appears, is 1-3; and PGX is a reagent used to attach a protecting group xe2x80x9cPG.xe2x80x9d The xe2x80x9cXxe2x80x9d portion is usually a halo or other leaving group which, when attached to PG, forms the reagent used to attach the protecting group. For example, if the protecting group is acetyl, a suitable PGX group would be acetyl chloride.
In general, compounds of general Formula I can be prepared according to the methods described in Schemes 1 and 2. In general, the sequences involve 1,4-addition of the appropriate organometallic reagent onto the desired 2-substituted 2-cyclopenten-1-one (1-1). The substituent at the two position of the 2-cyclopenten-1-one template contains a carboxylic acid or acid isostere suitably masked with the appropriate protecting group (see Protecting Groups in Organic Synthesis, Second Edition, T. W. Greene and P. G. M. Wuts, John Wiley and Sons, Inc., 1991). Alternatively, the carboxylic acid moiety may be linked to solid support resin, such as Wang (polystyrene) resin. Other acid isosteres can be employed by appropriately modifying these schemes using methods known to those skilled in the art (see Scheme 10 for example). If desired, the C-4 position of the 2-cyclopenten-1-one may contain a hydroxy group, also suitably protected. Preferred protecting groups for the hydroxy group include tert-butyldimethylsilyl or tetrahydropyranyl.
In Scheme 1, introduction of (E)-1,2-bis(tributylstannyl)ethylene (1-2) (see A. F. Renaldo, J. W. Labadie, and J. K. Stille in Org. Synth. (1989), 67, 86-97 for preparation) to the 2-substituted 2-cyclopenten-1-one is accomplished using the protocol described by J. R. Behling and coworkers (J. Am. Chem. Soc., 1988, 110, 2641-2643) to generate compound 1-3. Alternatively, 1-2 can be transformed to the lithium reagent by treatment with an alkyl lithium reagent such as MeLi, n-BuLi, or tert-BuLi in a reaction inert solvent, for example, an aprotic solvent such as tetrahydrofuran or diethyl ether at low temperature (xe2x88x9278xc2x0 C. to xe2x88x9240xc2x0 C.). Conversion of the lithium reagent to the cuprate is accomplished by treatment of the organolithium compound with a copper(I) reagent such as copper cyanide or copper iodide at low temperature (xe2x88x9278xc2x0 C. to 0xc2x0 C.). Addition of the cuprate derived from compound 1-2 to compounds of general formula 1-1 generates intermediate 1-3.
When A is H, to ensure the relative trans stereochemistry at the xcex1 and xcex2 positions on the ring system, equilibration of the resulting product to the trans product 1-3 is accomplished with a base, preferably sodium methoxide in methanol or potassium tert-butoxide in a reaction inert solvent such as tetrahydrofuran. Stille coupling of intermediate 1-3 to a variety of aryl halides or aryl triflates provides compounds of general formula 1-4. Stille coupling chemistry is reviewed in J. K Stille, Angew. Chem. Int. Ed. Engl. 1986, 25, 508-524 and T. N. Mitchell, Synthesis 1991, 803-815. The coupling is performed in the presence of a palladium catalyst, such as tetrakis(triphenylphosphine)palladium(0), palladium(0) bis(dibenzylideneacetone), tris(dibenzylideneacetone)dipalladium(0), palladium(II) bis(benzonitrile) dichloride, or palladium(II) bis(acetonitrile) dichloride. The reaction is preferably carried out in a solvent such as tetrahydrofuran, N,N-dimethylformamide, or toluene with or without the addition of a base such as diisopropyethylamine at temperatures ranging from 25xc2x0 C. to 130xc2x0 C. It is generally preferred that the temperature be maintained from 50xc2x0 C. to 100xc2x0 C. A ligand such as tri-2-furylphosphine or triphenylarsene may also be added to the reaction. In cases where A is H, removal of either the ester protecting group or the solid phase resin using methods known to those skilled in the art, such as trifluoroacetic acid, provides styrene compounds of general formula 1-5. If A is a protected hydroxy group, deprotection is accomplished using methods known to those skilled in the art. For example, if A is protected with a tert-butyldimethylsilyl group, this protecting group can be removed by treatment with tetrabutylammonium fluoride or by stirring in a mixture of acetic acid:water:tetrahydrofuran (3:1:1). If desired, hydrogenation of the styrene intermediate 1-4 followed by deprotection of the acidic moiety provides compounds of general formula 1-6. The hydrogenation is generally performed in the presence of a palladium or platinum catalyst and in reaction inert solvents such as methanol, ethanol, and/or ethyl acetate. These skilled in the art will recognize that certain substituents on the aromatic ring may not survive hydrogenation conditions. In those cases, a person skilled in the art would modify the synthesis accordingly, e.g., a hydrogenation method could be selected which is more selective for a double bond, or the substituents could be attached to the nucleus at a latter point in the synthesis using methods well known to those skilled in the art.
In an analogous fashion to Scheme 1, compounds of general formulas 2-9 and 2-11 can be prepared as set forth in Scheme 2. The vinyl stannane intermediate 1-3 is coupled with an appropriate acid chloride in the presence of a palladium catalyst, such as tetrakis(triphenylphosphine)palladium(0), palladium(0) bis(dibenzylideneacetone), tris(dibenzylideneacetone)dipalladium(0), palladium(II) bis(benzonitrile) dichloride, or palladium(II) bis(acetonitrile) dichloride. The reaction is typically performed in a reaction inert solvent such as toluene, tetrahydrofuran, or chloroform with or without the presence of a base. Ordinarily amines such as diisopropylethylamine or triethylamine are used, with diisopropylethylamine being preferred. The reaction is generally performed under an atmosphere of carbon monoxide. A ligand such as tri-2-furylphosphine or triphenylarsene may also be added to the reaction. Alternatively, compounds of formula 1-3 can be treated with an aromatic halide or aromatic triflate under an atmosphere of carbon monoxide to provide intermediates of formula 2-8.
Alternative methods for the preparation of compounds of general formulas 1-5 and 2-9 are shown in Schemes 3 and 4. Intermediate 3-12 is prepared by 1,4-addition of a vinyl organometallic reagent such as vinylmagnesium bromide in the presence of a copper(I) catalyst, such as copper cyanide, copper iodide, or copper bromide. The reaction is generally performed in a reaction inert, aprotic solvent such as tetrahydrofuran or diethyl ether at low temperature (e.g., xe2x88x9278xc2x0 C. to 0xc2x0 C.). Subsequent Heck coupling of 3-12 with an aryl halide (preferably an aryl bromide or aryl iodide), aryl triflate, or a ring system which contains a vinyl iodide, vinyl bromide or vinyl triflate is performed using a palladium catalyst, such as palladium acetate or tetrakis(triphenylphosphine)palladium(0) in the presence of a trialkylamine such as triethylamine. When performing a Heck coupling with an aryl bromide, a triarylphosphine may be added to the reaction. The reaction is typically performed in dimethylformamide or acetonitrile at temperatures ranging from 0xc2x0 C. to 150xc2x0 C. and preferably from 50xc2x0 C. to about 100xc2x0 C. Using the sequences described above in Scheme 1, compounds of general formula 1-5 and 1-7 can be obtained. In a similar fashion, compounds of general formula 2-9 and 2-11 can be prepared by Heck coupling of intermediate 3-12 with a variety of acid chlorides (see Scheme 4). In cases where M represents a partially saturated ring system, hydrogenation will generate a saturated ring system.
The aromatic halides and aromatic acid chlorides used in the above Schemes are commonly available from commercial sources. If desired, an aromatic acid may be converted to the acid chloride by treatment with a chlorinating reagent such as thionyl chloride, phosphorous trichloride, or phosphorous pentachloride in an inert solvent. Aromatic triflates can be prepared from commercially available aromatic alcohols by treatment with triflic anhydride or N-phenyltrifluoromethanesulfonimide in the presence of a base such as pyridine.
As described in Scheme 5, compounds of general formula 1-1 can be prepared from compounds of formula 5-1 using the methods described by Ono and coworkers (Synthesis, 1981, 12, 1003-4). The method involves condensation of 4-(1-cyclopenten-1-yl)morpholine with the appropriate aldehyde containing a protected acidic functional group. This condensation is carried out by heating the two reagents in a solvent such as benzene or toluene with continual removal of the resulting water. The enamine which forms is cleaved by stirring with an aqueous acid. The double bond is isomerized by heating the compound of formula 5-2 in an alcoholic solvent, such as methanol, in the presence of a strong acid, such as hydrogen chloride to generate a compound of formula 1-1. Compounds of formula 1-1 where Z is a cyano group can be prepared in an analogous manner. The Z group can be converted to a tetrazole at this step or a later step and then protected as described in Scheme 10.
Scheme 6 sets forth an alternative method for the preparation of 2-substituted 2-cyclopenten-1-ones of general formula 1-1 and follows procedures analogous to those described by C. R. Johnson and coworkers (J. Am. Chem. Soc. 1993, 115, 11014-5). The protocol involves Suzuki coupling of a 2-iodo-2-cyclopenten-1-one (6-1) (see C. R. Johnson and coworkers in Tetrahedron Lett., 33, 917, 1992) with an alkylborane which contains the desired acidic functional group suitably protected. The coupling is performed in the presence of a palladium catalyst, preferably bis(diphenylphosphino)ferrocene palladium(II) chloride, which is complexed to a ligand, such as triphenylarsene. The reaction requires addition of a base, such as cesium carbonate, and is performed in a reaction inert solvent such as a mixture of water and an organic solvent. Said organic sovent is, for example, N,N-dimethylformamide, tetrahydrofuran, or 1,2-dimethoxyethane. The alkylborane is prepared from the appropriate alkenyl compound (6-2) by addition of a boron reagent, preferably 9-borabicyclo[3.3.1]nonane (9-BBN) in an inert solvent such as tetrahydrofuran. Compounds of formula 6-2 where Z is a cyano group can be prepared in an analogous manner. The Z group can be converted at this step or a later step to a tetrazole and then protected as described in Scheme 10.
Numerous methods known to those skilled in the art exist for preparing the aldehydes of formula (5-3) which can be used for the preparation of the intermediates of general formula 1-1. Scheme 7 sets forth a preferred preparation of ester aldehydes of general formula 7-2. The protocol follows the methods of S. L. Schreiber and coworker-s (Org. Synth. 1986, 64, 150-6) and involves ozonolytic cleavage of a commercially available cycloalkene (7-1). The reaction is performed in a mixture of a reaction inert solvent, preferably a combination of dichloromethane and methanol at low temperature, preferably xe2x88x9278xc2x0 C., by addition of ozone gas. Treatment with acetic anhydride and a suitable base such as triethylamine provides the desired methyl ester aldehydes 7-2. An alternative preparation of compounds of formula 5-3 is set forth in Scheme 8. Aryl halides or triflates of formula 8-1 are treated with allyl alcohol; a suitable Pd catalyst, preferably palladium acetate; a suitable base, preferably sodium bicarbonate; and tetrabutylammonium chloride in a suitable reaction inert, aprotic solvent such as N,N-dimethylformamide. The mixture is allowed to react at temperatures in the range of 0-125xc2x0 C., preferably 40-80xc2x0 C. Workup of the reaction mixture affords aldehydes of general structure 5-3. Compounds of formula 5-3 where Z is a cyano group can be prepared in an analogous manner. The Z group can be converted at this step or a later step to a tetrazole and then protected as described in Scheme 10.
Starting alkenes of general formula 6-2 can be prepared using the methods set forth in Schemes 9 through 11. For example, in Scheme 9, olefins of general formula 6-2 can be prepared by Wittig olefination of aldehydes of general formula 9-1. Condensation of methylidene(triphenyl)phosphorane, derived from methyltriphenylphosphonium bromide and a base such as n-butyl lithium, with 9-1 provides the desired alkenes 6-2 (see I. Gosney and A. G. Rowley in Organophosphomus Reagents in Organic Synthesis, ed. J. I. G. Cadogan, Academic Press, London, 1979 or B. E. Marynoff and A. B. Reitz, Chem. Rev. 1989, 89, 863). Compounds of formula 6-2 where Z is a cyano group can also be prepared in an analogous manner. The Z group can be converted at this step or a later step to a tetrazole and then protected as described in Scheme 10.
Scheme 10 sets forth a method which can be used to prepare alkenes of general formula 6-2 where Z represents a suitably protected tetrazole moiety. For example, treatment of commercially available alkenyl nitrites (10-1) with dibutyltin oxide, trimethylsilylazide, in toluene at reflux (S. J. Wittenberger and B. G. Donner, J. Org. Chem. 1993, 58, 4139-4141) provides alkenyl tetrazoles of general formula 10-2. An alternative preparation of the compounds of 10-2 involves treatment of a compound of 10-1 with sodium azide and ammonium chloride. The reaction is normally carried out in the presence of catalytic lithium chloride at temperatures ranging from 50xc2x0-150xc2x0 C. For a review on preparations of tetrazoles see R. N. Butler, Tetrazoles, In Comprehensive Heterocyclic Chemistry; Potts, K. T. Ed.; Pergamon Press: Oxford, 1984, Vol. 5, pp 791-838. The alkenyl tetrazole is protected with protecting groups such as triphenylmethyl or benzyl using methods known to those skilled in the art to provide compounds of general formula 10-3. Using the method described in Scheme 5, 10-3 may be coupled to 5-1 to provide 2-substituted 2-cyclopenten-1-ones (1-1).
Compounds of formula 6-2 can be prepared as set forth in Scheme 11 by reacting compounds of formula 8-1 with compounds of formula 11-1 using a variety of methods. Examples of such methods are described in the references below and include but are not limited to palladium catalyzed processes and Grignard type reactions: Meyers, A. I. Et al. J. Org. Chem.; 39; 1974; 2787-2793. Sibille, Soline; Ratovelomanana, Victorin; Perichon, Jacques; J.Chem.Soc.Chem.Commun.; 3; 1992; 283-284. Wenkert, Ernest; Fernandes, Joao Battista; Michelotti, Enrique L.; Swindell, Charles S.; 9; 1983; 701-703. Efange, S. M. N.; Michelson, R. H.; Dutta, A. K.; Parsons, S. M.; J.Med.Chem.; 34; 8; 1991; 2638-2643. Heck, R. F.; J.Amer.Chem.Soc.; 90; 20; 1968; 5531-5534. Johnson, David K.; Ciavarri, Jeffrey P.; Ishmael, Faoud T.; Schillinger, Kurt J.; Geel, Thomas A. P. van; Stratton, Stephen M; Tetrahedron Lett.; 36; 47; 1995; 8565-8568. Bumagin, N. A.; Kasatkin, A. N.; Beletskaya, I. P.; Bull.Acad.Sci.USSR Div.Chem.Sci.(Engl.Transl.); 33; 1984; 588-594; Izv.Akad.Nauk SSSR Ser.Khim.; 3; 1984; 636-642.
It will be recognized that the compounds of Formulas I and IA of this invention can exist in radiolabelled form, i.e., said compounds may contain one or more atoms containing an atomic mass or mass number different from the atomic mass or mass number ordinarily found in nature. Radioisotopes of hydrogen, carbon, phosphorous, fluorine and chlorine include 3H, 14C, 32P , 18F and 36Cl, respectively. Compounds of Formulas I and IA of this invention which contain those radioisotopes and/or other radioisotopes of other atoms are within the scope of this invention. Tritiated, i.e., 3H, and carbon-14, i.e., 14C, radioisotopes are particularly preferred for their ease of preparation and detectability. Radiolabelled compounds of Formulas I and IA of this invention can generally be prepared according to methods well known to those skilled in the art. Conveniently, such radiolabelled compounds can be prepared by carrying out the procedures disclosed in the above Schemes and/or in the Examples and Preparations below by substituting a readily available radiolabelled reagent for a non-radiolabelled reagent.
Those skilled in the art will recognize that anti-resorptive agents (for example progestins, polyphosphonates, bisphosphonate(s), estrogen agonists/antagonists, estrogen, estrogen/progestin combinations, Premarin, estrone, estriol or 17xcex1- or 17xcex2-ethynyl estradiol) may be used in conjunction with the compounds of this invention.
Exemplary progestins are available from commercial sources and include: algestone acetophenide, altrenogest, amadinone acetate, anagestone acetate, chlormadinone acetate, cingestol, clogestone acetate, clomegestone acetate, delmadinone acetate, desogestrel, dimethisterone, dydrogesterone, ethynerone, ethynodiol diacetate, etonogestrel, flurogestone acetate, gestaclone, gestodene, gestonorone caproate, gestrinone, haloprogesterone, hydroxyprogesterone caproate, levonorgestrel, lynestrenol, medrogestone, medroxyprogesterone acetate, melengestrol acetate, methynodiol diacetate, norethindrone, norethindrone acetate, norethynodrel, norgestimate, norgestomet, norgestrel, oxogestone phenpropionate, progesterone, quingestanol acetate, quingestrone, and tigestol.
Preferred progestins are medroxyprogestrone, norethindrone and norethynodrel.
Exemplary bone resorption inhibiting polyphosphonates include polyphosphonates of the type disclosed in U.S. Pat. No. 3,683,080, the disclosure of which is incorporated herein by reference. Preferred polyphosphonates are geminal diphosphonates (also referred to as bis-phosphonates). Tiludronate disodium is an especially preferred polyphosphonate. Ibandronic acid is an especially preferred polyphosphonate. Alendronate is an especially preferred polyphosphonate. Other preferred polyphosphonates are 6-amino-1-hydroxy-hexylidene-bisphosphonic acid and 1-hydroxy-3(methylpentylamino)-propylidene bisphosphonic acid. The polyphosphonates may be administered in the form of the acid, or of a soluble alkali metal salt or alkaline earth metal salt. Hydrolyzable esters of the polyphosphonates are likewise included. Specific examples include ethane-1-hydroxy 1,1-diphosphonic acid, methane diphosphonic acid, pentane-1-hydroxy-1,1-diphosphonic acid, methane dichloro diphosphonic acid, methane hydroxy diphosphonic acid, ethane-1-amino-1,1-diphosphonic acid, ethane-2-amino-1,1-diphosphonic acid, propane-3-amino-1-hydroxy-1,1-diphosphonic acid, propane-N,N-dimethyl-3-amino-1-hydroxy-1,1-diphosphonic acid, propane-3-3-dimethyl-3-amino-1-hydroxy-1,1-diphosphonic acid, phenyl amino methane diphosphonic acid,N,N-dimethylamino methane diphosphonic acid, N(2-hydroxyethyl) amino methane diphosphonic acid, butane-4-amino-1-hydroxy-1,1-diphosphonic acid, pentane-5-amino-1-hydroxy-1,1-diphosphonic acid, hexane-6-amino-1-hydroxy-1,1-diphosphonic acid and pharmaceutically acceptable esters and salts thereof.
In particular, the compounds of this invention may be combined with a mammalian estrogen agonist/antagonist. Any estrogen agonist/antagonist may be used as the second compound of this invention. The term estrogen agonist/antagonist refers to compounds which bind with the estrogen receptor, inhibit bone turnover and prevent bone loss. In particular, estrogen agonists are herein defined as chemical compounds capable of binding to the estrogen receptor sites in mammalian tissue, and mimicking the actions of estrogen in one or more tissue. Estrogen antagonists are herein defined as chemical compounds capable of binding to the estrogen receptor sites in mammalian tissue, and blocking the actions of estrogen in one or more tissues. Such activities are readily determined by those skilled in the art according to standard assays including estrogen receptor binding assays, standard bone histomorphometric and densitometer methods, and Eriksen E. F. et al., Bone Histomorphometry, Raven Press, New York, 1994, pages 1-74; Grier S. J. et. al., The Use of Dual-Energy X-Ray Absorptiometry In Animals, Inv. Radiol., 1996, 31(1):50-62; Wahner H. W. and Fogelman I., The Evaluation of Osteoporosis: Dual Energy X-Ray Absorptiometry in Clinical Practice., Martin Dunitz Ltd., London 1994, pages 1-296). A variety of these compounds are described and referenced below.
A preferred estrogen agonist/antagonist is droloxifene: (phenol, 3-[1-[4-[2-(dimethylamino)ethoxy]phenyl]-2-phenyl-1-butenyl]-, (E)-) and related compounds which are disclosed in U.S. Pat. No. 5,047,431, the disclosure of which is incorporated herein by reference.
Another preferred estrogen agonist/antagonist is tamoxifen: (ethanamine,2-[-4-(1,2-diphenyl-1-butenyl)phenoxy]-N,N-dimethyl, (Z)-2-, 2-hydroxy-1,2,3-propanetricarboxylate(1:1)) and associated compounds which are disclosed in U.S. Pat. No. 4,536,516, the disclosure of which is incorporated herein by reference.
Another related compound is 4-hydroxy tamoxifen which is disclosed in U.S. Pat. No. 4,623,660, the disclosure of which is incorporated herein by reference.
A preferred estrogen agonist/antagonist is raloxifene: (methanone, [6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl],-hydrochloride) which is disclosed in U.S. Pat. No. 4,418,068, the disclosure of which is incorporated herein by reference.
Another preferred estrogen agonist/antagonist is toremifene: (ethanamine, 2-[4-(4-chloro-1,2-diphenyl-1-butenyl)phenoxy]-N,N-dimethyl-, (Z)-, 2-hydroxy-1,2,3-propanetricarboxylate (1:1) which is disclosed in U.S. Pat. No. 4,996,225, the disclosure of which is incorporated herein by reference.
Another preferred estrogen agonist/antagonist is centchroman: 1-[2-[4-(-methoxy-2,2-dimethyl-3-phenyl-chroman-4-yl)-phenoxy]-ethyl]-pyrrolidine, which is disclosed in U.S. Pat. No. 3,822,287, the disclosure of which is incorporated. herein by reference. Also preferred is levormeloxifene.
Another preferred estrogen agonist/antagonist is idoxifene: pyrrolidine, 1-[-4-[[1-(4-iodophenyl)-2-phenyl-1-butenyl]phenoxy]ethy] which is disclosed in U.S. Pat. No. 4,839,155, the disclosure of which is incorporated herein by reference.
Another preferred estrogen agonist/antagonist is 6-(4-hydroxy-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-naphthalen -2-ol which is disclosed in U.S. Pat. No. 5,484,795, the disclosure of which is incorporated herein by reference.
Another preferred estrogen agonist/antagonist is {4-[2-(2-aza-bicyclo[2.2.1]hept-2-yl)-ethoxy]-pheny}-[6-hydroxy-2-(4-hydroxy-phenyl)-benzo[b]thiophen-3-yl]-methanone which is disclosed, along with methods of preparation, in PCT publication no. WO 95/10513 assigned to Pfizer Inc.
Other preferred estrogen agonist/antagonists include compounds as described in commonly assigned U.S. Pat. No. 5,552,412, the disclosure of which is incorporated herein by reference. Especially preferred compounds described therein are:
cis-6-(4-fluoro-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;
(xe2x88x92)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]5,6,7,8-tetrahydro-naphthalene-2-ol;
cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;
cis-1-[6xe2x80x2-pyrrolodinoethoxy-3xe2x80x2-pyrdyl]-2-phenyl-6-hydroxy-1,2,3,4-tetrahydronaphthalene;
1-(4xe2x80x2-pyrrolidinoethoxyphenyl)-2-(4xe2x80x3-fluoro-phenyl)6-hydroxy-1,2,3,4-tetrahydroisoquinoline;
cis-6-(4-hydroxyphenyl)-5-[4-(2-piperdin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol; and
1-(4xe2x80x2-pyrrolidinolethoxyphenyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline.
Other estrogen agonist/antagonists are described in U.S. Pat. No. 4,133,814 (the disclosure of which is incorporated herein by reference). U.S. Pat. No. 4,133,814 discloses derivatives of 2-phenyl-3-aroyl-benzothiophene and 2-phenyl-3-aroylbenzothiophene-1-oxide.
Those skilled in the art will recognize that other bone anabolic agents (bone mass augmenting agents) may be used in conjunction with the compounds of this invention. A bone mass augmenting agent is a compound that augments bone mass to a level which is above the bone fracture threshold (as detailed in the World Health Organization Study World Health Organization, xe2x80x9cAssessment of Fracture Risk and its Application to Screening for Postmenopausal Osteoporosis (1994). Report of a WHO Study Group. World Health Organization Technical Series 843xe2x80x9d).
Any prostaglandin, or prostaglandin agonist/antagonist may be used as the second compound of this invention (this includes utilizing two different compounds of Formula IA of this invention). Those skilled in the art will recognize that IGF-1, sodium fluoride, parathyroid hormone (PTH), active fragments of parathyroid hormone, growth hormone or growth hormone secretagogues may also be used. The following paragraphs describe exemplary second compounds of this invention in greater detail.
Any prostaglandin may be used as the second compound of this invention. The term prostaglandin refers to compounds which are analogs of the natural prostaglandins PGD1, PGD2, PGE2, PGE1 and PGF2 which are useful in the treatment of osteoporosis. These compounds bind to the prostaglandin receptors. Such binding is readily determined by those skilled in the art according to standard assays (e.g., An S. et al., Cloning and Expression of the EP2 Subtype of Human Receptors for Prostaglandin E2, Biochemical and Biophysical Research Communications, 1993, 197(1):263-270).
Prostaglandins are alicyclic compounds related to the basic compound prostanoic acid. The carbon atoms of the basic prostaglandin are numbered sequentially from the carboxylic carbon atom through the cyclopentyl ring to the terminal carbon atom on the adjacent side chain. Normally the adjacent side chains are in the trans orientation. The presence of an oxo group at C-9 of the cyclopentyl moiety is indicative of a prostaglandin within the E class while PGE2 contains a trans unsaturated double bond at the C13-C14 and a cis double bond at the C5-C6 position.
A variety of prostaglandins are described and referenced below, however, other prostaglandins will be known to those skilled in the art. Exemplary prostaglandins are disclosed in U.S. Pat. Nos. 4,171,331 and 3,927,197, the disclosures of each of which are incorporated herein by reference.
Norrdin et al., The Role of Prostaglandins in Bone In Vivo, Prostaglandins Leukotriene Essential Fatty Acids 41, 139-150, 1990 is a review of bone ariabolic prostaglandins.
Any prostaglandin agonist/antagonist may be used as the second compound of this invention. The term prostaglandin agonist/antagonist refers to compounds which bind to prostaglandin receptors (e.g., An S. et al., Cloning and Expression of the EP2 Subtype of Human Receptors for Prostaglandin E2, Biochemical and Biophysical Research Communications, 1993, 197(1):263-270) and mimic the action of prostaglandin in vivo (e.g., stimulate bone formation and increase bone mass). Such actions are readily determined by those skilled in the art according to standard assays. Eriksen E. F. et al., Bone Histomorphometry, Raven Press, New York, 1994, pages 1-74; Grier S. J. et. al., The Use of Dual-Energy X-Ray Absorptiometry In Animals, Inv. Radiol., 1996, 31(1):50-62; Wahner H. W. and Fogelman I., The Evaluation of Osteoporosis: Dual Energy X-Ray Absorptiometry in Clinical Practice., Martin Dunitz Ltd., London 1994, pages 1-296. A variety of these compounds are described and referenced below; however, other prostaglandin agonists/antagonists will be known to those skilled in the art. Exemplary prostaglandin agonists/antagonists are disclosed as follows.
Commonly assigned U.S. Pat. No. 3,932,389, the disclosure of which is incorporated herein by reference, discloses 2-descarboxy-2-(tetrazol-5-yl)-11-desoxy-15-substituted-omega-pentanorprostaglandins useful for bone formation activity.
Commonly assigned U.S. Pat. No. 4,018,892, the disclosure of which is incorporated herein by reference, discloses 16-aryl-13,14-dihydro-PGE2 p-biphenyl esters useful for bone formation activity.
Commonly assigned U.S. Pat. No. 4,219,483, the disclosure of which is incorporated herein by reference, discloses 2,3,6-substituted-4-pyrones useful for bone formation activity.
Commonly assigned U.S. Pat. No. 4,132,847, the disclosure of which is incorporated herein by reference, discloses 2,3,6-substituted-4-pyrones useful for bone formation activity.
U.S. Pat. No. 4,000,309, the disclosure of which is incorporated herein by reference, discloses 16-aryl-13,14-dihydro-PGE2 p-biphenyl esters useful for bone formation activity.
U.S. Pat. No. 3,982,016, the disclosure of which is incorporated herein by reference, discloses 16-aryl-13,14-dihydro-PGE2 p-biphenyl esters useful for bone formation activity.
U.S. Pat. No. 4,621,100, the disclosure of which is incorporated herein by reference, discloses substituted cyclopentanes useful for bone formation activity.
U.S. Pat. No. 5,216,183, the disclosure of which is incorporated herein by reference, discloses cyclopentanones useful for bone formation activity.
Sodium fluoride may be used as the second compound of this invention. The term sodium fluoride refers to sodium fluoride in all its forms (e.g., slow release sodium fluoride, sustained release sodium fluoride). Sustained release sodium fluoride is disclosed in U.S. Pat. No. 4,904,478, the disclosure of which is incorporated herein by reference. The activity of sodium fluoride is readily determined by those skilled in the art according to biological protocols (e.g., see Eriksen E. F. et al., Bone Histomorphometry, Raven Press, New York, 1994, pages 1-74; Grier S. J. et. al., The Use of Dual-Energy X-Ray Absorptiometry In Animals, Inv. Radiol., 1996, 31(1):50-62; Wahner H. W. and Fogelman I., The Evaluation of Osteoporosis: Dual Energy X-Ray Absorptiometry in Clinical Practice., Martin Dunitz Ltd., London 1994, pages 1-296).
Any parathyroid hormone (PTH) may be used as the second compound of this invention. The term parathyroid hormone refers to parathyroid hormone, fragments or metabolites thereof and structural analogs thereof which can stimulate bone formation and increase bone mass. Also included are parathyroid hormone related peptides and active fragments and analogues of parathyroid related peptides see PCT publication no. WO 94101460. Such bone anabolic functional activity is readily determined by those skilled in the art according to standard assays (e.g., see Eriksen E. F. et al., Bone Histomorphometry, Raven Press, New York, 1994, pages 1-74; Grier S. J. et al., The Use of Dual-Energy X-Ray Absorptiometry In Animals, Inv. Radiol., 1996, 31(1):50-62; Wahner H. W,. and Fogelman I., The Evaluation of Osteoporosis: Dual Energy X-Ray Absorptiometry in Clinical Practice., Martin Dunitz Ltd., London 1994, pages 1-296). A variety of these compounds are described and referenced below, however, other parathyroid hormones will be known to those skilled in the art. Exemplary parathyroid hormones are disclosed in the following references.
xe2x80x9cHuman Parathyroid Peptide Treatment of Vertebral Osteoporosisxe2x80x9d, Osteoporosis Int., 3, (Supp 1):199-203.
xe2x80x9cPTH 1-34 Treatment of Osteoporosis with Added Hormone Replacement Therapy: Biochemical, Kinetic and Histological Responsesxe2x80x9d Osteoporosis Int. 1:162-170.
Any growth hormone or growth hormone secretagogue may be used as the second compound of this invention. The term growth hormone secretagogue refers to a compound which stimulates the release of growth hormone or mimics the action of growth hormone (e.g., increases bone formation leading to increased bone mass). Such actions are readily determined by those skilled in the art according to standard assays well known to those of skill in the art A variety of these compounds are disclosed in the following published PCT patent applications: WO 95/14666; WO 95/13069; WO 94/19367; WO 94/13696; and WO 95/34311. However, other growth hormone or growth hormone secretagogues will be known to those skilled in the art.
In particular a preferred growth hormone secretagogue is N-[1-(R)-[1,2-Dihydro-1-methanesulfonylspiro[3H-indole-3,4xe2x80x2-piperidin]-1xe2x80x2-yl)carbonyl]-2-(phenylmethyloxy)ethyl]-2-amino-2-methylpropanamide:MK-677.
Other preferred growth hormone secretagogues include
2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo-[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide or its L-tartaric acid salt;
2-amino-N-{1-(R)-benzyloxymethyl-2-[3a-(R)-(4-fluoro-benzyl)-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl]-2-oxo-ethyl}isobutyramide;
2-amino-N-[2-(3a-(R)-benzyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)benzyloxymethyl-2-oxo-ethyl]isobutyramide; and
2-amino-N-1-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-[3-oxo-3a-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl-ethyl}2-methyl-propionamide.
Some of the preparation methods useful for the preparation of the compounds described herein may require protection of remote functionality (e.g., primary amine, secondary amine, carboxyl in Formula I or Formula IA precursors). The need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparation methods. The need for such protection is readily determined by one skilled in the art. The use of such protection/deprotection methods is also within the skill in the art. For a general description of protecting groups and their use, see T. W. Greene, Protective Groups in Organic Synthesis, John Wiley and Sons, New York, 1991.
The starting materials and reagents for the above described compounds are also readily available or can be easily synthesized by those skilled in the art using conventional methods of organic synthesis. For example, many of the compounds used herein are related to, or are derived from, compounds found in nature, in which there is a large scientific interest and commercial need, and accordingly many such compounds are commercially available or are reported in the literature or are easily prepared from other commonly available substances by methods which are reported in the literature. Such compounds include, for example, prostaglandins.
All of the compounds of this invention have at least one asymmetric carbon atom and therefore are enantiomers or diastereomers. Diasteromeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods known per se, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diasteromeric mixture by reaction with an appropriate optically active compound (e.g., alcohol), separating the diastereomers and converting (e.g., hydrolyzing, including both chemical hydrolysis methods and microbial lipase hydrolysis methods, e.g., enzyme catalyzed hydrolysis) the individual diastereomers to the corresponding pure enantiomers. All such isomers, including diastereomers, enantiomers and mixtures thereof are considered as part of this invention. Also, some of the compounds of this invention are atropisomers (e.g., substituted biaryls) and are considered as part of this invention.
Many of the compounds of this invention, including the compounds of Formulas I and IA, the anti-resorptive agents, bone anabolic agents, prostagiandin agonists/antagonists, parathyroid hormones, growth hormones and growth hormone secretagogues, are acidic and they form a salt with a pharmaceutically acceptable cation. Some of the compounds of this invention, including the compounds of Formulas I and IA, the anti-resorptive agents, bone anabolic agents, prostaglandin agonists/antagonists, parathyroid hormones, growth hormones and growth hormone secretagogues, are basic and they form a salt with a pharmaceutically acceptable anion. All such salts are within the scope of this invention and they can be prepared by conventional methods. For example, they can be prepared simply by contacting the acidic and basic entities, usually in a stoichiometric ratio, in either an aqueous, non-aqueous or partially aqueous medium, as appropriate. The salts are recovered either by filtration, by precipitation with a non-solvent followed by filtration, by evaporation of the solvent, or, in the case of aqueous solutions, by lyophilization, as appropriate.
In addition, when the compounds of this invention, including the compounds of Formulas I and IA, the anti-resorptive agents, bone anabolic agents, prostaglandin agonists/antagonists, parathyroid hormones, growth hormones and growth hormone secretagogues, form hydrates or solvates they are also within the scope of the invention.
In addition, all prodrugs of the compounds of this invention, including the compounds of Formulas I and IA, the anti-resorptive agents, bone anabolic agents, prostaglandin agonists/antagonists, parathyroid hormones, growth hormones and growth hormone secretagogues, are within the scope of this invention.
The compounds of this invention are all adapted to therapeutic use as agents that stimulate bone formation and increase bone mass in vertebrates, e.g., mammals, and particularly humans. Since bone formation is closely related to the development of osteoporosis and bone related disorders, these compounds, by virtue of their action on bone, prevent, arrest and/or regress osteoporosis.
The utility of the compounds of the present invention as medical agents in the treatment of conditions which present with low bone mass (e.g., osteoporosis) in vertebrates, e.g., mammals (e.g. humans, particularly the female) is demonstrated by the activity of the compounds of this invention in conventional assays, including the in vivo assay, a receptor binding assay, the cyclic AMP assay and the fracture healing assay (all of which are described below). The in vivo assay (with appropriate modifications within the skill in the art) may be used to determine the activity of other anabolic agents as well as the prostaglandin agonists of this invention. The estrogen agonist/antagonist protocol may be used to determine the activity of estrogen agonists/antagonists in particular and also other anti-resorptive agents (with appropriate modifications within the skill in the art). The combination and sequential treatment protocol described below is useful for demonstrating the utility of the combinations of the anabolic agents (e.g., the compounds of this invention) and anti-resorptive agents (e.g., estrogen agonists/antagonists) described herein. Such assays also provide a means whereby the activities of the compounds of this invention (or the other anabolic agents and anti-resorptive agents described herein) can be compared to each other and with the activities of other known compounds. The results of these comparisons are useful for determining dosage levels in vertebrates, e.g., mammals, including humans, for the treatment of such diseases.
The activity of anabolic bone agents in stimulating bone formation and increasing bone mass can be tested in intact male or female rats, sex hormone deficient male (orchidectomy) or female (ovariectomy) rats.
Male or female rats at different ages (such as 3 months of age) can be used in the study. The rats are either intact or castrated (ovariectomized or orchidectomized), and subcutaneously injected or gavaged with EP2 agonists at different doses (such as 1, 3, or 10 mg/kg/day) for 30 days. In the castrated rats, treatment is started at the next day after surgery (for the purpose of preventing bone loss) or at the time bone loss has already occured (for the purpose of restoring bone mass). During the study, all rats are allowed free access to water and a pelleted commercial diet (Teklad Rodent Diet #8064, Harlan Teklad, Madison, Wis.) containing 1.46% calcium, 0.99% phosphorus and 4.96 IU/g of Vitamin D3. All rats are given subcutaneous injections of 10 mg/kg calcein on days 12 and 2 before sacrifice. The rats are sacrificed. The following endpoints are determined:
Femoral Bone Mineral Measurements
The right femur from each rat is removed at autopsy and scanned using dual energy X-ray absorptiometry (DXA, QDR 1000/W, Hologic Inc., Waltham, Mass.) equipped with xe2x80x9cRegional High Resolution Scanxe2x80x9d software (Hologic Inc., Waltham, Mass.). The scan field size is 5.08xc3x971.902 cm, resolution is 0.0254xc3x970.0127 cm and scan speed is 7.25 mm/second. The femoral scan images are analyzed and bone area, bone mineral content (BMC), and bone mineral density (BMD) of whole femora (WF), distal femoral metaphyses (DFM), femoral shaft (FS), and proximal femora (PF) are determined.
Tibial Bone Histomorphometric Analyses
The right tibia is removed at autopsy, dissected free of muscle, and cut into three parts. The proximal tibia and the tibial shaft are fixed in 70% ethanol, dehydrated in graded concentrations of ethanol, defatted in acetone, then embedded in methyl methacrylate (Eastman Organic Chemicals, Rochester, N.Y.).
Frontal sections of proximal tibial metaphyses at 4 and 10 xcexcm thickness are cut using a Reichert-Jung Polycut S microtome. The 4 xcexcm sections are stained with modified Masson""s Trichrome stain while the 10 xcexcm sections remained unstained. One 4 xcexcm and one 10 xcexcm sections from each rat are used for cancellous bone histomorphometry.
Cross sections of tibial shaft at 10 xcexcm thickness are cut using a Reichert-Jung Polycut S microtome. These sections are used for cortical bone histomorphometric analysis.
Cancellous bone histomorphometry: A Bioquant OS/2 histomorphometry system (RandM Biometrics, Inc., Nashville, Tenn.) is used for the static and dynamic histomorphometric measurements of the secondary spongiosa of the proximal tibial metaphyses between 1.2 and 3.6 mm distal to the growth plate-epiphyseal junction. The first 1.2 mm of the tibial metaphyseal region needs to be omitted in order to restrict measurements to the secondary spongiosa. The 4 xcexcm sections are used to determine indices related to bone volume, bone structure, and bone resorption, while the 10 xcexcm sections are used to determine indices related to bone formation and bone turnover.
I) Measurements and calculations related to trabecular bone volume and structure: (1) Total metaphyseal area (TV, mm2): metaphyseal area between 1.2 and 3.6 mm distal to the growth plate-epiphyseal junction. (2) Trabecular bone area (BV, mm2): total area of trabeculae within TV. (3) Trabecular bone perimeter (BS, mm): the length of total perimeter of trabeculae. (4) Trabecular bone volume (BV/TV, %): BV/TVxc3x97100. (5) Trabecular bone number (TBN, #/mm): 1.199/2xc3x97BS/TV. (6) Trabecular bone thickness (TBT, xcexcm): (2000/1.199)xc3x97(BV/BS). (7) Trabecular bone separation (TBS, xcexcm): (2000xc3x971.199)xc3x97(TVxe2x88x92BV).
II) Measurements and calculations related to bone resorption: (1) Osteocdast number (OCN, #): total number of osteoclast within total metaphyseal area. (2) Osteoclast perimeter (OCP, mm): length of trabecular perimeter covered by osteoclast. (3) Osteoclast number/mm (OCN/mm, #/mm): OCN/BS. (4) Percent osteoclast perimeter (%OCP, %): OCP/BSxc3x97100.
III) Measurements and calculations related to bone formation and turnover: (1) Single-calcein labeled perimeter (SLS, mm): total length of trabecular perimeter labeled with one calcein label. (2) Double-calcein labeled perimeter (DLS, mm): total length of trabecular perimeter labeled with two calcein labels. (3) Inter-labeled width (ILW, xcexcm): average distance between two calcein labels. (4) Percent mineralizing perimeter (PMS, %): (SLS/2+DLS)/BSxc3x97100. (5) Mineral apposition rate (MAR, xcexcm/day): ILW/label interval. (6) Bone formation rate/surface ref. (BFR/BS, xcexcm2/d/ xcexcm): (SLS/2+DLS)xc3x97MAR/BS. (7) Bone turnover rate (BTR, %/y): (SLS/2+DLS)xc3x97MAR/BVxc3x97100.
Cortical bone histomorphometry: A Bioquant OS/2 histomorphometry system (RandM Biometrics, Inc., Nashville, Tenn.) is used for the static and dynamic histomorphometric measurements of tibial shaft cortical bone. Total tissue area, marrow cavity area, periosteal perimeter, endocortical perimeter, single labeled perimeter, double labeled perimeter, and interlabeled width on both periosteal and endocortical surface are measured, and cortical bone area (total tissue area marrow cavity area), percent cortical bone area (cortical area/total tissue areaxc3x97100), percent marrow area (marrow cavity area/total tissue areaxc3x97100), periosteal and endocortical percent labeled perimeter [(single labeled perimeter/2+double labeled perimeter)/total perimeterxc3x97100], mineral apposition rate (interlabeled width/intervals), and bone formation rate [mineral apposition ratexc3x97[(single labeled perimeter/2+double labeled perimeter)/total perimeter] are calculated.
Statistics
Statistics can be calculated using StatView 4.0 packages (Abacus Concepts, Inc., Berkeley, Calif.). The analysis of variance (ANOVA) test followed by Fisher""s PLSD (Stat View, Abacus Concepts Inc., 1918 Bonita Ave, Berkeley, Calif. 94704-1014) are used to compare the differences between groups.
cDNAs representing the complete open reading frames of the human EP2 and EP2 receptors are generated by reverse transcriptase polymerase chain reaction using oligonucleotide primers based on published sequences (1,2) and RNA from primary human kidney cells (EP2) or primary human lung cells (EP4) as templates. cDNAs are cloned into the multiple cloning site of pcDNA3 (Invitrogen Corporation, 3985B Sorrento Valley Blvd., San Diego, Calif. 92121) and used to transfect 293-S human embryonic kidney cells via calcium phosphate co-precipitation. G418-resistant colonies are expanded and tested for specific [3H]PGE2 binding. Transfectants demonstrating high levels of specific [3H]PGE2 binding are further characterized by Scatchard analysis to determine Bmax and Kds for PGE2. The lines selected for compound screening have approximately 338,400 receptors per cell and a Kd=12 nM for PGE2 (EP2), and approximately 256,400 receptors per cell and a Kd=2.9 nM for PGE2 (EP4). Constituitive expression of both receptors in parental 293-S cells is negligible. Cells are maintained in RPMI supplemented with fetal bovine serum (10% final) and G418 (700 ug/ml final).
cAMP responses in the 293-S/EP2 and 293-S/EP4 lines are determined by detaching cells from culture flasks in 1 ml of Ca++ and Mg++ deficient PBS via vigorous pounding, adding serum-free RPMI to a final concentration of 1xc3x97106 cells/ml, and adding 3-isobutyl-1-methylxanthine (IBMX) to a final concentration of 1 mM. One milliliter of cell suspension is immediately aliquoted into individual 2 ml screwcap microcentrifuge and incubated for 10 minutes, uncovered, at 37xc2x0 C., 5% CO2, 95% relative humidity. The compound to be tested is then added to cells at 1:100 dilutions such that final DMSO or ethanol concentrations is 1%. Immediately after adding compound, the tubes are covered, mixed by inverting two times, and incubated at 37xc2x0 C. for 12 minutes. Samples are then lysed by incubation at 100xc2x0 C. for 10 minutes and immediately cooled on ice for 5 minutes. Cellular debris is pelleted by centrifugation at 1000xc3x97g for 5 minutes, and cleared lysates are transferred to fresh tubes. cAMP concentrations are determined using a commercially available cAMP radioimmunoassay kit RIA (NEK-033, DuPont/NEN Research Products, 549 Albany St., Boston, Mass. 02118) after diluting cleared lysates 1:10 in cAMP RIA assay buffer (included in kit). Typically, one treats cells with 6-8 concentrations of the compound to be tested in 1 log increments. EC50 calculations are performed on a calculator using linear regression analysis on the linear portion of the dose response curves.
References
1. Regan, J. W. Bailey, T. J. Pepperl, D. J. Pierce, K. L. Bogardus, A. M. Donello, J. E. Fairbaim, C. E. Kedzie, K. M. Woodward, D. F. and Gil, D. W. 1994 Cloning of a Novel Human Prostaglandin Receptor with Characteristics of the Pharmaclogically Defined EP2 Subtype. Mol. Pharmacology 46:213-220.
2. Bastien, L., Sawyer, N., Grygorczyk, R., Metters, K., and Adam, M. 1994 Cloning, Functional Expression, and Characterization of the Human Prostaglandin E2 Receptor EP2 Subtype. J. Biol. Chem. Vol 269, 16:11873-11877.
Membrane Preparation: All operations are performed at 4xc2x0 C. Transfected cells expressing prostaglandin E2 type 1 receptors (EP1), type 2 (EP2), type 3 (EP3) or type 4 (EP4) receptors are harvested and suspended to 2 million cells per ml in Buffer A [50 mM Tris-HCl (pH 7.4), 10 mM MgCl2, 1 mM EDTA, 1 mM Pefabloc peptide, (Sigma, St. Louis, Mo.), 10 uM Phosporamidon peptide, (Sigma, St. Louis, Mo.), 1 uM pepstatin A peptide, (Sigma, St. Louis, Mo.), 10 xcexcM elastatinal peptide, (Sigma, St. Louis, Mo.), 100 uM antipain peptide, (Sigma, St. Louis, Mo.)]. These are lysed by sonification with a Branson Sonifier (Model #250, Branson Ultrasonics Corporation, Danbury, Conn.) in 2 fifteen second bursts. Unlysed cells and debris are removed by centrifugation at 100xc3x97g for 10 min. Membranes are then harvested by centrifugation at 45,000xc3x97g for 30 minutes. Pelleted membranes are resuspended to 3-10 mg protein per ml, protein concentration being determined according to the method of Bradford [Bradford, M., Anal. Biochem., 72, 248 (1976)]. Resuspended membranes are then stored frozen at xe2x88x9280xc2x0 C. until use.
Binding Assay: Frozen membranes prepared as above are thawed and diluted to 1 mg protein per ml in Buffer A above. One volume of membrane preparation is combined with 0.05 volume test compound or buffer and one volume of 3 nM 3H-prostaglandin E2 (#TRK 431, Amersham, Arlington Heights, Ill.) in Buffer A. The mixture (205 xcexcL total volume) is incubated for 1 hour at 25xc2x0 C. The membranes are then recovered by filtration through type GF/C glass fiber filters (#1205-401, Wallac, Gaithersburg, Md.) using a Tomtec harvester (Model Mach II/96, Tomtec, Orange, Conn.). The membranes with bound 3H-prostaglandin E2 are trapped by the filter, while the buffer and unbound 3H-prostaglandin E2 pass through the filter into waste. Each sample is then washed 3 times with 3 ml of [50 mM Tris-HCl (pH 7.4), 10 mM MgCl2, 1 mM EDTA]. The filters are then dried by heating in a microwave oven. To determine the amount of 3H-prostaglandin bound to the membranes, the dried filters are placed into plastic bags with scintillation fluid and counted in a LKB 1205 Betaplate reader (Wallac, Gaithersburg, Md.). IC50s are determined from the concentration of test compound required to displace 50% of the specifically bound 3H-prostaglandin E2.
Fracture Technique: Sprage-Dawley rats at 3 months of age are anesthetized with Ketamine. A 1 cm incision is made on the anteromedial aspect of the proximal part of the right tibia or femur. The following describes the tibial surgical technique. The incision is carried through to the bone, and a 1 mm hole is drilled 4 mm proximal to the distal aspect of the tibial tuberosity 2 mm medial to the anterior ridge. Intramedullary nailing is performed with a 0.8 mm stainless steel tube (maximum load 36.3 N, maximum stiffness 61.8 N/mm, tested under the same conditions as the bones). No reaming of the medullary canal is performed. A standardized closed fracture is produced 2 mm above the tibiofibular junction by three-point bending using specially designed adjustable forceps with blunt jaws. To minimize soft tissue damage, care is taken not to displace the fracture. The skin is closed with monofilament nylon sutures. The operation is performed under sterile conditions. Radiographs of all fractures are taken immediately after nailing, and vertebrates with fractures outside the specified diaphyseal area or with displaced nails are excluded. The remaining animals are divided randomly into the following groups with 10-12 animals per each subgroup per time point for testing the fracture healing. The first group receives daily gavage of vehicle (water: 100% Ethnanol=95:5) at 1 ml/rat, while the others receive daily gavage from 0.01 to 100 mg/kg/day of the compound to be tested (1 ml/rat) for 10, 20, 40 and 80 days.
At 10, 20, 40 and 80 days, 10-12 rats from each group are anesthetized with Ketamine and autopsied by exsanguination. Both tibiofibular bones are removed by dissection and all soft tissue is stripped. Bones from 5-6 rats for each group are stored in 70% ethanol for histological analysis, and bones from another 5-6 rats for each group are stored in a buffered Ringers solution (+4xc2x0 C., pH 7.4) for radiographs and biomechanical testing which is performed.
Histological Analysis: The methods for histologic analysis of fractured bone have been previously published by Mosekilde and Bak (The Effects of Growth Hormone on Fracture Healing in Rats: A Histological Description. Bone, 14:19-27, 1993). Briefly, the fracture side is sawed 8 mm to each side of the fracture line, embedded undecalcified in methymethacrylate, and cut frontals sections on a Reichert-Jung Polycut microtome in 8 xcexcm thick. Masson-Trichrome stained mid-frontal sections (including both tibia and fibula) are used for visualization of the cellullar and tissue response to fracture healing with and without treatment. Sirius red stained sections are used to demonstrate the characterisitics of the callus structure and to differentiate between woven bone and lamellar bone at the fracture site. The following measurements are performed: (1) fracture gapxe2x80x94measured as the shortest distance between the cortical bone ends in the fracture, (2) callus length and callus diameter, (3) total bone volume area of callus, (4) bony tissue per tissue area inside the callus area, (5) fibrous tissue in the callus, and (6) cartilage area in the callus.
Biomechanical Analysis: The methods for biomechanical analysis have been previously published by Bak and Andreassen (The Effects of Aging on Fracture Healing in Rats. Calcif Tissue Int 45:292-297, 1989). Briefly, radiographs of all fractures are taken prior to the biomechanical test The mechanical properties of the healing fractures are analyzed by a destructive three- or four-point bending procedure. Maximum load, stiffness, energy at maximum load, deflection at maximum load, and maximum stress are determined.
Fracture Technique: Female or male beagle dogs at approximately 2 years of age are used in the study. Transyerse radial fractures are produced by slow continuous loading in three-point bending as described by Lenehan et al. (Lenehan, T. M.; Balligand, M.; Nunamaker, D. M.; Wood, F. E.: Effects of EHDP on Fracture Healing in Dogs. J Orthop Res 3:499-507; 1985). The wire is pulled through the fracture site to ensure complete anatomical disruption of the bone. Thereafter, local delivery of EP2 agonists to the fracture site is achieved by slow release of compound delivered by slow release pellets or by administration of the compounds in a suitable formulation such as a paste gel solution or suspension for 10, 15, or 20 weeks.
Histological Analysis: The methods for histologic analysis of fractured bone have been previously published by Peter et al. (Peter, C. P.; Cook, W. O.; Nunamaker, D. M.; Provost, M. T.; Seedor, J. G.; Rodan, G. A. Effects of alendronate on fracture healing and bone remodeling in dogs. J. Orthop. Res. 14:74-70, 1996) and Mosekilde and Bak (The Effects of Growth Hormone on Fracture Healing in Rats: A Histological Description. Bone, 14:19-27, 1993). Briefly, the fracture side is sawed 3 cm to each side of the fracture line, embedded undecalcified in methymethacrylate, and cut on a Reichert-Jung Polycut microtome in 8 xcexcm thick of frontal sections. Masson-Trichrome stained mid-frontal sections (including both tibia and fibula) are used for visualization of the cellullar and tissue response to fracture healing with and without treatment. Sirius red stained sections are used to demonstrate the characterisitics of the callus structure and to differentiate between woven bone and lamellar bone at the fracture site. The following measurements are performed: (1) fracture gap-measured as the shortest distance between the cortical bone ends in the fracture, (2) callus length and callus diameter, (3) total bone volume area of callus, (4) bony tissue per,tissue area inside the callus area, (5) fibrous tissue in the callus, (6) cartilage area in the callus.
Biomechanical Analysis: The methods for biomechanical analysis have been previously published by Bak and Andreassen (The Effects of Aging on Fracture Healing in Rats. Calcif Tissue Int 45:292-297, 1989) and Peter et al. (Peter, C. P.; Cook, W. O.; Nunamaker, D. M.; Provost, M. T.; Seedor, J. G.; Rodan, G. A. Effects of Alendronate On Fracture Healing And Bone Remodeling In Dogs. J. Orthop. Res. 14:74-70, 1996). Briefly, radiographs of all fractures are taken prior to the biomechanical test. The mechanical properties of the healing fractures are analyzed by a destructive three- or four-point bending procedures. Maximum load, stiffness, energy at maximum load, deflection at maximum load, and maximum stress are determined.
Estrogen agonist/antagonists are a class of compounds which inhibit bone turnover and prevent estrogen-deficiency induced bone loss. The ovariectomized rat bone loss model has been widely used as a model of post-menopausal bone loss. Using this model, one can test the efficacy of the estrogen agonist/antagonist compounds in preventing bone loss and inhibiting bone resorption.
Sprague-Dawley female rats (Charles River, Wilmington, Mass.) at different ages (such as 5 months of age) are used in these studies. The rats are singly housed in 20 cmxc3x9732 cmxc3x9720 cm cages during the experimental period. All rats are allowed free access to water and a pelleted commercial diet (Agway ProLab 3000, Agway County Food, Inc., Syracuse, N.Y.) containing 0.97% calcium, 0.85% phosphorus, and 1.05 IU/g of Vitamin D3.
A group of rats (8 to 10) are sham-operated and treated p.o. with vehicle (10% ethanol and 90% saline, 1 ml/day), while the remaining rats are bilaterally ovariectomized (OVX) and treated with either vehicle (p.o.), 17xcex2-estradiol (Sigma, E-8876, E2, 30 xcexcg/kg, daily subcutaneous injection), or estrogen agonist/antagonists (such as droloxifene at 5, 10, or 20 mg/kg, daily p.o.) for a certain period (such as 4 weeks). All rats are given subcutaneous injections of 10 mg/kg calcein (fluorochrome bone marker) 12 and 2 days before being sacrificed in order to examine the dynamic changes in bone tissue. After 4 weeks of treatment, the rats are sacrificed and autopsied. The following endpoints are, determined:
Body Weight Gain: Body weight at autopsy minus body weight at surgery.
Uterine Weight and Histology: The uterus is removed from each rat during autopsy, and weighed immediately. Thereafter, the uterus is processed for histologic measurements such as uterine cross-sectional tissue area, stromal thickness, and luminal epithelial thickness.
Total Serum Cholesterol: Blood is obtained by cardiac puncture and allowed to clot at 4xc2x0 C., and then centrifuged at 2,000 g for 10 min. Serum samples are analyzed for total serum cholesterol using a high performance cholesterol calorimetric assay (Boehringer Mannheim Biochemicals, Indianapolis, Ind.).
Femoral Bone Mineral Measurements: The right femur from each rat is removed at autopsy and scanned using dual energy X-ray absorptiometry (DEXA, QDR 1000/W, Hologic Inc., Waltham, Mass.) equipped with xe2x80x9cRegional High Resolution Scanxe2x80x9d software (Hologic Inc., Waltham, Mass.). The scan field size is 5.08xc3x971.902 cm, resolution is 0.0254xc3x970.0127 cm and scan speed is 7.25 mm/second. The femoral scan images are analyzed and bone area, bone mineral content (BMC), and bone mineral density (BMD) of whole femora (WF), distal femoral metaphyses (DFM), femoral shaft (FS), and proximal femora (PF) is determined.
Proximal Tibial Metaphyseal Cancellous Bone Histomorphometric Analyses: The right tibia is removed at autopsy, dissected free of muscle, and cut into three parts. The proximal tibia is fixed in 70% ethanol, dehydrated in graded concentrations of ethanol, defatted in acetone, then embedded in methyl methacrylate (Eastman Organic Chemicals, Rochester, N.Y.). Frontal sections of proximal tibial metaphyses at 4 and 10 xcexcm thickness are cut using a Reichert-Jung Polycut S microtome. One 4 xcexcm and one 10 xcexcm sections from each rat are used for cancellous bone histomorphometry. The 4 xcexcm sections are stained with modified Masson""s Trichrome stain while the 10 xcexcm sections remained unstained.
A Bioquant OS/2 histomorphometry system (RandM Biometrics, Inc., Nashville, Tenn.) is used for the static and dynamic histomorphometric measurements of the secondary spongiosa of the proximal tibial metaphyses between 1.2 and 3.6 mm distal to the growth plate-epiphyseal junction. The first 1.2 mm of the tibial metaphyseal region is omitted in order to restrict measurements to the secondary spongiosa. The 4 xcexcm sections are used to determine indices related to bone volume, bone structure, and bone resorption, while the 10 xcexcm sections are used to determine indices related to bone formation and bone tumover.
I. Measurements and Calculations Related to Trabecular Bone Volume and Structure
1. Total metaphyseal area (TV, mm2): metaphyseal area between 1.2 and 3.6 mm distal to the growth plate-epiphyseal junction.
2. Trabecular bone area (BV, mm2): total area of trabeculae within TV.
3. Trabecular bone perimeter (BS, mm): the length of total perimeter of trabeculae.
4. Trabecular bone volume (BV/TV, %): BV/TVxc3x97100.
5. Trabecular bone number (TBN, #/mm): 1.199/2xc3x97BS/TV.
6. Trabecular bone thickness (TBT, xcexcm): (2000/1.199)xc3x97(BV/BS).
7. Trabecular bone separation (TBS, xcexcm): (2000xc3x971.199)xc3x97(TVxe2x88x92BV).
II. Measurements and Calculations Related to Bone Resorption
1. Osteoclast number (OCN, #): total number of osteoclast within total metaphyseal area.
2. Osteoclast perimeter (OCP, mm): length of trabecular perimeter covered by osteoclast.
3. Osteoclast number/mm (OCN/mm, #/mm): OCN/BS.
4. Percent osteoclast perimeter (%OCP, %): OCP/BSxc3x97100.
III. Measurements and Calculations Related to Bone Formation and Turnover
1. Single-calcein labeled perimeter (SLS, mm): total length of trabecular perimeter labeled with one calcein label.
2. Double-calcein labeled perimeter (DLS, mm): total length of trabecular perimeter labeled with two calcein labels.
3. Inter-labeled width (ILW, xcexcm): average distance between two calcein labels.
4. Percent mineralizing perimeter (PMS, %): (SLS/2+DLS)/BSxc3x97100.
5. Mineral apposition rate (MAR, xcexcm/day): ILW/label interval.
6. Bone formation rate/surface ref. (BFR/BS, xcexcm2/d/xcexcm): (SLS/2+DLS)xc3x97MAR/BS.
7. Bone turnover rate (BTR, %/y): (SLS/2+DLS)xc3x97MAR/BVxc3x97100.
Statistics
Statistics are calculated using StatView 4.0 packages (Abacus Concepts, Inc., Berkeley, Calif.). The analysis of variance (ANOVA) test followed by Fisher""s PLSD (Stat View, Abacus Concepts Inc. 1918 Bonita Ave, Berkeley, Calif. 94704-1014) is used to compare the differences between groups.
The following protocols can of course be varied by those skilled in the art. For example, intact male or female rats, sex hormone deficient male (orchidectomy) or female (ovariectomy) rats may be used. In addition, male or female rats at different ages (such as 12 months of age) can be used in the studies. The rats can be either intact or castrated (ovariectomized or orchidectomized), and administrated with anabolic agents such as the compounds of this invention at different doses (such as 1, 3 or 6 mg/kg/day) for a certain period (such as two weeks to two months), and followed by administration of an anti-resorptive agent such as droloxifene at different doses (such as 1,5,10 mg/kg/day) for a certain period (such as two weeks to two months), or a combination treatment with both anabolic agent and anti-resorptive agent at different doses for a certain period (such as two weeks to two months). In the castrated rats, treatment can be started at the next day after surgery (for the purpose of preventing bone loss) or at the time bone loss has already occurred (for the purpose of restoring bone mass).
The rats are sacrificed under ketamine anesthesia. The following endpoints are determined:
Femoral bone mineral measurements are performed as described above in the estrogen agonist/antagonist protocol.
Lumbar Vertebral Bone Mineral Measurements: Dual energy X-ray absorptiometry (QDR 1000/W, Hologic, Inc., Waltham, Mass.) equipped with a xe2x80x9cRegional High Resolution Scanxe2x80x9d software (Hologic, Inc., Waltham, Mass.) is used to determined the bone area, bone mineral content (BMC), and bone mineral density (BMD) of whole lumbar spine and each of the six lumbar vertebrae (LV1-6) in the anesthetized rats. The rats are anesthetized by injection (i.p.) of 1 ml/kg of a mixture of ketamine/rompun (ratio of 4 to 3), and then placed on a rat platform. The scan field sized is 6xc3x971.9 cm, resolution is 0.0254xc3x970.0127 cm, and scan speed is 7.25 mm/sec. The whole lumbar spine scan image is obtained and analyzed. Bone area (BA), and bone mineral content (BMC) is determined, and bone mineral density is calculated (MBC divided by BA) for the whole lumbar spine and each of the six lumbar vertebrae (LV1-6).
Proximal tibial metaphyseal cancellous bone histomorphometric analyses are performed as described above for in the estrogen agonist/antagonist protocol.
Measurements and calculations related to trabecular bone volume and structure are performed as described above in the estrogen agonist/antagonist protocol. Further, measurements and calculations related to bone resorption are also performed as described above in the estrogen agonist/antagonist protocol. Still further, measurements and calculations related to bone formation and turnover are performed as described above in the estrogen agonist/antagonist protocol. Further still, the data obtained is analyzed using the statistical manipulations described above in the estrogen agonist/antagonist protocol.
The role of an prostaglandin selective agonist in kidney regeneration is investigated by the ability of Prostaglandin E2 (PGE2) or a selective prostaglandin agonist to induce the expression of Bone Morphogenetic Protein 7 (BMP-7) in wild type 293S cells and in 293S cells transfected with EP2.
Methods: 293S and EP2 293S cells are grown in Dulbecco""s Modified Egale medium (DMEM, Gibco, BRL; Gaithersburg, Md.). One day prior to treatment with PGE2 or an prostaglandin agonist, cells are plated at a density of 1.5xc3x97106 cells/10 cm dish. Generally about 16 to 24 hours later the cell monolayer is washed once with OptiMEM (Gico, BRL) followed by the addition of 10 ml OptiMEM/dish in the presence and absense of vehicle (DMSO), PGE2 (10xe2x88x926M) or an prostaglandin selective agonist (10xe2x88x926M). Cells are harvested and RNA is extracted at 8, 16 and 24 hours. Northern blot analysis of total (20 mg/lane ) is carried out by probing the blots with 32P-labeled BMP-7 probe. The blots are normalized for RNA loading by hybridization with 32P-labeled 18s ribosomal RNA probe. PGE2 and prostaglandin selective agonists induce the expression of BMP-7 in the EP2 293S cells in a time dependent manner. Such induction of expression is generally not observed in the parental cell line. Given the known role of BMP-7 in kidney regeneration and the ability of an prostaglandin agonist to induce BMP-7 expression in 293S kidney cells in a time and receptor specific manner indicates a role for prostaglandin agonist in kidney regeneration.
Administration of the compounds of this invention can be via any method which delivers a compound of this invention systemically and/or locally (e.g., at the site of the bone fracture, osteotomy, or orthopedic surgery). These methods include oral routes, parenteral, intraduodenal routes, etc. Generally, the compounds of this invention are administered orally, but parenteral administration (e.g., intravenous, intramuscular, transdermal, subcutaneous, rectal or intramedullary) may be utilized, for example, where oral administration is inappropriate for the target or where the patient is unable to ingest the drug.
The compounds are used for the treatment and promotion of healing of bone fractures and osteotomies by the local application (e.g., to the sites of bone fractures of osteotomies) of the compounds of this invention or compositions thereof. The compounds of this invention are applied to the sites of bone fractures or osteotomies, for example, either by injection of the compound in a suitable solvent (e.g., an oily solvent such as arachis oil) to the cartilage growth plate or, in cases of open surgery, by local application thereto of such compounds in a suitable carrier such as bone-wax, demineralized bone powder, polymeric bone cements, bone sealants, etc. Alternatively, local application can be achieved by applying a solution or dispersion of the compound in a suitable carrier onto the surface of, or incorporating it into solid or semi-solid implants conventionally used in orthopedic surgery, such as dacron-mesh, gel-foam and kiel bone, or prostheses.
The compounds of this invention may also be applied locally to the site of the fracture or osteotomy in a suitable carrier in combination with one or more of the anabolic agents or bone anti-resorptive agents described above.
Such combinations within the scope of this invention can be co-administered simultaneously or sequentially in any order, or a single pharmaceutical composition comprising a Formula I compound, a prodrug thereof or a pharmaceutical salt of said compound or said prodrug as described above and a second compound as described above in a pharmaceutically acceptable carrier can be administered.
For example, a bone anabolic agent can be used in this invention alone or in combination with an anti-resorptive agent for three months to three years, followed by an anti-resorptive agent alone for three months to three years, with optional repeat of the full treatment cycle. Alternatively, for example, the bone anabolic agent can be used alone or in combination with an anti-resorptive agent for three months to three years, followed by an anti-resorptive agent alone for the remainder of the patient""s life. For example, in one preferred mode of administration, a Formula I or Formula IA compound, or a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug as described above may be administered once daily and a second compound as described above (e.g., estrogen agonist/antagonist) may be administered daily in single or multiple doses. Alternatively, for example, in another preferred mode of administration the two compounds may be administered sequentially wherein the Formula I or Formula IA compound, prodrug thereof or pharmaceutically acceptable salt of said compound or said prodrug as described above may be administered once daily for a period of time sufficient to augment bone mass to a level which is above the bone fracture threshold (World Health Organization Study xe2x80x9cAssessment of Fracture Risk and its Application to Screening for Postmenopausal Osteoporosis (1994). Report of a World Health Organization Study Group. World Health Organization Technical Series 843xe2x80x9d) followed by administration of a second compound, as described above (e.g., estrogen agonist/antagonist), daily in single or multiple doses. It is preferred that the first compound as described above is administered once daily in a rapid delivery form such as oral delivery.
In any event, the amount and timing of compounds administered will, of course, be dependent on the subject being treated, on the severity of the affliction, on the manner of administration and on the judgment of the prescribing physician. Thus, because of patient to patient variability, the dosages given below are a guideline and the physician may titrate doses of the drug to achieve the treatment (e.g., bone mass augmentation) that the physician considers appropriate for the patient. In considering the degree of treatment desired, the physician must balance a variety of factors such as bone mass starting level, age of the patient, presence of preexisting disease, as well as presence of other diseases (e.g., cardiovascular disease).
In general an amount of a compound of this invention is used that is sufficient to augment bone mass to a level which is above the bone fracture threshold (as detailed in the World Health Organization Study previously cited herein).
In general an effective dosage for the anabolic agents used in this invention described above is in the range of 0.001 to 100 mg/kg/day, preferably 0.01 to 50 mg/kg/day.
The following paragraphs provide preferred dosage ranges for various anti-resorptive agents.
The amount of the anti-resorptive agent to be used is determined by its activity as a bone loss inhibiting agent. This activity is determined by means of the pharmacokinetics of an individual compound and its minimal versus maximal effective dose in inhibition of bone loss using a protocol such as described above (e.g., Estrogen Agonist/Antagonist Protocol).
In general, an effective dosage for an anti-resorptive agent is about 0.001 mg/kg/day to about 20 mg/kg/day.
In general, an effective dosage for progestins is about 0.1 to 10 mg per day: the preferred dose is about 0.25 to 5 mg per day.
In general, an effective dosage for polyphosphonates is determined by its potency as a bone resorption inhibiting agent according to standard assays.
Ranges for the daily administration of some polyphosphonates are about 0.001 mg/kg/day to about 20 mg/kg/day.
In general an effective dosage for the treatment of this invention, for example the bone resorption treatment of this invention, for the estrogen agonists/antagonists of this invention is in the range of 0.01 to 200 mg/kg/day, preferably 0.5 to 100 mg/kg/day.
In particular, an effective dosage for droloxifene is in the range of 0.1 to 40 mg/kg/day, preferably 0.1 to 5 mg/kg/day.
In particular, an effective dosage for raloxifene is in the range of 0.1 to 100 mg/kg/day, preferably 0.1 to 10 mg/kg/day.
In particular, an effective dosage for tamoxifen is in the range of 0.1 to 100 mg/kg/day, preferably 0.1 to 5 mg/kg/day.
In particular, an effective dosage for
cis-6-(4-fluoro-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl)-5,6,7,8-tetrahydro-naphthalene-2-ol;
(xe2x88x92)-cis-6-phenyl-5-(4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;
cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;
cis-1-[6xe2x80x2-pyrrolodinoethoxy-3xe2x80x2-pyridyl]-2-phenyl-6-hydroxy-1,2,3,4-tetrahydronaphthalene;
1-(4xe2x80x2-pyrrolidinoethoxyphenyl)-2-(4xe2x80x3-fluoro-phenyl)-6-hydroxy-1,2,3,4-tetrahydroisoquinoline;
cis-6-(4-hydroxyphenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol; or
1-(4xe2x80x2-pyrrolidinolethoxyphenyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline
is in the range of 0.0001 to 100 mg/kg/day, preferably 0.001 to 10 mg/kg/day.
In particular, an effective dosage for 4-hydroxy tamoxifen is in the range of 0.0001 to 100 mg/kg/day, preferably 0.001 to 10 mg/kg/day.
The compounds of the present invention are generally administered in the form of a pharmaceutical composition comprising at least one of the compounds of this invention together with a pharmaceutically acceptable vehicle or diluent. Thus, the compounds of this invention can be administered individually or together in any conventional oral, parenteral, rectal or transdermal dosage form.
For oral administration a pharmaceutical composition can take the form of solutions, suspensions, tablets, pills, capsules, powders, and the like. Tablets containing various excipients such as sodium citrate, calcium carbonate and calcium phosphate are employed along with various disintegrants such as starch and preferably potato or tapioca starch and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes. Solid compositions of a similar type are also employed as fillers in soft and hard-filled gelatin capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols. When aqueous suspensions and/or elixirs are desired for oral administration, the compounds of this invention can be combined with various sweetening agents, flavoring agents, coloring agents, emulsifying agents and/or suspending agents, as well as such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.
For purposes of parenteral administration, solutions in sesame or peanut oil or in aqueous propylene glycol can be employed, as well as sterile aqueous solutions of the corresponding water-soluble salts. Such aqueous solutions may be suitably buffered, if necessary, and the liquid diluent first rendered isotonic with sufficient saline or glucose. These aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal injection purposes. In this connection, the sterile aqueous media employed are all readily obtainable by standard techniques well-known to those skilled in the art.
For purposes of transdermal (e.g.,topical) administration, dilute sterile, aqueous or partially aqueous solutions (usually in about 0.1% to 5% concentration), otherwise similar to the above parenteral solutions, are prepared.
Methods of preparing various pharmaceutical compositions with a certain amount of active ingredient are known, or will be apparent in light of this disclosure, to those skilled in this art. For examples of methods of preparing pharmaceutical compositions, see Remington""s Pharmaceutical Sciences, Mack Publishing Company, Easter, Pa., 15th Edition (1975).
Pharmaceutical compositions according to the invention may contain 0.1%-95% of the compound(s) of this invention, preferably 1%-70%. In any event, the composition or formulation to be administered will contain a quantity of a compound(s) of this invention in an amount effective to treat the disease/condition of the subject being treated, e.g., a bone disorder.
Since the present invention has an aspect that relates to the augmentation and maintenance of bone mass by treatment with a combination of active ingredients which may be administered separately, the invention also relates to combining separate pharmaceutical compositions in kit form. The kit comprises two separate pharmaceutical compositions: a compound of Formula I or Formula IA, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a second compound as described above. The kit comprises container means for containing the separate compositions such as a divided bottle or a divided foil packet. Typically the kit comprises directions for the administration of the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing physician.
An example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process recesses are formed in the plastic foil. The recesses have the size and shape of the tablets or capsules to be packed. Next, the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet. Preferably the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.
It may be desirable to provide a memory aid on the kit, e.g., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen which the tablets or capsules so specified should be ingested. Another example of such a memory aid is a calendar printed on the card e.g., as follows xe2x80x9cFirst Week, Monday, Tuesday, . . . etc . . . Second Week, Monday, Tuesday, . . . xe2x80x9d etc. Other variations of memory aids will be readily apparent. A xe2x80x9cdaily dosexe2x80x9d can be a single tablet or capsule or several pills or capsules to be taken on a given day. Also a daily dose of a Formula I or Formula IA compound, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug can consist of one tablet or capsule while a daily dose of the second compound can consist of several tablets or capsules and vice versa. The memory aid should reflect this.
In another specific embodiment of the invention a dispenser designed to dispense the daily doses one at a time in the order of their intended use is provided. Preferably, the dispenser is equipped with a memory-aid, so as to further facilitate compliance with the regimen. An example of such a memory-aid is a mechanical counter which indicates the number of daily doses that has been dispensed. Another example of such a memory-aid is a battery-powered microchip memory coupled with a liquid crystal readout, or audible reminder signal which, for example, reads out the date that the last daily dose has been taken and/or reminds one when the next dose is to be taken.
The compounds of this invention either alone or in combination with each other or other compounds generally will be administered in a convenient formulation. The following formulation examples only are illustrative and are not intended to limit the scope of the present invention.
In the formulations which follow, xe2x80x9cactive ingredientxe2x80x9d means a compound or compounds of this invention.
Formulation 1: Gelatin Capsules
Hard gelatin capsules are prepared using the following:
A tablet formulation is prepared using the ingredients below:
Formulation 2: Tablets
The components are blended and compressed to form tablets.
Alternatively, tablets each containing 0.25-100 mg of active ingredients are made up as follows:
Formulation 3: Tablets
The active ingredients, starch, and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resultant powders which are then passed through a No. 14 mesh U.S. sieve. The granules so produced are dried at 50xc2x0-60xc2x0 C. and passed through a No. 18 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through a No. 60 U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets.
Suspensions each containing 0.25-100 mg of active ingredient per 5 ml dose are made as follows:
Formulation 4: Suspensions
The active ingredient is passed through a No. 45 mesh U.S. sieve and mixed with the sodium carboxymethyl cellulose and syrup to form smooth paste. The benzoic acid solution, flavor, and color are diluted with some of the water and added, with stirring. Sufficient water is then added to produce the required volume. An aerosol solution is prepared containing the following ingredients:
Formulation 5: Aerosol
The active ingredient is mixed with ethanol and the mixture added to a portion of the propellant, cooled to 30xc2x0 C., and transferred to a filling device. The required amount is then fed to a stainless steel container and diluted with the remaining propellant The valve units are then fitted to the container. Suppositories are prepared as follows:
Formulation 6: Suppositories
The active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimal necessary heat. The mixture is then poured into a suppository mold of nominal 2 g capacity and allowed to cool.
An intravenous formulation is prepared as follows:
Formulation 7: Intravenous Solution
The solution of the above ingredients is intravenously administered to a patient at a rate of about 1 mL per minute.
The active ingredient above may also be a combination of agents.
The abbreviations xe2x80x9cMexe2x80x9d, xe2x80x9cEtxe2x80x9d, xe2x80x9ciPrxe2x80x9d, xe2x80x9cTfxe2x80x9d, xe2x80x9cBuxe2x80x9d, xe2x80x9cPhxe2x80x9d, xe2x80x9cEDCxe2x80x9d and xe2x80x9cAcxe2x80x9d, where used herein, define the terms xe2x80x9cmethylxe2x80x9d, ethyl isopropylxe2x80x9d, xe2x80x9ctriflylxe2x80x9d, xe2x80x9cbutylxe2x80x9d, xe2x80x9cphenylxe2x80x9d, xe2x80x9c1-(3-dimethylaminopropyl)-3-carbodiimide hydrochloridexe2x80x9d and xe2x80x9cacetylxe2x80x9d, respectively.
Proton NMR spectra were recorded on a Varian XL-300, Varian UNITY Plus-400, a Varian XL-250 (manufactured by Varian Co., Palo Alto, Calif.) or a Bruker AM-300 spectrometer (Bruker Co., Billerica, Mass.) at about 23xc2x0 C. Chemical shifts are expressed in parts per million downfield from trimethylsilane. The peak shapes are denoted as follows: s, singlet; d, doublet; t, triplet, q, quartet; m, multiplet; bs=broad singlet. Resonances designated as exchangeable did not appear in a separate NMR experiment where the sample was shaken with several drops of D2O in the same solvent. Atmospheric pressure chemical ionization (APCI) mass spectra were obtained on a Fisons Platform II Spectrometer. Chemical ionization mass spectra were obtained on a Hewlett-Packard 5989 instrument (Hewlett-Packard Co., Palo Alto, Calif.) (ammonia ionization, particle beam mass spectrometer). Where the intensity of chlorine or bromine-containing ions are described, the expected intensity ratio was observed (approximately 3:1 for 35Cl/37Cl-containing ions) and 1:1 for 79Br/81Br-containing ions) and the intensity of only the lower mass ion is given.
Column chromatography was performed with either Baker Silica Gel (40 xcexcm) (J. T. Baker, Phillipsburg, N.J.) or Silica Gel 60 (EM Sciences, Gibbstown, N.J.) in glass columns under low nitrogen pressure. Radial Chromatography was performed using a Chromatatron (model 7924T, Harrison Research, 840 Moana Court, Palo Alto, Calif., 93406). Unless otherwise specified, reagents were used as obtained from commercial sources. Dimethylformamide, 2-propanol, tetrahydrofuran, and dichloromethane used as reaction solvents were the anhydrous grade supplied by Aldrich Chemical Company (Milwaukee, Wis.). Microanalyses were performed by Schwarzkopf Microanalytical Laboratory, Woodside, N.Y. The terms xe2x80x9cconcentratedxe2x80x9d and xe2x80x9ccoevaporatedxe2x80x9d refer to removal of solvent at water aspirator pressure on a rotary evaporator with a bath temperature of less than 45xc2x0 C. Reactions conducted at xe2x80x9c0-20xc2x0 C. xe2x80x9d or xe2x80x9c0-25xc2x0 C.xe2x80x9dwere conducted with initial cooling of the vessel in an insulated ice bath which was allowed to warm to room temperature over several hours. The abbreviation xe2x80x9cminxe2x80x9d and xe2x80x9chxe2x80x9d stand for xe2x80x9cminutesxe2x80x9d and xe2x80x9choursxe2x80x9d, respectively. | {
"pile_set_name": "USPTO Backgrounds"
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JP-2013-027172-A discloses a technique for a stator of a motor in which a segmented coil is used not only to suppress the height of a spanning portion while ensuring a high space factor but also to simplify the fabrication process. Specifically, as shown in FIG. 22, a stator 100 of an electric rotary machine includes a stator core assembly 101 which includes, in turn, a stator core 103 and plural coil bars 105 which are inserted individually in plural slots 104 in the stator core 103 and a pair of base plate assemblies 102 which include plural base plates 106 and plural end coil connections 107 which are individually disposed in the base plates 106 to form spanning portions to connect coil bars 105 of the same phase together. The pair of base plate assemblies 102 are disposed at axial ends of the stator core assembly 101.
In the field of electric rotary machines, it is general practice to increase the numbers of turns of coil or pole pairs as a specification of an electric rotary machine changes. However, in the stator 100 of the electric rotary machine of JP-2013-027172-A, when the numbers of turns of coil or pole pairs are attempted to be increased, the number of end coil connections 107 needs to be increased accordingly. Thus, it is necessary that the end coil connections 107 are made thinner or an outside diameter of the stator 100 is increased. When the number of end coil connections 107 is increased by making them thinner, since it is necessary to increase the number of insulation layers in association with the increase in the number of end coil connections 107, the space factor may be reduced. In addition, it may also affect the joining of the end coil connections 107 with the coil bars 105, which is not preferable from the viewpoint of fabrication of the stator. On the other hand, when the outside diameter of the stator 100 is increased, the installation properties of the electric rotary machine may be deteriorated, and the electric rotary machine may not satisfy the recent demand for reduction in size. Thus, there still remains room for improvement in the stator 100. | {
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People try to take good care of the external surface of their bodies. Specific skin related issues that people care about include good skin health free of infections, good skin tone and skin hygiene. Skin hygiene is generally achieved by keeping them free of infections. One way to tackle infections is to treat them with antimicrobials after the infection has set in. Another approach is to leave a minimal amount of antimicrobial active on the surface so that any invading microorganism is killed or inactivated to minimize spread of diseases. Yet another approach is improving the innate immunity of the desired surface. Some of the bacteria like E. coli, S aureus are generally exists on the skin. These bacteria does not have any pathogenic effect per se on the skin. However when this goes inside the body through ingestion, they induces their pathogenic effect. Therefore keeping the external surface of the body e.g. hand, scalp free of this bacteria helps in achieving the desired hygiene.
AMPs form an integral part of the skin's own defense system. AMPs were initially discovered in insects and in animals and ever since their initial discovery AMPs are regarded as promising antimicrobials. AMPs are ubiquitous in nature and they typically exhibit a broad spectrum of activity against invading bacteria, fungi, enveloped viruses and parasites (Braff and Gallo, 2006. AMPs are generally short peptides and in humans about 90 different AMPs are reported to be present. AMPs in general have two major physical features and they are—a) cationic charge and b) a significant proportion of hydrophobic residues. The cationic charge of the AMPs promotes selectivity for negatively charged microbial cytoplasmic membranes whereas the hydrophobicity facilitates interactions with the cell membrane of the microbial species.
Niacinamide is known in the art for inducing AMP generation on the skin thereby providing antimicrobial benefit.
WO 2015/172801 (Unilever, 2015) discloses a new use of niacinamide for triggering generation of AMPs (antimicrobial peptides) on skin. This has application in improving the immunity of skin, scalp and oral cavity against attack by microorganisms.
The present inventors have been working to provide hygiene benefits to consumers through the route of enhancing the AMP levels in the skin.
It is therefore an object of the present invention to provide an antimicrobial composition.
It is another object of the present invention to provide an antimicrobial composition for through the route of enhancing the AMP levels in the skin.
It is yet another object of the present invention to provide an antimicrobial composition for leave-on application, which has antimicrobial efficacy for long time.
The present inventors while working extensively on this have surprisingly found that a composition comprising Niacinamide and picolinamide in a particular ratio provides significantly better antimicrobial benefit by inducing AMP when compared to Niacinamide alone, thereby satisfies one or more of the above said objects. | {
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1. Field of the Invention
The present invention is for a medicinal information label system, and more particularly, pertains to a resealable pamphlet system having fold out informational panels for dissemination of medical and drug product information.
2. Description of the Prior Art
Prior art medical printed informational material has been difficult to read, at best, due to a myriad of required informational medical information which must be attached or included on the medical product or drug container. Reading of this small print information often requires the use of optical devices such as glasses or magnifying devices. Often dosages were improperly interpreted or conveniently ignored because it was difficult to extricate such valuable information. Users are often prone to neglect such small and difficult to read information for the above and other reasons.
Often medical printed informational material was printed in the same small type fashion and included in loose leaf form in a packaging container along with a pill bottle. The user was then free to discard the packaging container, along with the informational material, with utter disregard to retaining the information for further reference in the future. Had the user the foresight to attempt to retain the informational material, the material could be separated from the medical device or drug container and lost. The informational material could also become damaged or dog-eared if left in an unsecured state.
Clearly what is needed is a resealable product information label system which attaches to a medical product or drug container and which includes a sufficient amount of label material for sufficiently large printing. | {
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1. Field of the Invention
The present invention relates to a measurement method, a measurement apparatus, an exposure apparatus, and a device fabrication method.
2. Description of the Related Art
In recent years, a projection optical system (projection lens) built into a projection exposure apparatus is required to have a performance high enough to suppress wavefront aberrations (transmission wavefront aberration) below 10 mλ RMS (e.g., wavelength λ=248 nm or 193 nm). This makes it necessary to measure the wavefront aberration of the projection optical system with high precision (about 1 mλ), with the projection optical system built into the exposure apparatus. Simplification, speed-up, and the like of the measurement are also important to increase productivity.
An interferometer is used to measure the wavefront aberration of a projection optical system by measuring the wavefronts of the projection optical system at a plurality of points in its field region. The projection optical system is adjusted so as to minimize an aberration coefficient obtained by the polynomial expansion (e.g., using the Zernike function) of the wavefronts measured by the interferometer.
To improve the resolution of an exposure apparatus, polarized illumination has come to be used in place of non-polarized illumination. This makes it necessary to measure not only the wavefront aberration (non-polarization wavefront) of a projection optical system with respect to non-polarized light but also its wavefront aberration (polarization wavefront) with respect to arbitrary polarized light.
Japanese Patent Laid-Open Nos. 2-116732 and 2000-071515 propose techniques of measuring the wavefront aberration of a projection optical system with respect to arbitrary polarized light. These techniques measure the birefringent characteristics of the projection optical system to obtain its wavefront aberration with respect to arbitrary polarized light using the measured birefringent characteristics. More specifically, the technique disclosed in Japanese Patent Laid-Open No. 2-116732 measures the birefringent characteristics (the magnitude and fast axis azimuth of birefringence) of the projection optical system by guiding linearly polarized light beams along four different azimuths (e.g., 0°, 90°, 180°, and 270°) to it. Also, the technique disclosed in Japanese Patent Laid-Open No. 2000-071515 measures the non-polarization wavefront and birefringent characteristic (the magnitude of birefringence) of the projection optical system by guiding linearly polarized light beams along two different azimuths (e.g., 0° and 90°) to it.
Unfortunately, it is difficult for the conventional techniques to simply measure the wavefront aberration with respect to arbitrary polarized light in a short period of time. For example, Japanese Patent Laid-Open No. 2-116732 requires a relatively long measurement time because the wavefront aberrations with respect to linearly polarized light beams along four azimuths must be measured. Furthermore, Japanese Patent Laid-Open No. 2-116732 guides linearly polarized light beams along four different azimuths by rotating a λ/2 plate (polarization switching unit) inserted immediately after a light source. To maintain the linearly polarized light beams along four azimuths, the optical path (optical system) from the polarization switching unit to the projection optical system must have a non-polarization characteristic. It is, however, very hard to form such an optical path.
Japanese Patent Laid-Open No. 2000-071515 need only measure the wavefronts with respect to linearly polarized light beams along two azimuths. In this case, the measurement can be done in a short period of time, but the fast axis azimuth of birefringence must be known in advance. In addition, since a polarization switching unit is inserted immediately after a light source as in Japanese Patent Laid-Open No. 2-116732, the optical path (optical system) from the polarization switching unit to the projection optical system must have a non-polarization characteristic. | {
"pile_set_name": "USPTO Backgrounds"
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1. Field of the Invention
The present invention relates to an organic electroluminescence (hereinafter referred to as “EL”) display device, and, in particular, to an organic electroluminescence display device having a high reliability in which occurrence of dark spots or the like due to moisture is suppressed.
2. Description of the Related Art
In an organic EL display device, an organic EL layer is sandwiched between a pixel electrode (lower electrode) and an upper electrode, a constant voltage is applied to the upper electrode, and a data signal voltage is applied to the lower electrode, to control light emission of the organic EL layer. And an organic EL display device forms an image. The supply of the data signal voltage to the lower electrode is executed through a thin film transistor (TFT). Organic EL display devices include a bottom-emission type in which the light emitted from the organic EL layer is emitted to a direction toward the glass substrate over which the organic EL layer or the like is formed and a top-emission type in which the light is emitted to a direction opposite to the direction toward the glass substrate over which the organic EL layer or the like is formed.
In the organic EL material which is used for the organic EL display device, the light emission characteristic is degraded when moisture is present. Because of this, when the organic EL display device is operated for a long period of time, locations where the organic EL material is degraded by the moisture stops emitting light. This location appears as a dark spot in the display region. The dark spot grows as time elapses, and becomes a defect of an image. Edge growth which is a phenomenon in which a region where the light is not emitted around the pixel increases is also caused by influence of the moisture.
In order to prevent occurrence or growth of the dark spot or the like, it is necessary to prevent intrusion of moisture into the organic EL display device or to remove the intruded moisture in the organic EL display device. For this purpose, an element substrate over which the organic EL layer is formed is sealed with a sealing substrate via a seal provided at the periphery, so that the intrusion of moisture into the organic EL display device from the outside is prevented. Then, the inside space which is sealed is filled with inert gas such as N2. In addition, in order to remove moisture which entered the organic EL display device, a desiccant is provided within the organic EL display device. Such an organic EL display device is called a hollow-seal organic EL display device.
In a hollow-seal organic EL display device, there are known problems such as that adjustment of the gap between the element substrate and the sealing substrate is difficult, that the adjustment inside the sealed space is difficult, that the organic EL material is contaminated by the gas discharged from the sealing agent when the substrates are sealed with the sealing agent, that the throughput is reduced, etc.
As a countermeasure to the problems of the hollow sealing, there is known a technique in which a resin sheet having a determined thickness is sandwiched between the element substrate and the sealing substrate and the organic EL material is protected from moisture with the resin sheet. This technique is called a solid sealing.
JP 2004-139977 A discloses an example of the solid sealing. FIGS. 18A, 18B, 18C, and 18D show a structure disclosed in JP 2004-139977 A. In FIGS. 18A, 18B, 18C, and 18D, a photo-curing resin 120 which is formed over a light-transmissive film 110 is affixed over an element substrate 10 over which an organic EL layer 22 is provided, using a pressure roller 105 which is heated to a temperature of 80° C. Then, ultraviolet ray is irradiated, to cure the photo-curing resin 120. The light-transmissive film 110 is removed, so that an organic EL display device which is sealed with the photo-curing resin 120 is obtained. In addition, this reference discloses a structure in which the organic EL element is covered with a silicon nitride film as necessary.
An article by Shinya SAEKI, Nikkei Electronics, Sep. 10, 2007, No. 960, pp. 10-11 discloses the following technique for sealing an organic EL display device, as shown in FIGS. 19A, 19B, 19C, 19D, and 19E. A resin film 107 is affixed on a location over a sealing substrate 40 corresponding to the location of an organic EL element 22, and a sealing agent 108 is drawn at the periphery of the resin film 107. The sealing substrate 40 over which the resin film 107 and the sealing agent 108 are formed and an element substrate 10 over which the organic EL element 22 is formed are affixed. Then, ultraviolet ray is irradiated from the side of the sealing substrate 40, and a thermal process of 80° C.-100° C. is applied so that the sealing agent 108 is cured and the resin film 107 now having a flowability spreads in and fills a space formed by the sealing substrate 40, the element substrate 10, and the sealing agent 108. Finally, the structure is divided into individual organic EL display panels. In this manner, an organic EL display panel is completed.
JP 2007-73225 A discloses a structure in which an adhesive member is formed on a flexible sealing member in which a separation region is formed, and this member is adhered to the glass substrate over which a plurality of organic EL elements are formed. JP 2007-73225 A discloses a structure in which, in order to separate only the portion of the flexible sealing member over which the adhesive member is formed and leave this portion over the organic EL display panel, a perforation or a half-cut portion for distinguishing the separation portion and the portion to be removed is formed at a boundary between the separation portion and the portion to be removed. | {
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1. Field of the Invention
This invention relates to a body viewing pouch. More specifically, this invention relates to a pouch having a viewing window and being fully flexible to receive a dead body at the hospital in the place of the normal body bag, to be used to transport the body to the funeral home for preparation and embalming, to display the body inside the open casket at the funeral service, to contain the body for delivery to the crematory and to be consumed in the cremation process. During the entire process, from hospital to cremation, the body need not be removed from the pouch.
2. Description of the Related Art
The prior art includes body bags which have been flexible and closeable by stitches, for instance, or zippers, and some of these have had windows for viewing of the face for identification of the body. An example is shown in the old U.S. Pat. No. 3,33,142 to James D. Marston, et al., which issued Dec. 29, 1885. This disclosure includes a wire structure inside the bag adapted to hold the window off the face of the deceased. There have also been provided burial cases of metal sometimes adapted to be vacuumized to help preserve the dead body within. Some of these cases have had windows An example of such a device is shown in the U.S. Pat. No. 1,431,727, which issued Oct. 10, 1922 to George W. Dunn. (Copies of these patents are enclosed in compliance with 37 CFR 1.97.)
The present invention serves the purpose of the body bag and burial case, and at the same time is crematable. By way of background, the public's urgent concern with respect to certain communicable diseases now growing by epidemic proportion has demanded strict and careful segregation of any body having died from such a disease from contact with the public. Indeed, even the personnel in some funeral homes have refrained from servicing dead bodies having died from such a disease.
In the past, when a human has died in a hospital or at an accident scene, he has been transported in a zippered funeral body bag to the funeral home where he has been taken out of the body bag, embalmed, made up and laid out in a fabric-lined casket for viewing by the public. After the funeral service the body has been removed from the casket, unless it is intended to cremate the casket with the body, and has been placed in a cremation container and transferred to the crematory. The multiple handling by employees of the hospital and ambulance corps, the funeral home employees and the crematory personnel is clearly unsuitable for the body of a person who has died from a highly contagious disease. It is also highly undesirable that the body itself be exposed to public viewing without some kind of intermediate guard to prevent real or imagined transfer of communicable elements. | {
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The strengthening of glass articles through the introduction of compressive stresses into the surfaces of the articles can be accomplished by thermal tempering, ion-exchange or chemical tempering, and the lamination of glass surface layers to glass core layers. Thermal tempering involves rapidly cooling the surfaces of a hot glass article to set the surface glass while allowing the core glass to contract through slower cooling. Ion-exchange strengthening or so-called chemical tempering typically involves exchanging large mobile ions from the surfaces of the glass with smaller ions in the interior of glass which can introduce compressive stresses into the glass surfaces. In laminar strengthening, glass surface layers or skins of relatively low thermal expansion are fused to glass core layers of relatively high thermal expansion so that compressive stress can develop in skins as the laminated articles are cooled following fusion.
While each of these known methods of glass strengthening has been employed successfully to improve the suitability of glass for a number of existing technical applications, new applications have imposed higher demands on the ability of glass materials to resist surface damage in use. In some flat glass applications, for example, the damage resistance of one of the surfaces of the glass needs to be superior to the damage resistance of the other surface, because one of the surfaces sees more abuse in day-to-day use than the other surface. Touch screen displays are an example of an application where increased surface damage resistance in the active or exposed surface of the displays is presently required.
In most instances the known methods of glass strengthening have been used to induce uniform compressive stresses and uniform depths of surface compression on each of the two surfaces of the glass article being strengthened. While resistance to surface damage can be improved in some cases through modifications of these methods to increase the levels of surface compression in the articles, the results are not satisfactory for a number of applications. One disadvantage, for example, is that increasing surface compression can correspondingly increase core tension. High core tensions in strengthened glass articles can undesirably increase the fracture energy of the article in the event of breakage. | {
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The present invention resides generally in the field of devices and methods useful for the deployment of prosthetic devices, and in a particular aspect relates to the deployment of prosthetic devices within the vasculature of a patient to treat complications, such as a varicose vein condition, resultant of venous reflux.
As further background, vascular vessels are comprised of tissue and are the conduit for circulating blood through a mammalian body. A vascular vessel that carries blood from the heart is known as an artery. A vascular vessel that returns blood to the heart is known as a vein. There are three types of veins in a human: deep veins, which are located deep in the body close to the bones, superficial veins, which are located close to the skin, and perforating veins, which are smaller veins that connect the deep veins to the superficial veins.
To assist blood flow, venous vascular vessels contain venous valves. Each venous valve is located inside the vein and typically includes at least two valve leaflets, which are disposed annularly along the inside wall of the vein. These leaflets open to permit blood flow toward the heart and close, upon a change in pressure, such as a transition from systole to diastole, to restrict the back flow of blood. When blood flows towards the heart, the venous pressure forces the valve leaflets to move apart in a downstream flexing motion, thereby creating an open path for blood flow. The leaflets normally flex together when moving in the upstream direction; therefore, they return to a closed position to restrict or prevent blood flow in the upstream, or retrograde, direction after the venous pressure is relieved. The leaflets, when functioning properly, extend radially inward toward one another such that the leaflet tips, or cusps contact each other when the valve is closed.
On occasion, and for a variety of reasons, such as congenital valve or vein weakness, disease in the vein, obesity, pregnancy, and/or an occupation requiring long periods of standing, one or more valves in a vein will allow deleterious retrograde flow to occur. When a valve allows such retrograde flow, blood will collect, or pool in vessels beneath the valve. This pooling of blood causes an increase in the venous pressure below the valve. Venous valves that allow such deleterious retrograde flow are known as incompetent or inadequate venous valves. The condition resulting from such incompetent venous valves is known as venous valve insufficiency.
In the condition of venous valve insufficiency, the venous valve leaflets do not function properly. Incompetent venous valves can cause the veins to bulge, can cause swelling in the patient's lower extremities, and can result in varicose veins and/or chronic venous insufficiency. If left untreated, venous valve insufficiency can cause venous stasis ulcers of the skin and subcutaneous tissue.
A common method of treatment for venous valve insufficiency is the placement of an elastic stocking around the patient's leg to apply external pressure to the vein, forcing the walls radially inward to force the leaflets into apposition. Although sometimes successful, the tight stocking is quite uncomfortable, especially in warm weather, because the stocking must be constantly worn to keep the leaflets in apposition. The elastic stocking also affects the patient's physical appearance, thereby potentially having an adverse psychological affect. This physical and/or psychological discomfort can lead to the patient removing the stocking, thereby inhibiting treatment.
Surgical methods for treatment of venous valve insufficiency have also been developed. A vein with incompetent venous valves can be surgically constricted to bring incompetent leaflets into closer proximity in hopes of restoring natural valve function. Methods for surgical constriction of an incompetent vein include implanting a frame around the outside of the vessel, placing a constricting suture around the vessel (e.g., valvuloplasty), or other types of treatment to the outside of the vessel to induce vessel contraction. Other surgical venous valve insufficiency treatment methods include bypassing or replacing damaged venous valves with autologous sections of veins containing competent valves.
Another surgical method includes vein stripping and ligation. In this procedure, the femoral vein and other major venous tributaries are disconnected from the greater saphenous vein (GSV) and tied off. Next, the GSV is removed from the leg by advancing a wire through the vein, tying the wire to a saphenous vein end, and then pulling the wire, and vein, out through an incision in the upper calf or ankle. Unfortunately, the above surgeries require at least one incision and have several undesirable side effects and risks, such as a long patient recovery time, the potential for scarring, and numerous other risks inherent with surgery, such as those associated with the administration of anesthesia.
Recently, various implantable prosthetic devices and minimally invasive methods for implantation of these devices have been suggested to treat venous valve insufficiency. Such prosthetic devices can be inserted intravascularly, for example from an implantation catheter. Prosthetic devices can function as a replacement venous valve, or enhance venous valve function by bringing incompetent valve leaflets into closer proximity. In one procedure, venous valve function can be enhanced by clipping the valve leaflets together with a clip made from a biocompatible material, such as a metal or polymer.
Recently, a number of methods have been suggested to treat varicose veins and venous valve leaflets with energy sources, such as radiofrequency (RF) energy. In one such method, valve leaflets can be fastened together with electrodes delivering RF energy. In another such method, a catheter having an electrode tip can be used to apply RF energy to cause localized heating and corresponding shrinkage of venous tissue. After treatment of one venous section is complete, the catheter can be repositioned to treat a different venous section.
Methods for treatment of varicose veins have also been developed involving various forms of sclerotherapy. Generally, sclerotherapy involves the delivery of one or more sclerosing agents to the lumen of a varicose or other small diameter vein, which induce the vein to collapse and the venous walls to fuse, thereby closing the vein.
In view of this background, the need remains for improved and alternative techniques, devices and systems for affecting the venous system to treat venous conditions. The present invention is addressed to these needs. | {
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This invention relates to an electric rotating machine of the type capable of rotating at more than 1,500 rpm.
More specifically, the present invention relates to a lead-out portion of a rotor winding for feeding electric power to an end of the rotor winding of the electric rotating machine from the exterior, and also relates to a method of connection of the lead-out portion.
A conventional feeder lead wire of field coil is of such a construction as disclosed in Japanese Utility Model Unexamined Publication No. 53-96604, and its construction is determined in view of a cooling performance. However, any structural measures have not particularly been taken against the centrifugal force acting on a rising portion of the feeder lead wire.
For example, in the above conventional construction, laminated thin plates are used as the feeder lead wire, and because of their flexibility, the feeder lead wire is flexible with respect to the deformation due to the centrifugal force.
Where the laminated thin plates are not used, a thick plate is bent and is used as the feeder lead wire. In this case, a material of a low hardness having a cold-processing rate of about 25% is used in order to ensure a bending processability.
Even where a copper material of a relatively high hardness is used, the end of the rotor winding is joined to the upper portion of the feeder lead wire by brazing, and therefore the brazed portion has tended to be much lowered in hardness under the influence of the heat generated by the brazing.
Such construction and tendency will now be specifically described with reference to FIGS. 5 to 10.
FIG. 10 is a schematic cross-sectional view of an electric rotating machine. A rotor 30 supported at its opposite ends by bearings 20 comprises a rotatable shaft 40 provided with a rotor core, a rotor winding wound and received in a laminated manner in slots formed in the rotor core, and a support ring 6 shrinkage-fitted on the rotatable shaft 40 to support an end portion of the rotor winding 3 partially projecting axially from the rotor core.
Field current is supplied to the rotor winding 3 from the exterior of the rotor via collector rings 70, a lead wire 5 received in a central bore of the rotatable shaft 40, a terminal bolt 90 and a feeder lead wire 4.
The rotor 30 is rotated by an associated prime mover while generating a magnetomotive force by the field current, thereby generating a rotating field.
The rotating field causes a stator coil 110 to produce electric power, the stator coil 110 being arranged in surrounding relation to the rotor 30.
The stator coil 110 is supported in slots in an iron core 120, and the iron core is supported by a stator frame 130 provided around the iron core.
FIGS. 5 and 6 are an enlarged cross-sectional view and an enlarged perspective view of an end portion (shown in FIG. 10) of the rotor winding partially projecting axially from the rotor core, respectively.
In FIGS. 5 and 6, the rotor 30 has slots 2 (not shown in FIG. 5) formed in a surface thereof and receiving the winding, and the ends of the winding in the direction of the axis of the rotor are connected together to form a magnetic pole.
The thus connected rotor winding 3 is connected at its end to the feeder lead wire 4, and this feeder lead wire 4 extends inwardly of the end of the winding, and is passed into a central hole in the rotor 30. A support ring 6 is shrinkage-fitted on an end portion of the rotor 30 after the winding connecting operation. The end of the winding 3 and the feeder lead wire 4 are connected together in a manner shown in FIG. 7. Namely, the end of the winding 3 is extended substantially in a circumferential direction of the rotor 30, and is connected at its distal end to the end of the feeder lead wire 4 by brazing. Because of the nature of its construction, the feeder lead wire 4 has a rising portion 4a, and the rising portion 4a is connected at its distal end to the end of the winding 3 by brazing. Conventionally, this brazing operation is carried out in a manner shown in FIG. 9. Namely, a Cooling portion 4b spaced a certain distance X from a brazing portion 4c is provided at the feeder lead wire 4, and the brazing operation is carried out while the feeder lead wire 4 is cooled through the cooling portion 4b. The feeder lead wire 4 is made of a copper alloy in order to have a satisfactory electrical performance, and the copper alloy is softened by the head applied for brazing purposes, so that the compression-resistant hardness of the copper alloy tends to be lowered. The above cooling is carried out in order to limit the extent of the metal softening as much as possible.
In the case where a plate of the copper alloy is shaped by forging, it is known that the relation between the stress and the strain as shown in FIG. 8 is provided when heat of around 700.degree. C. is applied to the copper alloy plate. Namely, when the copper alloy plate is thermally affected, a large strain develops in the copper alloy plate even with a small stress.
In the feeder lead wire softened by the heat, a large centrifugal force acts particularly on its rising portion 4a during a high-speed rotation of the rotor, and as a result a compressive strain develops, and during a long period of the operation of the electric rotating machine, such compressive strain is accumulated.
With respect to the above technique, force withstanding the centrifugal force is not taken into consideration when this technique is applied to the rotor of the electric rotating machine subjected to a large centrifugal force, and therefore there has been encountered a problem that the feeder lead wire is abnormally deformed due to a large centrifugal force and also plastically shrink due to a centrifugal compressive force.
When such abnormal deformation or plastic shrinkage develops, the feeder lead wire and its support structural member are displaced out of position from each other, and loads and displacement acting on each of them become excessive, which may cause cracks and a rupture. | {
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1. Field Of The Invention
This invention relates to burners for burning petroleum products during well testing, and more particularly, to a burner apparatus having a body which may have multiple burner nozzles therein and an easily disassembled and cleaned water spray ring assembly.
2. Description Of The Prior Art
When well tests are performed, disposal of the petroleum or other hydrocarbon products therefrom is generally carried out by burning. One problem with burning the hydrocarbon products is in insuring that the burner can adequately handle the amount of hydrocarbons to be burned. This requires that the nozzles in the burner atomize the petroleum products as much as possible and that an adequate air supply be provided to insure as Complete combustion as possible. There is also a necessity to protect the rest of the well installation from the great amount of heat generated by the burner and to reduce the black smoke produced.
U.S. Pat. No. 3,894,831 to Glotin et al. discloses a burner having multiple individual burner assemblies or nozzles which are pointed in slightly divergent directions. A ring-like water injection system is disposed around each burner nozzle, and the water injection system has a plurality of individual nozzles which direct a spray of water toward the flame. The water acts to reduce the radiated heat from the burner and also to reduce the amount of black smoke generated in the combustion process. The apparatus may be swiveled so that the flame is directed downwind from the well. Other burners which have multiple nozzles, are rotatable and have water sprays include those disclosed in British Patent No. 2,112,920 to Dewald; U.S. Pat. No. 4,348,171 to Issenmann; and U.S. Pat. No. 3,797,992 to Straitz, III. U.S. Pat. No. 3,980,416 to Goncalves et al. discloses a single nozzle burner which is rotatable and has ring-shaped water sprayers.
In the prior art burners with multiple nozzles, the nozzles are separate, individual assemblies and therefore require relatively complex piping systems. The relatively large number of connections increases the possibility of leaks of petroleum products, air and/or water, any of which could cause problems. The present invention solves this problem by providing a burner with a body which may have a plurality of nozzle ports therein. A single petroleum connection and a minimum of air connections to the body may be used.
An additional problem with prior art burners having water spray systems is that these utilize individual water nozzles. These water nozzles must be cleaned individually and are difficult to clean in the first place. The present invention solves this problem by providing a burner with a water ring which comprises an inner ring and an outer ring, wherein one of the rings has a plurality of notches therein. The notches form the water spray openings, and the rings are easily separated so that the notches are exposed for simple cleaning. | {
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Human immunodeficiency virus (hereinafter referred to HIV) which causes AIDS produces a precursor protein comprising Gag protein used for the formation of the said virus particles and reverse transcriptase in host cells. This precursor protein is cleaved by a protease (hereinafter referred to HIV protease) derived from the virus into a specific size to perform its function. Therefore, a HIV protease inhibitor exhibits antiviral activity by inhibiting an enzymatic activity of HIV protease to block the formation and maturation of infectious virus particles. Several kinds of HIV protease inhibitors have been already reported, comprising synthetic peptide-like compound called as a transition-state mimetic (T. Robins, J. Plattner, J. Acquir. Immun. Defic. Syndr. 6, 162 (1993)). Hydroxyethylamine type derivatives such as Ro 31-8959 comprising phenylalanine .psi.CH(OH)CH.sub.2 N! decahydroisoquinoline carboxylic acid skeleton similar to the amino acid sequence -Tyr . . . Pro- or -Phe . . . Pro- as a cleavage site of the HIV protease (N. A. Roberts et al., Science 248, 358-361 (1990)) and hydroxymethylcarboxamide type derivatives such as peptide derivatives comprising a norstatine skeleton phenylalanine .psi.CH(OH)C(O)N! proline were reported to be useful as a HIV protease inhibitor (T. F. Tam et al., J. Med. Chem. 35, 1318-1320 (1992)).
The present inventors also found that a group of synthetic peptides which were transition-state mimetic comprising 3-amino-2-hydroxy-4-phenylbutanoyl residue as the skeletal structure thereof strongly inhibited HIV protease activity to be useful as an anti-AIDS agent and proposed them as HIV protease inhibitors (Japanese laid-open patent No. 170722/1993).
These transition-state mimetics are considered as the most promising anti-AIDS agent of next generation following reverse transcriptase inhibitors of nucleic acid derivatives, such as AZT (azide thymidine), DDC (dideoxycytidine), DDI (dideoxyinosine), which are already used clinically as anti-AIDS agents and clinical use, clinical tests and researches thereof are in progress. That is, clinical application of HIV protease inhibitors has been tried to suppress the formation of virus particles in host cell and prevent the proliferation and infection of HIV, resulting in the prevention of onset of AIDS (Nakajima et al., Gekkan-Yakuji, vol. 35, 2983-2989 (1993)).
However, among these peptide-like compounds, conventional-type of compounds belonging to hydroxymethylcarboxamide derivatives exhibiting excellent HIV protease inhibitory activity have hydrophobic acyl group at N-terminal amino group of tripeptide chain. Therefore, in many cases, problems, such as, (1) their insolubility in water, (2) unstability in vivo, (3) low oral absorptivity have been reported (Hiroaki Mitsuya, Kagaku, vol. 64, No. 7, p462-470 (1994)). Since anti-AIDS agents are consecutively administered for long duration, development of compound with higher bioavailability, that is, easily absorbed and stable in vivo, especially in the case of oral administration has been desired. Development of a peptide compound with excellent HIV protease inhibitory activity which has a low molecular weight and is resistant against degradation by various kinds of digestive enzymes or proteolytic enzymes, is desired. More specifically development of a novel peptide compound with a small size of acyl group linked to N-terminal amino group which comprises only low molecular weight dipeptide-structure as transition-state mimetic is desired.
An object of the present invention is to provide a novel dipeptide compound which has nearly the same anti-HIV protease inhibitory activity as that of a transition-state mimetic peptide compound having a tripeptide chain and has a lower molecular weight than that. The object of the present invention is to provide a novel dipeptide compound which is different from various types of hydroxymethylcarboxamide tripeptide compound designed as a conventional HIV protease inhibitor with respect to peptide chain length and exhibit an excellent HIV protease inhibitory activity or suppressive action on the proliferation of HIV virus. Another object of the present invention is to provide a suppressive agent against HIV virus proliferation comprising a novel dipeptide compound as an effective ingredient.
The present inventors studied eagerly to design and prepare a novel dipeptide compound which has a clearly different structure from that of a conventional hydroxymethylcarboxamide-type peptide compound. The present inventors investigated whether or not these dipeptide compounds have a HIV protease inhibitory activity as designed and found that they exhibited excellent activities and accomplished the present invention. | {
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Many formulations such as inks, paints, millbases and plastics materials require effective dispersants for uniformly distributing a particulate solid in a polar organic medium or a non-polar organic medium. For inks, it is desirable for ink manufacturers to generate printed products of high resolution and quality. The adaptability of printing process to cater for the ever widening range of base substrates, resins and pigments is a challenge. The pigment dispersion should be compatible with the different formulations used to ensure good adhesion and resistance of the final coating. Poor pigment dispersion or stabilisation can result in agglomeration or settling within the polar organic liquid medium or a non-polar organic liquid medium (e.g., ink or coating) lowering the gloss and aesthetic appeal.
U.S. Pat. No. 7,265,197 discloses dispersing pigments in ink compositions with a dispersant having formula:
where R1 is individually selected from the group consisting of H and CH3, and n is an integer from 4 to 400).
International publication WO 2008/028954 discloses imide dispersant compounds containing terminal acidic groups in both a polar and a non-polar organic medium, where the dispersant compound is represented by the structure
where T is —(CH2)3— or —CH2CH(CH3)—; R′ is H or C1-50-optionally substituted hydrocarbyl group, or C1-50-optionally substituted hydrocarbonyl; Y is C2-4-alkyleneoxy; x is 2 to 90; and q is 1 or 2, with the proviso that in Formula (1a), when q is 1, T is (CH2)3—, and when q is 2, T is —(CH2)3— or —CH2CH(CH3)—.
U.S. Pat. No. 5,688,312 discloses an ink composition comprised of a colourant and an imide or bisimide with a viscosity of from about 1 centipoise to about 10 centipoise at a temperature of from about 125 to about 180° C. The imide or bisimide may be prepared by reacting phthalic anhydride and a mono- or di-amine. The monoamine may be for example dodecylamine, or stearylamine. The diamine may be 1,12-dodecanediamine.
International Patent Application WO 2007/139980 discloses a reaction product of at least one di-anhydride with at least two reactants which are different from each other, each of which reactants contains a primary or secondary amino, hydroxyl or thiol functional group, and at least one of which reactants is polymeric. The reaction product is useful in compositions such as inks and coatings.
U.S. Pat. No. 6,440,207 discloses a process for preparing dispersible dry organic pigments for aqueous systems by (a) milling a mixture containing (1) one or more organic pigments, (2) at least about 1% by weight, relative to the organic pigment, of one or more aromatic polyalkylene oxide dispersants, (3) 0 to about 10 parts by weight, relative to the organic pigment, of a milling liquid in which the organic pigment is substantially insoluble, (4) 0 to about 50% by weight, relative to the organic pigment, of one or more milling additives other than dispersant (2), and (5) 0 to about 20% by weight, relative to the organic pigment, of one or more surface treatment additives; (b) optionally, adding to the milled pigment (6) one or more liquids in which the organic pigment is substantially insoluble in amounts such that the total solids content is not reduced below about 10%, and (7) one or more multivalent metal salts and/or one or more quaternary ammonium salt; and (c) isolating the milled organic pigment. The aromatic polyalkylene oxide dispersant may be prepared by reacting in an autoclave containing 250 g of deionized water 19.8 (0.100 mol) of 1,8-naphthalic anhydride and 105 (0.105 mol) of Jeffamine™XTJ-506 (83 wt % ethylene oxide, 17 wt % propylene oxide). The autoclave was sealed, heated with stirring to 150° C., and maintained at 150° C. for five hours. After the reaction had cooled, the resultant brown liquid was discharged into a beaker to which was then added 15 g of decolourizing charcoal. After stirring overnight, the suspension was filtered and the filter cake washed with water, yielding approximately 500 g of an amber-coloured filtrate having a 23.63% solids content. The dry pigment can be employed in water-based paint systems.
International Patent application PCT/US13/038114, filed 25 Apr. 2013, entitled “Aromatic Dispersant Composition” (by Shooter, Thetford and Richards) discloses a polymer comprising a polymer chain having at least one non-fused aromatic imide pendant group, wherein the polymer is represented by formula:
wherein Pol is a homopolymer chain or a copolymer chain, wherein the polymer chain is selected from the group consisting essentially of a poly(ether), poly(ester), poly(ester amide), poly(amide), poly(alkylene), and mixtures thereof, Q is a non-fused aromatic ring containing 4n+2 π-electrons, wherein n=2 or more, and Q is bonded to the imide group in such a way to form a 5 or 6 membered imide ring. Further disclosed is a millbase, paint or ink composition comprising a particulate solid, a non-polar organic medium, and the polymer disclosed therein.
International Patent application PCT/US13/037928, filed 24 Apr. 2013, entitled “Aromatic Dispersant Composition” (by Shooter, Thetford and Richards) discloses a polymer comprising a polymer chain having at least one fused aromatic imide pendant group, wherein the polymer is represented by formula:
wherein Pol may be a homopolymer chain of ethylene oxide or a copolymer chain of ethylene oxide, wherein the ethylene oxide constitutes 40 wt % to 99.99 wt % of the copolymer chain; and Q may be a non-fused aromatic ring containing 4n+2 π-electrons, and Q is bonded to the imide group in such a way to form a 5 or 6 membered imide ring. Also disclosed is a millbase, paint or ink composition comprising a particulate solid (typically a pigment or filler), an aqueous medium, and the polymer chain disclosed therein. | {
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Unmanned vehicles such as unmanned aerial vehicles (UAVs) can be used to perform surveillance, reconnaissance, and exploration tasks for a wide variety of military and civilian applications. In some instances, a UAV can include a plurality of functional modules that control the operation of UAV components such as propulsion units. The functional modules can be controlled by a central control module.
Existing approaches for communication between a central control module and multiple functional modules may not be optimal in some instances. For example, some communication schemes may be limited to unidirectional signal transmission from the control module to the functional modules, which may prevent the control module from obtaining feedback information directly from the functional modules. | {
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A bypass turbine engine generally comprises, from upstream to downstream in the gas flow direction, a shrouded fan, an annular primary flow space and an annular secondary flow space. The air mass aspired by the fan is therefore divided into a primary flow F1, which circulates in the primary flow space, and a secondary flow F2, which is concentric with the primary flow F1 and circulates in the secondary flow space.
The primary flow space passes through a primary body comprising one or more compressor stages, for example a lowpressure compressor and a highpressure compressor, a combustion chamber, one or more turbine stages, for example a highpressure turbine and a lowpressure turbine, and a gas exhaust nozzle.
Moreover, in a manner known per se, the turbine engine comprises an intermediate casing the hub whereof is arranged between the low pressure compressor casing and the highpressure compressor casing. The intermediate casing comprises discharge valves or VBV, the role of which is to regulate the flow rate at the inlet of the highpressure compressor so as, in particular, to limit the risks of surge in the low pressure compressor by discharging a portion of the air outside the primary flow space.
As illustrated in FIG. 1, which is a partial axial section view of a dual-spool bypass airplane turbojet of a known type, the hubs 2 of the intermediate casings usually comprise two coaxial annular shrouds, respectively inner 3 and outer 5, mutually connected by an upstream transverse flange 7 and a downstream transverse flange 9.
The upstream flange 7 is arranged downstream of the lowpressure compressor while the downstream flange 9 is arranged upstream of the highpressure compressor.
The inner shroud 3 delimits the annular primary flow space 10 of the primary flow F1 of the turbine engine and comprises air inlet openings 4 distributed circumferentially around an axis X of the inner shroud 3 (which is coaxial with the hub 2), which are blocked by a corresponding discharge valve 12 designed to regulate the flow rate of the highpressure compressor.
Such a discharge valve 12 can take the form of a door which is mounted pivotally on the inner shroud 3 between a closed position, in which the door 12 closes the corresponding inlet opening 4 and is flush with the inner shroud 3 of the intermediate casing 1 while forming a substantially continuous surface to best reduce the risks of aerodynamic perturbations of the primary flow F1, and an open position (see FIG. 1), in which the door 12 protrudes radially toward the inside with respect to the inner shroud 3 and thus allows the collection of a portion of the primary flow F1 in the primary flow space 10.
For its part, the outer shroud 5 delimits the secondary flow space 14 of the secondary flow F2 of the turbine engine, and comprises air outlet openings 6 arranged downstream of the downstream transverse flange 9 and distributed circumferentially around the axis X.
When the airflow rate which can enter the highpressure compressor is reduced, a surplus of air in the secondary flow space 14 can then be bled through these outlet openings 6, thus avoiding surge phenomena which can lead to deterioration or complete destruction of the lowpressure compressor.
The turbine engine further comprises discharge streams, formed between the inlet openings 14 and the outlet openings 6. Each discharge stream is delimited, from upstream to downstream, between an inlet opening 4 and an associated outlet opening 6, by an intermediate annular space 16, delimited by the shrouds 3, 5 and the transverse flanges 7, 9, then by a discharge stream duct 18 (also known by the acronym kit engine), configured to guide the air flow to the secondary flow space 14. The discharge stream duct 18 further comprises an intermediate opening 19, which leads into the intermediate space 16 at the upstream surface of the downstream transverse flange 9.
The doors 12, the intermediate spaces 16 and the associated discharge stream ducts 18 thus form together a system for discharging air to the secondary flow space 14 of the turbine engine.
The hub 2 of the intermediate casing 1 therefore includes a plurality of such systems distributed around the axis X.
Moreover, when a door 12 of a discharge valve is in the open position, an air flow scooped by it passes through the intermediate space 16, the corresponding discharge stream duct 18, then reaches the secondary flow space 14 through a discharge grating 20 comprising fins, or the VBV grating. The discharge streams and the fins of the VBV gratings 20 are inclined with respect to the flow direction of the secondary flow F2, so as to redirect the air flow from the primary flow space and align it as much as possible with that of the secondary flow F2.
Modern turbine engines operate at ever greater dilution ratios (better known as bypass ratios). In order to limit shock losses in supersonic flows at the tip of the fan, the angular rotation speed of the fan is reduced. This has the effect of reducing the compression ratio of the fan. At lower compression ratios, the head and secondary flow F2 separation losses therefore have a greater impact and must be limited as much as possible. These head losses are present in the zone having surface irregularities in particular.
The Applicant, however, has noted the fact that the presence of the VBV grating 20 created a stream irregularity capable of create head losses when the discharge stream is not discharging (i.e. when the door 12 of the discharge valve is in the closed position), typically during cruise. In fact, the VBV grating 20 forms a porous surface into which air can enter and capable of create head losses and/or separation layer in the secondary flow F2.
Proposed therefore, in document FR 15 52811, filed 1 Apr. 2015 in the Applicant's name, is an intermediate casing hub for a bypass turbine engine comprising: a set of discharge fins, attached in the discharge stream duct, at the outlet opening of the outer shroud, and blocking means, configured to adjust a passage cross-section of the outlet opening depending on the position of the movable door.
The blocking means are movable between an open configuration, in which an air flow from the inlet opening is able to pass through the discharge fins, and a closed configuration, in which the blocking means block a passage cross-section of the outlet opening. These blocking means can in particular be formed by discharge fins which are then mounted pivotally in the discharge stream duct between the open configuration and the closed configuration.
However, these blocking means require the implementation of servo control means and therefore the addition of components into the engine and therefore the increase of its mass. Typically, in patent application FR 15 52811, the coupling is accomplished by means of a digital control system or a servo-control system mechanically or hydraulically connecting the door to the blocking means and thus ensuring their simultaneous opening and closing.
Document US 2013/269366 describes an intermediate casing hub comprising a discharge stream duct which leads into a secondary flow space through an outlet opening and discharge fins, the opening and the closing of the discharge fins being synchronized by means of a pivoting rod. | {
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The present invention broadly relates to an improved liquid coating composition and more particularly to an improved waterborne pigmented acrylic hydrosol coating composition and process which overcomes many of the problems and disadvantages associated with acrylic hydrosol compositions of the types heretofore known.
A variety of waterborne liquid coating compositions incorporation acrylic copolymers including acrylic hydrosols have heretofore been used or proposed for use. Typical of such coating formulations are those described in U.S. Pat. Nos. 3,705,124; 3,943,187; and 4,477,609; and British Patent Nos. 1,114,133 and 1,109,656. A method for preparing acrylic hydrosols suitable for forming waterborne acrylic coating compositions is described in a publication entitled "Acrylic Hydrosols--A New Concept in Aqueous Coating Systems" by Beardsley et al, published in Volume 40, number 521, June, 1968 of the Journal of Paint Technology, pages 263-270. A continuing problem associated with such waterborne liquid acrylic coating compositions of the types heretofore known has been the inclusion of surfactant-type dispersing and/or emulsifying agents to provide for a stable coating composition in which the surfactant upon drying of the coating composition is incorporated into the resultant polymeric film. The presence of such surfactants in the liquid coating composition can result in flash rusting of corrosion susceptible substrates upon application and the presence of such surfactants in the resultant film renders them moisture sensitive and therefore susceptible to deterioration upon exposure to high moisture-containing environments such as, for example, those encountered by exterior coatings for automotive applications.
The present invention overcomes such disadvantages in providing a waterborne pigmented acrylic hydrosol coating composition and method of preparing such composition which is substantially devoid of any surfactant-type dispersants and/or emulsifying agents providing a liquid coating composition having excellent physical properties, which is resistant to rust formation when applied to corrosion susceptible substrates, which can be directly applied to ferrous substrates without causing flash rusting upon application and can also be applied over rusted surfaces with good adhesion, which produces polymeric films that are resistant to deterioration upon exposure to high moisture environments, which are compatible with and can be directly applied over painted surfaces without lifting of the underlying coating and which in turn is receptive to a further topcoating as may be desired or required in some instances, and which possesses excellent filling and sealing characteristics when applied to previously painted surfaces. The coating composition of the present invention is further characterized by its versatility enabling pigmentation thereof with any one or combinations of conventionally employed pigmenting agents of the types used in waterborne coating systems and which can be formulated for air-dry as well as moderate or high temperature bake systems. | {
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1. Technical Field
The present invention relates to a semiconductor apparatus comprising a circuit composed of a device as typified by a thin film transistor (hereinafter, TFT) that is formed by means of bonding a release layer to a substrate to be transferred thereto and a method for manufacturing the semiconductor apparatus. The present invention relates, for example, to an electrooptical device such as a liquid crystal module, a light emitting apparatus such as an EL module, and an electric appliance installed with such apparatus as its components. In addition, the present invention relates to a peeling method of a device and transferring method of the device to a plastic substrate.
As used herein, the term “semiconductor device” refers to any device as a whole that operates by utilizing semiconductor characteristics. An electrooptical device, a light emitting apparatus, a semiconductor circuit, and an electric appliance are all included in the semiconductor device.
2. Background Art
Recently, attention has been paid to technology of composing a thin film transistor (TFT) using a semiconductor thin film (the thickness of about several to several hundreds nm) formed on a substrate having an insulating surface. The thin film transistor is widely applied to electronic devices such as IC, an electrooptical device, or the like. Especially, the development of the thin film transistor as a switching element for an image display apparatus has been quickened.
A variety of applications of such an image display apparatus have been expected, above all, utilization of the image display apparatus for mobile devices draws attention. Although a glass substrate, a quartz substrate, or the like is used in many image display apparatuses at present, it has disadvantages that they are easy to crack and heavy. Further, the glass substrate, the quartz substrate, or the like is unsuitable for mass production since it is difficult to be enlarged. Therefore, a TFT device has been attempted to be formed over a substrate having flexibility as typified by a flexible plastic film.
However, since the heat resistance of the plastic film is low, the highest temperature during process is required to be low, consequently, it is impossible at present to form the TFT that has high electric characteristics compared with the one being formed over a glass substrate. Hence, no high-performance liquid crystal display apparatus and light-emitting device using a plastic film has been realized.
If a light-emitting apparatus or a liquid crystal display device in which organic light-emitting device (OLED) is formed on a flexible substrate such as a plastic film or the like can be manufactured, the light-emitting apparatus or the liquid crystal display apparatus can be manufactured to have a thin thickness and light-weight and applied to a curved surface display, a show window, or the like. Thus, its utilization is not limited to a cellular phone and its application range is extremely wide.
However, in general, a substrate formed of plastic penetrates easily moisture or oxygen. An organic light-emitting layer is deteriorated due to these impurities, so that lifetime of a light-emitting apparatus becomes reduced. Therefore, moisture or oxygen is prevented from penetrating into the organic light-emitting layer by interposing an insulating film such as a silicon nitride, silicon oxynitride, or the like between the plastic substrate and an organic light-emitting device conventionally.
In addition, a substrate such as plastic films or the like is weak against heat generally. In case of increasing the deposition temperature for an insulating film such as silicon nitride, silicon nitroxide, or the like, a substrate becomes easily deformed. Further, too low deposition temperature causes decline in quality of the film and difficulty of preventing penetration of moisture or oxygen into a light-emitting device. There is also a problem of deforming and deterioration of a part of a substrate due to localized heat generation during driving of the device that is formed over a substrate such as plastic films or the like. | {
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Increases in network speeds combined with the benefits associated with viewing content from one's own home have resulted in the growing popularity of consuming content over a network. For example, a customer may watch a movie at home, without having to drive to a video rental store. In addition, the customer may avoid being inconvenienced by having to watch the movie at a pre-scheduled time (e.g., during a live television broadcast or according to play times at a movie theater). The ability to watch content over a network at a desired time provides flexibility to the customer's schedule. Furthermore, the customer may select from a wide variety of content based on individual preference and/or mood. For example, the customer may select from movies, television series, instructional videos, video logs to name just a few. In addition, the ability to watch content on a wide variety of devices (e.g., desktop computers, laptop computers, televisions, cell phones, gaming systems, tablet computers) may provide the additional convenience of watching the content in a variety of places (e.g., a coffee place, bookstore, or mall).
In addition to having access to a variety of content, consuming content over a network may allow the customer to take advantage of navigational features that may be available when viewing content over a network. For example, a customer may preview a segment of a movie via still image frames without having to skip to the actual segment of the movie. For instance, the customer may have access to a navigation preview that may display still content images captured from the movie when the navigation preview is activated by the customer. The content images may be associated with segments of the movie so that if the customer selects the content image from the navigation preview, then the movie play point may be repositioned to the segment selected by the customer. | {
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1. Field of the Invention
The present invention relates to a method and a system for depositing a private key used in an RSA (Rivest Shamir Adleman) cryptosystem, where a private key of a client user is deposited to a reliable organization such as a key management server, and a key to be deposited is changed, for the purpose of providing a security service such as a user authentication or a secret communication using the RSA cryptosystem between a client and a server in a computer network environment of a client-server system.
2. Description of the Background Art
In recent years, in conjunction with a down-sizing of computers and a spread of Internet, many activities have been undertaken in relation to a security in an open computer network environment. For example, the PEM (Privacy Enhanced Mail) has been standardized by the IETF as the first encrypted mail standard which incorporates cryptographic descriptions in Internet, and a specification in a form of RFC (Request For Comments) is currently issued.
In order to realize a safe communication in such a network, it is indispensable to establish a privacy of communication data and an authenticity of a user based a user authentication. The privacy and the authenticity can be realized by utilizing the cryptographic technique.
For instance, the public key cryptosystem is a cryptographic scheme in which a key for encryption (an encryption key) and a key for decryption (a decryption key) are set to be different from each other so as to make it difficult to guess the decryption key from the encryption key. Each user utilizing the public key cryptosystem has individually assigned encryption key and decryption key, and when a sender sends a message to a receiver, the sender encrypts the message by using the publicly disclosed encryption key of the receiver, and the receiver decrypts the received message by using his own decryption key, so as to realize a communication with a sufficient privacy. Also, by reversing an order of the encryption and the decryption, only a person who owns the decryption key (private key) can attach a digital signature to a message, and anyone who knows that person's encryption key (public key) can verify the digital signature of that person.
One of the most widely known examples of the public key cryptosystem is the RSA cryptosystem (see, R. L. Rivest, A. Shamir and L. Adleman: "A Method for Obtaining Digital Signatures and Public-key Cryptosystems", Communications of the ACM, Vol. 21(2), pp. 120-126, February 1978).
However, in a conventional method for realizing a safe communication by utilizing the cryptographic technique as described above, the private key which is unique to each user must be managed safely, and to this end, there are some known schemes including the following.
One scheme is to maintain the private key in a storage medium having a cryptographic processing function such as a smart card, so as to make it hard to take out the key from an external of the card, and to adopt a highly safe measure of outputting only cryptographically processed data obtained from entered input data by using the private key maintained inside the card.
Another scheme is to maintain the private key in an encrypted form obtained by using a key decryption key generated according to a password phrase of a user, where a legitimate user who knows the password can acquire the private key whenever necessary by entering the password, in response to which the same key decryption key is generated again and the encrypted private key is decrypted by using the generated key decryption key. This latter scheme is specified in the PKCS ("Private-Key Information Syntax Standard", Version 1.2, RSA Data Security Inc., November 1993) which is proposed by the RSA Laboratories as a standard implementation in a case of utilizing the public key cryptographic technique.
However, in the former scheme, there is a problem that it is necessary for a user to always carry around the private key as maintained in the storage medium such as a smart card. Also, in the latter scheme, there is a problem that it is possible to pretend the legitimate user by carrying out the cryptanalysis on the encrypted private key.
On the other hand, it is also possible to improve the safety by setting a period for updating the key shorter, but in the public key cryptosystem such as the RSA cryptosystem it is possible to commit an illegal conduct by generating an unauthorized key pair and pretending the other person. For this reason, in order to guarantee the relation between a user and his public key, a public key certificate which is signed by the private key of either a reliable third party organization or another trustworthy user will be issued normally. In a case of carrying out the mutual authentication between users, the public key certificate of the correspondent user is verified by using the public key of that third party organization or another trustworthy user, and his public key is used only after the correctness of the correspondent user's name and public key is confirmed.
However, at a time of the key updating, the public key is also changed when the private key is changed, so that there is a need to modify the public key certificate that has already been issued and publicly disclosed to many users, every time the key updating takes place, and therefore there is a problem that the key management becomes quite tedious. | {
"pile_set_name": "USPTO Backgrounds"
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1. Field of the Invention
The invention is related generally to the field of electromagnetic induction resistivity well logging instruments wherein the induction antennas are oriented transversely with respect to the longitudinal axis of the instrument. More specifically, the invention is related to an apparatus for transverse electromagnetic induction resistivity well logging operating in the frequency and/or time domain with reduced errors introduced into the acquired logging data.
2. Description of the Related Art
Electromagnetic induction resistivity well logging instruments are well known in the art. Electromagnetic induction resistivity well logging instruments are used to determine the electrical conductivity, and its converse, resistivity, of earth formations penetrated by a borehole. Formation conductivity has been determined based on results of measuring the magnetic field of eddy currents that the instrument induces in the formation adjoining the borehole. The electrical conductivity is used for, among other reasons, inferring the fluid content of the earth formations. Typically, lower conductivity (higher resistivity) is associated with hydrocarbon-bearing earth formations. The physical principles of electromagnetic induction well logging are well described, for example, in, J. H. Moran and K. S. Kunz, Basic Theory of Induction Logging and Application to Study of Two-Coil Sondes, Geophysics, vol. 27, No. 6, part 1, pp. 829-858, Society of Exploration Geophysicists, December 1962. Many improvements and modifications to electromagnetic induction resistivity instruments described in the Moran and Kunz reference, supra, have been devised, some of which are described, for example, in U.S. Pat. No. 4,837,517 issued to Barber, in U.S. Pat. No. 5,157,605 issued to Chandler et al and in U.S. Pat. No. 5,600,246 issued to Fanini et al.
The conventional geophysical induction resistivity well logging tool is a probe suitable for lowering into the borehole and it comprises a sensor section containing a transmitter and receiver and other, primarily electrical, equipment for measuring data to infer the physical parameters that characterize the formation. The sensor section, or mandrel, comprises induction transmitters and receivers positioned along the instrument axis, arranged in the order according to particular instrument or tool specifications and oriented parallel with the borehole axis. The electrical equipment generates an electrical voltage to be further applied to a transmitter induction coil, conditions signals coming from receiver induction coils, processes the acquired information, stores or by means of telemetry sending the data to the earth surface through a wire line cable used to lower the tool into the borehole.
In general, when using a conventional induction logging tool with transmitters and receivers (induction coils) oriented only along the borehole axis, the hydrocarbon-bearing zones are difficult to detect when they occur in multi-layered or laminated reservoirs. These reservoirs usually consist of thin alternating layers of shale and sand and, oftentimes, the layers are so thin that due to the insufficient resolution of the conventional logging tool they cannot be detected individually. In this case the average conductivity of the formation is evaluated.
Conventional induction well logging techniques employ coils wound on an insulating mandrel. One or more transmitter coils are energized by an alternating current. The oscillating magnetic field produced by this arrangement results in the induction of currents in the formations which are nearly proportional to the conductivity of the formations. These currents, in turn, contribute to the voltage induced in one or more receiver coils. By selecting only the voltage component which is in phase with the transmitter current, a signal is obtained that is approximately proportional to the formation conductivity. In conventional induction logging apparatus, the basic transmitter coil and receiver coil has axes which are aligned with the longitudinal axis of the well logging device. (For simplicity of explanation, it will be assumed that the bore hole axis is aligned with the axis of the logging device, and that these are both in the vertical direction. Also single coils will subsequently be referred to without regard for focusing coils or the like.) This arrangement tends to induce secondary current loops in the formations that are concentric with the vertically oriented transmitting and receiving coils. The resultant conductivity measurements are indicative of the horizontal conductivity (or resistivity) of the surrounding formations. There are, however, various formations encountered in well logging which have a conductivity that is anisotropic. Anisotropy results from the manner in which formation beds were deposited by nature. For example, xe2x80x9cuniaxial anisotropyxe2x80x9d is characterized by a difference between the horizontal conductivity, in a plane parallel to the bedding plane, and the vertical conductivity, in a direction perpendicular to the bedding plane. When there is no bedding dip, horizontal resistivity can be considered to be in the plane perpendicular to the bore hole, and the vertical resistivity in the direction parallel to the bore hole. Conventional induction logging devices, which tend to be sensitive only to the horizontal conductivity of the formations, do not provide a measure of vertical conductivity or of anisotropy. Techniques have been developed to determine formation anisotropy. See, e.g. U.S. Pat. No. 4,302,722. Transverse anisotrophy often occurs such that variations in resistivity occur in the azimuthal direction. Techniques for addressing such full anisotropy are discussed in WO 98/00733.
Thus, in a vertical borehole, a conventional induction logging tool with transmitters and receivers (induction coils) oriented only along the borehole axis responds to the average horizontal conductivity that combines the conductivity of both sand and shale. These average readings are usually dominated by the relatively higher conductivity of the shale layers and exhibit reduced sensitivity to the lower conductivity sand layers where hydrocarbon reserves are produced. To address this problem, loggers have turned to using transverse induction logging tools having magnetic transmitters and receivers (induction coils) oriented transversely with respect to the tool longitudinal axis. Such instruments for transverse induction well logging has been described in PCT Patent publication WO 98/00733 by Bear et al. and U.S. Pat. No. 5,452,761 by Beard et al.; U.S. Pat. No. 5,999,883 by Gupta et al.; and 5,781,436 by Forgang et al.
In the transverse induction logging tools the response of transversal coil arrays is also determined by an average conductivity, however, the relatively lower conductivity of hydrocarbon-bearing sand layers dominates in this estimation. In general, the volume of shale/sand in the formation can be determined from gamma-ray or nuclear well logging measurements. Then a combination of the conventional induction logging tool with transmitters and receivers oriented along the well axis and the transversal induction logging tool can be used for determining the conductivity of individual shale and sand layers.
One, if not the main, difficulties in interpreting the data acquired by a transversal induction logging tool is associated with vulnerability of its response to borehole conditions. Among these conditions is the presence of a conductive well fluid as well as wellbore fluid invasion effects. A known method for reducing these unwanted impacts on the transversal induction logging tool response was disclosed in L. A. Tabarovsky and M. I. Epov, Geometric and Frequency Focusing in Exploration of Anisotropic Seams, Nauka, USSR Academy of Science, Siberian Division, Novosibirsk, pp. 67-129 (1972) and L. A. Tabarovsky and M. I. Epov, Radial Characteristics Of Induction Focusing Probes With Transverse Detectors In An Anisotropic Medium, Soviet Geology And Geophysics, 20 (1979), pp. 81-90.
The known method has used a transversal induction logging tool comprising a magnetic transmitter and receiver (induction coils). By irradiating a magnetic field the induction transmitter induces currents in the formation adjoining the borehole; in turn, the receivers measure a responding magnetic field due to these currents. To enable a wide range of vertical resolution and effective suppression of the unwanted borehole effects, measurements of magnetic field from the formation can be obtained with different transmitter and receiver spacings that facititate geometric focusing and different frequencies to facilitate frequency focusing. See, for example U.S. Pat. No. 5,703,772 by Beard. However, even with these modifications, the data logs obtained with a conventional transversal induction logging instrument can be difficult to interpret, that has been exacerbated while logging through a sequence of layers.
In the induction logging instruments the acquired data quality depends on the formation electromagnetic parameter distribution (conductivity) in which the tool induction receivers operate. Thus, in the ideal case, the logging tool measures magnetic signals induced by eddy currents flowing in the formation. Variations in the magnitude and phase of the eddy currents occurring in response to variations in the formation conductivity are reflected as respective variations in the output voltage of receivers. In the conventional induction instruments these receiver induction coil voltages are conditioned and then processed using analog phase sensitive detectors or digitized by digital to analog converters and then processed with signal processing algorithms. The processing allows for determining both receiver voltage amplitude and phase with respect to the induction transmitter current or magnetic field waveform. It has been found convenient for further uphole geophysical interpretation to deliver the processed receiver signal as a vector combination of two voltage components: one being in-phase with transmitter waveform and another out-of-phase, quadrature component. Theoretically, the in-phase coil voltage component amplitude is the more sensitive and noise-free indicator of the formation conductivity.
There are a few hardware margins and software limitations that impact a conventional transversal induction logging tool performance and result in errors appearing in the acquired data.
The general hardware problem is typically associated with an unavoidable electrical field that is irradiated by the tool induction transmitter simultaneously with the desirable magnetic field, and it happens in agreement with Maxwell""s equations for the time varying field. The transmitter electrical field interacts with remaining modules of the induction logging tool and with the formation; however, this interaction does not produce any useful information. Indeed, due to the always-existing possibility for this field to be coupled directly into the receiver part of the sensor section through parasitic displacement currents, it introduces the noise. When this coupling occurs, the electrical field develops undesirable electrical potentials at the input of the receiver signal conditioning, primarily across the induction coil receiver, and this voltage becomes an additive noise component to the signal of interest introducing a systematic error to the measurements.
The problem could become even more severe if the induction logging tool operates in wells containing water-based fluids. The water-based mud has a significantly higher electrical permittivity compared to the air or to the oil-based fluid. In the same time, the electrical impedance to the above mentioned displacement currents can be always considered as capacitive coupling between the sourcexe2x80x94the induction transmitter and the point of coupling. This circumstance apparently would result in a fact that capacitive coupling and associated systematic errors are environment dependant because capacitive impedance will be converse to the well mud permittivity.
The conventional method in reducing this capacitive coupling in the induction logging instrument lays in using special electrical (Faraday) shields wrapped around both transmitter and receiver induction coils. These shields are electrically attached to the transmitter analog ground common point to fix their own electrical potential and to provide returns of the displacement currents back to their sourcexe2x80x94transmitter instead of coupling to any other place in the tool. However, geometry and layout effectiveness of Faraday shields becomes marginal and contradictory in the high frequency applications where conventional transverse induction tools can operate. These limitations occur due to the attenuation these shields introduce to the magnetic field known in the art as a shield xe2x80x9cskin effectxe2x80x9d. The shield design limitations are unavoidable and, therefore, the possibility for the coupling through displacement currents remains.
Another source of hardware errors introduced into the acquired log data is associated electrical potential difference between different tool conductive parts and, in particular, between transmitter and receiver pressure housings if these modules are spaced apart or galvanically separated. These housings cover respective electronic modules and protect them from exposure to the harsh well environment including high pressure and drilling fluids. Typically, the pressure housing has a solid electrical connection to the common point of the electronic module it covers, however, design options with xe2x80x9cgalvanicallyxe2x80x9d floating housings also exist. If for some reasons, mainlyxe2x80x94imperfections in conventional induction toolsxe2x80x94the common points of different electronic modules have an electrical potential difference between them, this difference will appear on the pressure housings. It may occur even in a design with xe2x80x9cgalvanicallyxe2x80x9d floating housings if the instrument operates at the high frequencies and, in particular, through the capacitive coupling that these metal parts might have to the electronic modules encapsulated in a conductive metallic package.
Having different electrical potentials on separate pressure housings will force the electrical current to flow between them. This current would have a conductive nature and high magnitude if the induction tool is immersed in a conductive well fluid and it will be a displacement current of typically much less magnitude for tool operations in a less conductive or oil-based mud. In both cases this current is time varying, therefore, it produces an associated time varying magnetic field that is environmentally dependent and measured by the induction receiver. For those who are skilled in the art it should be understood that the undesirable influence of those currents on the log data would be significantly higher in the conventional transverse induction tool compared to the instruments having induction coils coaxial with the tool longitudinal axis only. In particular, this is due to the commonly accepted overall design geometry of induction logging tools where transmitter and receiver sections are axially separated by the mandrel. It can be noticed that employing the induction tool in the logging string where it has mechanical and electrical connections (including telemetry) with instruments positioned both above and below could also result in the appearance of the above-mentioned currents.
Another source of the housings"" potential offsets is the induction tool transmitter itself. The remaining electrical field that this transmitter irradiates simultaneously with a magnetic field could be different on the surface of separate pressure housings. Severity of this error also depends on Faraday shields"" imperfections as described earlier.
There is an additional problem that the potential difference creates in conventional tool layouts having transmitter and receiver electronic modules spaced apart and using interconnection wires running throughout the sensor (mandrel) section. These wires should be electrically and magnetically shielded from induction receiver coils in the sensor section. The entire bundle of wires is placed inside of a highly conductive metal shield that is electrically connected to the common points of separated transmitter and receiver electronic modules. This shield""s thickness is selected to enable sufficient suppression of mutual crosstalk between wires and sensor section coils within the entire operational frequency bandwidth and, primarily, at its lower end. In some cases, this shield is a hollow copper pipe with a relatively thick wall.
However, besides protecting the sensor section transmitter and receiver coils and interconnecting wires from mutual crosstalk, this shield simultaneously creates a galvanic path for the currents that could be driven by pressure housings and/or electronic potential difference. This path apparently exists along the shield""s external surface. The time varying currents also generate a respective magnetic field that crosses induction receiver coils and induces error voltages. Unfortunately, these error voltages are also environmentally dependent and their changes cannot be sufficiently calibrated out during tool manufacturing. The overall analysis of the potential difference influence demonstrates that in the conductive well fluid, galvanic currents flowing through the fluid along external surface of the induction tool would dominate and, decreasing fluid conductivity redirects these currents to flow along the internal connection between housings. The superposition and magnitude of these galvanic currents strongly depend up on the ambient temperature that pushes the conventional induction tool performance to further deterioration.
Another source of systematic errors introduced in the log data is directly determined by uncertainties in mechanical dimensions of multi-component transmitter and receiver coils in the sensor section related both to their overall dimensions and positions with respect to each other. Thus, to keep required signal phase relationships, conventional tool designs have relied on the mechanical stability and electrical properties of advanced ceramics and plastic materials to build the mandrel. However, even slight physical assembly deviations in the coil wires position and non-uniform coil form material temperature dependencies might destroy a factory pre-set bucking (compensation of the transmitter primary magnetic field coupled in the receiver coil) during well logging, and create non-recoverable errors due to mechanical displacement or imperfections.
Another limitation found in certain induction instrumentation systems is that an insufficient number of signal samples that are gathered for appropriate data stacking. Such data insufficiency occurs due to the necessary measurement xe2x80x9cidle timexe2x80x9d required for sequentially changing the operational transmitter frequency in a switched frequency tool. It can be demonstrated that by simply switching the transmitter frequency from one frequency to another requires a finite amount of decay time for spurious transient transmitter electronic signals to decay to a sufficiently low level to obtain accurate data measurements. If during this xe2x80x9cidle timexe2x80x9d the tool continues to take samples or measurements, these measurements will be inaccurate and essentially useless. Therefore, prior receiver designs have provided for xe2x80x9cidle timexe2x80x9d windows in the measurements during transient decay time, thereby potentially stacking a relatively small and possibly insufficient number of data samples. A better instrumentation design would drastically reduce required idle time. Each of the above-mentioned problems, by itself or a combination with another problem adds to the data error, thereby decreasing the accuracy of the induction downhole tool samples and measurements. Finally, as discussed in the U.S. Pat. No. 3,124,742 by Schneider, galvanic electrodes used in conjunction with induction coils are useful, however, subject to the above mentioned problems.
It is an object of the present invention to advance the performance of wellbore induction logging tools operating in the frequency and/or time domain. The present invention improves measurement of the formation induction response in the presence of the primary magnetic field generated by a logging tool""s transmitter. In a preferred embodiment of the present invention, a structure is provided having a new combination of electrical and mechanical design features which provide structure for high thermal stability coil forms for the tool""s induction transmitter and receiver magnetic antenna coils, thereby improving the temperature stability of the antenna coil. The present invention also provides a single coil verification transmitter for in situ verification of the real and phase-shifted quadrature components of data collected by the tool during operation. It is another object of the present invention to provide the tool sensor assembly structure that exhibits improved symmetry in the transmitter and receiver wiring, shielding and input circuitry to minimize systematic errors due to capacitive coupling of electrical field induced by the logging tool""s transmitter signal into the tool""s receiver circuitry.
It is another object of the present invention to provide electrical grounding and isolation to the receiver and electrically isolate the receiver electronics from the mandrel or housing, or alternatively, provide electrical grounding to the transmitter and let the receiver electronics electrically float to reduce errors caused by potential differences between galvanically separated receiver and transmitter housings in a logging tool. The present invention decreases the influence of electrical field errors by providing floating electronics driving transmitter coils and high-speed differential amplifiers in the receiver signal conditioning circuitry. Employing this combination enables a high rejection of the parasitic signal introduced as the common mode voltage at the receiver input. It is another object of the present invention to provide a sweep oscillator to obtain the primary transmitter magnetic field waveforms for continuous formation response sampling necessary rate sufficient for appropriate data stacking.
In one aspect of the invention, a logging tool is provided for measuring the properties of a geological formation adjacent to a borehole comprising a transmitter comprising at least one coil for inducing eddy currents in the formation; a receiver comprising at least one coil; and an analog ground connection to at least one of the transmitter, and, the receiver for reducing a galvanic current flow between the transmitter and the receiver. In another aspect of the invention a logging tool is provided further comprising an insulator for insulating the receiver from electrical contact with the housing and thus the bore hole. In another aspect of the invention a logging tool is provided further comprising insulating material adjoining the receiver. In another aspect of the invention a logging tool is provided further comprising a feed through pipe having an insulator between the feed through pipe and the receiver. In another aspect of the invention a logging tool is provided further comprising an analog ground connection isolated from a housing for at least one of the transmitter, and, the receiver. In another aspect of the invention a logging tool is provided further comprising an oscillator having a transmitted signal frequency swept over a frequency range. In another aspect of the invention a logging tool is provided further comprising a split-coil transmitter having bucking coil interposed between the split transmitter coils. In another aspect of the invention a logging tool is provided further comprising a split-coil transmitter comprising symmetrical coils. In another aspect of the invention a logging tool is provided further comprising a split-coil transmitter symmetrical shield. In another aspect of the invention a logging tool is provided further comprising a bucking coil shield. In another aspect of the invention a logging tool is provided further comprising a verification winding for coupling a verification signal into the receiver coil. In another aspect of the invention a logging tool is provided further comprising a controllable phase shifting element in the verification check winding to couple a controllable phase shifted and or quadrature verification signal into the receiver coil. In another aspect of the present invention a galvanic electrode and current source are housed in the same mandrel with the induction receiver and transmitter for complementary formation resistivity measurement and interpretation. | {
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Respiration monitoring is useful in diagnosing and managing pathological conditions. Respiratory rates can be measured and respiratory effort can be observed during clinical office visits but potentially important changes that occur outside of the clinical setting cannot be observed. Heart failure patients can experience dyspnea (labored breathing) upon exertion. As heart failure worsens, dyspnea can occur at relatively low levels of exertion, at rest and during certain postures. Heart failure patients can also experience disrupted breathing patterns such as Cheyne-Stokes breathing and sleep apnea. Episodes of disrupted breathing patterns are not easily captured during clinical office visits. Ambulatory monitoring of respiration is desirable for capturing useful diagnostic data and tracking a patient's disease state. Implantable devices used for chronic monitoring of patients are generally minimized in size to avoid patient discomfort. It is desirable to include respiration monitoring capabilities in an implantable monitoring device without substantially adding to the overall size and complexity of the device. | {
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Conventional content addressable memory (CAM) has been implemented primarily using static random access memory (SRAM) cells. SRAM-based CAMs have received widespread use due to the high access speed of SRAM memory cells and the static nature of the cells. Furthermore, SRAM cells can be manufactured using a pure-logic type fabrication process, which is commonly used for non-memory circuit blocks.
In addition to random access memory (RAM) functions, such as writing and reading data, CAMs are also capable of performing searches. Generally, stored data is retrieved and compared with target data for determining if the stored and target data match. If the stored and target data do match, a match result is indicated, otherwise a mismatch result is indicated. Thus, CAMs are particularly useful for fully associative memories such as look-up tables and memory-management units.
Many current applications utilize ternary CAMs, which are capable of storing three logic states. For example, the three logic states are logic ‘0’, logic ‘1’ and ‘don't care’. Therefore, such CAM cells require two memory cells to store the logic states, as well as a comparison circuit for comparing stored data with search data provided to the CAM.
However, various problems exist with semiconductor memories and, thus, affect CAMs as well. One such type of error, referred to as “soft errors”, are a well-known problem. The major cause of soft errors is alpha particle radiation, which can generate numerous electron hole pairs when it strikes a transistor diffusion area. These electron hole pairs can flip the state of data stored in a semiconductor memory cell. Clearly this is an undesirable occurrence. It is often important to detect that such an error has occurred and correct it if possible.
Error detection and correction has been attempted previously by using Hamming codes. Hamming codes typically require 5 extra bits per 32 bits or 7 extra bits per 64 bits, resulting in a data storage overhead of 15.6% or 10.9% respectively. Hamming codes in CAMs typically require 8 extra bits per 72 bits, for a data storage overhead of 11.1%. Evaluating the Hamming code also requires additional logic cycles and, thus, it can be time consuming to detect an error.
Alternately, it is possible to use parity bits. Generally, a parity bit is a bit that is appended to a word for representing the number of bits in the word that have a value ‘1’. In an example of odd parity, if the number of bits that are a ‘1’ is even, then the parity bit is ‘1’. If the number of bits that are ‘1’ is odd, then the parity bit is ‘0’. The concept of parity bits in general is well known in the art and need not be described in greater detail.
The concept of using horizontal and vertical parity in a semiconductor memory is described in U.S. Pat. Nos. 4,456,980 and 4,747,080 issued to Yamada et al. Generally, however, the method described by Yamada requires complex circuitry and many wide buses to implement. However the requirement for many wide buses renders this idea impractical as the area consumed to route so many signals makes the design cost prohibitive to manufacture.
In addition, reference may be made to the following patents and publications. U.S. Pat. No. 6,353,910 (Carnevale) discloses the storing ECC data within the array and exemplifies the complexity of non-parity based systems. U.S. Pat. No. 5,127,014 (Raynham) discloses the addition of ECC to a DRAM memory and the scrubbing of errors during a refresh cycle. The ECC data adds significant overhead. U.S. Pat. Nos. 4,456,980 and 4,747,080 (see above) introduce the XY parity concept in a semiconductor memory. However they require significant wide bussing and are not practical. U.S. Pat. No. 4,183,463 (Kemmetmueller) discloses a two-dimensional parity scheme. U.S. Pat. No. 6,125,466 (Close) discloses two-dimensional parity in a subset of the array. U.S. Pat. No. 5,134,616 (Barth) discloses a memory with hamming codes at the end of the wordline. It adds redundancy. U.S. Pat. Nos. 4,688,219 and 4,768,193 (Takemae) disclose another two-dimensional parity scheme with very complex bussing. Finally, in a paper by Pinaki Mazumder (Pinaki Mazumder, “An On-Chip ECC Circuit for Correcting Soft Errors in DRAM's with Trench Capacitors”, IEEE JSSC, Vol. 27, No. 11, November 1992), a horizontal, vertical and diagonal parity scheme is disclosed with all the parity bits stored on the same word line. However, this paper does not disclose true horizontal and vertical parity in space, as all parity bits are stored on the same wordline.
A need, therefore, exists for an improved circuit and method for error detection and correction in CAMs. Consequently, it is an object of the present invention to obviate or mitigate at least some of the above mentioned disadvantages. | {
"pile_set_name": "USPTO Backgrounds"
} |
The present invention relates to a two-part interlocking handle assembly that enables the user to quickly attach or detach flexible handle straps, such as those common on soft-sided luggage and sport bags. The handle assembly provides strain relief while carrying the bag by distributing the load more evenly and comfortably across the fingers and palm of the hand. The handle assembly's quick detach feature provides easy access to the bag's main opening that is between the handle straps.
Previous interlocking handles have been designed, such as that described in U.S. Pat. No. 5,210,904 to Pratt. The Pratt handle, having a cradle design, involves two interlocking pieces where one piece fits almost entirely in a recessed channel in the second piece. Thus, to interlock the pieces of the Pratt handle when carrying a bag, a user must raise one piece above the other to get it into the recessed channel. Another disadvantage of the Pratt handle is that it requires two different molds to manufacture the two different-shaped handle pieces.
The present invention, in contrast, allows the user to interlock the pieces at the same height. Additionally, the handle pieces can be manufactured from the same mold, making the handle assembly more economical to produce. | {
"pile_set_name": "USPTO Backgrounds"
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Many portable computing devices are capable of wireless connection to a computer network, such as the Internet, a local network, a corporate network and others. As a result, these devices do not require any wired connections to carry out their functions (e.g., email, web browsing, etc.). Batteries, particularly rechargeable batteries, are commonly used to power the devices, since they provide complete freedom of movement to the users of these devices. Alternatively, power adapters may be used to power the devices using electrical sockets. However, this approach requires tethering the devices to a stationary power supply with cords, reducing portability and usefulness.
These devices typically include a user-viewable screen which includes a battery status display that provides the user with an estimation of a remaining life of the battery. The remaining battery life is based on a battery capacity which is calculated by using a coulomb-counting system (“CCS”) which measures a current flow into and out of the battery and integrates the current flow over time. The battery capacity is calculated and recorded by electronics disposed within a battery pack. Over time, however, the calculation introduces an error which may get so large that performance of the device is adversely affected (e.g., reduction in battery life, data loss, memory corruption, etc.). Thus, the calculation may need to be calibrated at a regular interval. However, the calibration is typically performed only when the battery reaches a threshold state (e.g., full charge and then full discharge). Thus, the user has the burden of ensuring that the battery reaches the threshold state so that the CCS may be re-calibrated.
The batteries used in these devices are typically composed of a natural substance (e.g., Li-ion, Li-polymer, NiCad, NiMh). Over time, the natural substance will age and breakdown chemically, thereby reducing effective capacity of the battery. Without performing the calibration at regular intervals, the device typically does not account for this aging and the chemical breakdown that occurs therewith. Thus, the device may inaccurately display the remaining battery life to the user. | {
"pile_set_name": "USPTO Backgrounds"
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An endotracheal tube (ETT) is often used in the medical profession to provide a direct pathway for air, oxygen, or other such gases into a patient's lungs. The ETT is inserted through a patients mouth and is positioned in the trachea a certain distance. As a result, a patient's lungs can be supplied with gas from a ventilator. Moreover, an ETT is often necessary when a patient is not spontaneously breathing in order to properly move gas into the lungs.
Upon insertion, an ETT will likely not stay in position due to various intervening factors. Such factors include back pressure from the ETT and the lungs which tends to expel the ETT. Another frequent occurrence is patient movements which tends to move or dislodge the ETT from its optimum position. If the ETT becomes dislodged, the patient's life can be endangered due to the lack of gas being supplied to the patient.
Accordingly, a number of devices have been developed which serve to hold an ETT in position. U.S. Pat. Nos. 3,927,676; 5,306,233; 5,448,985; 5,490,504 and 5,501,216 each disclose devices for securing an endotracheal tube. However, each of these devices uses a strap which wraps around the patient's head or neck. Such straps can be hard to install and are uncomfortable for the patient.
U.S. Pat. No. 3,924,636 discloses an ETT holder which attaches to the patient's face via a facial strip with a central opening. This strip encompasses the patient's entire mouth. A tube-attaching strap is used to wrap around the ETT and is permanently attached to the bottom of a tube support. The tube support, however, is narrow-based and thereby does not adequately distribute stresses across the facial strip. The facial strip also encompasses the patient's mouth, a feature that will likely cause discomfort to the patient. Further, the permanent tube-attachment strap allows little relative movement of the inserted ETT against the tube support which can also cause further patient discomfort. U.S. Pat. No. 4,683,882 also discloses an ETT holder which poses similar problems having an adhesive facial attachment strip and a permanently attached C-clamp or notched strap clamp for attaching the ETT.
Still other types of attachments include U.S. Pat. No. 4,460,356, which disclose a pre-cut anchor tape with an upper and lower portion for securing an intravenous catheter to the arm of a person. The tape strip is adhered to the person along an upper portion, and a lower portion wrapped around a catheter running over the tape. U.S. Pat. No. 5,308,339 discloses a universal clamp for holding an article to an object. The clamp includes a base strip which is secured to an object and a releasably attached flap is placed over the article to hold it to the base strip.
Accordingly, the known prior art does not disclose an easy to use ETT holder which will securely and yet comfortably hold an ETT inserted into the patient. What is needed in the field is an ETT holder which securely attaches to the patient's face, yet minimizes contact area and related discomfort for the patient. Also a device is needed with a wider-based support structure for attaching the ETT, thereby more adequately distributing motion stresses across the holder. The device provides firm securement of the ETT inside the patient, allows for patient movement, is comfort to the patient, and allows for quick detachment of the ETT for repositioning if necessary. | {
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1. Field of the Invention
The present invention relates to a power supply unit which receives an AC power supply and supplies an output of a self-contained power transformer as a power source.
2. Description of the Prior Art
In a power supply unit which receives an AC power supply as an input source or an electronic apparatus which incorporates such a power supply unit, at least a power switch and a power transformer are contained therein and those parts are usually connected through electric wires.
FIG. 1 shows a prior art power supply unit which is designed to meet a North American Safety Standard. A plug receptacle 2, a power switch 3 and a transformer 4 are fixed on a chassis 1 of an electronic apparatus. A plug 6 which is one end of a power supply cord having the other end thereof connected to an AC power supply is plugged in and out to and from the plug receptacle 2. Numeral 7 denotes a filtering capacitor. One wire 8 of at least two wires connected to the plug receptacle 2 is connected to the transformer 4 and the other wire 9 is connected to one terminal of the power switch 3, and a wire 10 connected to the other terminal of the power switch 3 is connected to the transformer 4 so that the AC power is supplied to the transformer 4 and the power switch 3. The transformer 4 is connected to a printed circuit board 11 fixed to the chassis 1 through a wire 12, and the capacitor 7 is also connected to the printed circuit board 11 through a wire 13.
In the illustrated example, the wires 8, 9 and 10 are double insulated wires in order to meet the North American Safety Standard, and those wires must be covered by tubes 14, 15 and 16 in order to assure safety of those portions which might contact a metal part, that is, the transformer 4.
Tubes 17 and 18 are required to fix and prevent detachment of soldered portions of the wires 9 and 10 and the power switch 3, and tubes 19 and 20 are required to prevent the wires soldered to the printed circuit board 11 from contacting the metal part of the power transformer when the wires are detached.
Thus, the prior art power supply unit needs many wire connections and the use of double insulated wires for the purpose of safety and the application of the tubes to prevent the movement of the wires is required because a high AC voltage is applied to those wires. Accordingly, a number of parts and a number of assembling steps increase, and hence manufacturing cost increases. | {
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Medical treatments involving ablation of the endometrium of the uterus are well known in the prior art. The endometrium is the portion of the uterine lining to which an embryo normally attaches and is responsible for the menstrual cycles. Such ablation treatments typically involve either the direct or indirect application of heat or cold to the endometrial tissue. Commonly, ablation devices and techniques have been used to treat menorrhagia (a condition of excessive menstrual bleeding) by cauterizing, or inducing necrosis of the endometrial lining. This cauterization prevents further proliferation of the endometrium and may result in permanent relief of menorrhagia symptoms.
Apparatuses for thermal balloon ablation are well known in the prior art. For applications to treat the endometrium of the uterus, thermal balloon ablation apparatuses typically comprise a distensible balloon which is inserted into the uterus through the external opening of the cervix. The balloon is then inflated with a liquid to expand the balloon such that it is in contact with substantially all of the uterine cavity. This liquid is then heated to a controlled temperature by a heating element within the balloon and the liquid is maintained at this temperature for a predetermined period of time. After this period of time has elapsed, the liquid is withdrawn and the balloon removed from the uterus. The heat energy which is transferred from the liquid filled balloon to the surrounding tissues of the uterus causes the desired cauterization of the endometrium. There are many examples of such devices in the prior art, for example those disclosed by Stevens et al—U.S. Pat. No. 5,800,493, and Wallsten et al—U.S. Pat. No. 5,693,080 & U.S. Pat. No. 5,571,153.
Typically the volume of liquid required to inflate the balloon ranges between 5 ml and 30 ml and is dependent on the natural volume of the uterine cavity and the liquid pressure. According to studies published in the medical literature, the liquid pressure should not exceed 180 mmHg applied to the uterine cavity walls above which there is risk of mechanical damage to the deeper tissue of the uterus.
Variations on thermal balloon apparatuses and methodologies include cryogenic apparatuses which use cooled liquid rather than heated liquid to achieve necrosis of the tissue (such as that disclosed by Lafontaine et al—U.S. Pat. No. 5,868,735) and apparatuses in which heated liquid is circulated through the uterus without the benefit of a flexible balloon to contain the liquid (such as that disclosed by Goldrath—U.S. Pat. No. 5,437,629).
A variety of alternatives to thermal balloon ablation are known for cauterization of endometrial tissue. These includes the use of microwave, RF, laser, electrical current or similar energy sources to heat a surgical probe inserted through the cervix and which is manipulated by means of direct hysteroscopic visualization. These devices typically require a highly skilled operator and produce treatment results which are more variable than those which can be achieved through thermal balloon ablation techniques. Such alternative ablation techniques also pose higher risk of perforating the uterus, normally require use of general anesthesia, and have a higher incidence of post-operative complications than thermal balloon ablation techniques.
In spite of the potential advantages of thermal balloon ablation techniques over alternative treatment methodologies, problems with the thermal balloon ablation apparatuses in the prior art have prevented such devices from being adopted widely for use in the treatment of menorrhagia.
Thermal balloon ablation systems in the prior art typically rely on heating elements located within the balloon. During heating, these devices often develop temperature gradients in the liquid which can result in uneven treatment of the endometrial surface. Typically the observed effect is to over-treat the area of the endometrium directly above the heating element and under-treat the area of the endometrium located directly below. This effect is magnified if the heating element within the balloon is inserted at an angle relative to the anterior/posterior plane of the uterus such that after inflation the heating element is located closer to the anterior wall of the balloon. Placement of the heating element relative to the balloon walls is difficult to control in practice. To reduce this problem, some inventions in the prior art include provision of an impeller, reciprocating piston or similar mechanical means to stir the liquid during heating (such as those disclosed by Neuwirth et al—U.S. Pat. No. 5,460,628 and Saadat et al U.S. Pat. No. 5,827,269) or utilize balloons which allow injection and re-circulation of heated liquid via multiple lumens, typically an “intake” lumen and an “exhaust” lumen (such as that disclosed by Lafontaine et al—U.S. Pat. No. 5,868,735). Furthermore, pulsing the liquid pressure is an alternative means to achieve more uniform mixing of the liquid (as described by Wallsten et al U.S. Pat. No. 5,957,962). However, such circulating methodologies add cost and complexity to the apparatus and the ability to achieve desired temperature uniformity depends among other factors on the volume of liquid within the balloon.
Thermal balloon ablation devices in the prior art such as that disclosed by Stevens et al—U.S. Pat. No. 5,800,493 have also relied on the operator to provide the liquid for inflation of the balloon and heating. This has limited the variety of liquids to those typically found in a clinical environment (e.g. D5% W or saline). Such liquids are generally water based and therefore cannot be heated above approximately 100C, at which temperature these solutions begin to boil at sea level. Heating liquid to the boiling point can result in a dangerous increase in balloon volume due to expansion of gas and in uneven treatment since the presence of this gas pockets in the balloon act to thermally insulate the adjacent tissue. The maximum temperature limitation of these liquids has resulted in relatively long treatment times; it is well established in the research and in clinical practice that it requires in approximately 8 minutes to cauterize the endometrium by thermal balloon ablation using liquid temperatures of 85 C. Furthermore, the use of liquid temperatures in the range of 70-90 C makes the use of liquid heating means external to the uterus or balloon ineffective since in this temperature range there is insufficient heat energy contained within the volume of liquid within the uterus to adequately cauterize the endometrium. In devices that employ heating means external to the balloon in the uterus and which use liquid temperatures below 100 C (such as that disclosed by Chin U.S. Pat. No. 5,449,380) it is generally necessary to continuously circulate the liquid between the balloon and the external heating means in order to maintain an elevated liquid temperature within the uterus and to achieve the desired treatment. In addition, devices with heating elements located in the balloon within the uterus prohibit the use high viscosity liquids (such as 100% Glycerin) which resist flow at ambient temperatures but once heated become less viscous and can readily flow through a catheter to inflate a balloon placed in the uterus.
Systems which require the operator to supply the inflation liquid are also complicated for the operator to use. It is necessary for the operator to obtain a source of sterile liquid, inject the liquid into the system, check for leaks, purge gas or excess liquid from the system, and then dispose of the heated liquid after treatment. This process also compromises the sterility of the system since there is potential for non-sterile or contaminated liquid to circulate within the balloon. In the event of a balloon leak or rupture, this non-sterile liquid is released into the uterine cavity and could result in infection.
Devices in the prior art typically rely on mechanical actuators, syringes, or liquid pumps which come into contact with the treatment liquid in order to control inflation and pressurization of the balloon, these can be expensive, unreliable, and subject to contamination. Often these systems require the operator to manually inject liquid to fill the balloon. Furthermore such systems (such as that disclosed by Stevens et a—U.S. Pat. No. 5,800,493) typically have expensive disposable components as these components often include hoses, valves, connectors, electrical wiring, syringes, and heating elements which must be disposed of after each use. Wallsten et al have attempted to address this problem in the invention disclosed in U.S. Pat. No. 5,957,962 in order to provide an inexpensive disposable component however the described system still requires the addition of liquid from an external source, purging of gas from the system and relies on a mechanical apparatus and actuators to inject and remove liquid from the treatment balloon.
Often it is difficult for the operator to control inflation pressure and there is not adequate means to control this pressure in response to changes in uterine volume during treatment (typically the uterus relaxes and expands as treatment progresses and therefore it is desirable to increase the volume of liquid in the balloon to maintain a constant inflation pressure). Wallsten et al U.S. Pat. No. 5,693,080 discloses apparatus intended to allow automated control of inflation pressure through mechanical actuation of syringes or similar means however this is costly and does not allow fine control of pressures. Wallsten et al further disclose a means for providing overpressure relief in the event of a increase in balloon pressure such as that which might be caused by a sudden contraction of the uterus during treatment however this does not provide a practical or inexpensive means for automated control of balloon inflation, deflation, and liquid pressure.
Prior art devices also rely on the operator to sound the depth of the uterus then insert a catheter or treatment element to a depth of no greater than the previously sounded depth. This requires effort on the part of the user to measure depth and observe insertion depth as marked on the treatment device. There is a danger of perforating the uterus by over-inserting the catheter if the clinician does not perform this operation properly.
In providing thermal balloon ablation treatment, it is desirous to: provide uniform cauterization of the endometrial tissue; ensure that any material which can potentially come into contact with the patient is sterile; provide the treatment in as short a period of time as possible; deliver the treatment in a manner which does not depend on the skill level of the operating clinician; and minimize the cost of any disposable components associated with the treatment apparatus. It is further desirable to avoid cauterization of the cervical canal during treatment, and to minimize the risk of perforation of the uterus when the balloon is inserted through the cervical opening or during the treatment period.
Ideally the device should be simple for the operator to use and should require minimal preparation for use by the operating clinician.
Accordingly, the present invention provides an apparatus for causing necrosis of a body cavity or duct, specifically the uterus, said apparatus comprising:
a disposable portion of the apparatus comprising a sealed system consisting of a liquid within said sealed system, an elongated distal section with a flexible balloon (or bladder) attached to it, a proximal flexible balloon (or bladder), and a means for connection to a permanent non-disposable apparatus;
a means for heating said liquid; and
a permanent non-disposable apparatus comprising, a pneumatic pressurizing means for initiating flow of the liquid within said sealed system of the disposable portion of the apparatus, connection means for said disposable portion to permanent portion, and a controlling means for heating, pneumatic pressure, and time.
An object of the invention is to provide an apparatus which furnishes a means for shortened treatment time by incorporating a sealed disposable component containing a volume of liquid provided by the manufacturer. A liquid filled and sealed disposable apparatus provides one advantage as it allows the use of liquids which are not typically encountered in a clinical environment and which can be heated to temperatures in excess of 100 C without boiling (for example 100% Glycerin). This allows improved cauterization of the endometrial lining of the uterus and shortens treatment times from 8 minutes at 85 C to approximately 1.5 minutes at 165 C. Furthermore, by pre-heating the liquid external to the patient, high viscosity liquids (such as 100% Glycerin) can be used which flow readily at higher treatment temperatures. Because of the high viscosity at ambient temperatures, such liquids could not be readily utilized in apparatus where the heating means is located inside the balloon which is inserted into the uterus.
Another object of the invention is to provide a means of ensuring uniform treatment of the uterine cavity. The apparatus achieves the objective by injecting a pre-heated, isothermal volume of liquid into the distal flexible bladder within uterine cavity. Therefore at the time of injection into the uterus, all areas of the uterus are contacted with a uniform high temperature (approximately 165 degrees Celsius) liquid.
Another objective of the apparatus is to provide a low cost, easy to use system, that is safe and effective. The described apparatus provides for improved ease of use and reduced costs by using a disposable component comprising primarily: two flexible enclosures joined by a liquid path and containing a liquid; and a fitting which permits the proximal flexible enclosure to be sealed inside the re-usable pneumatic chamber. By using a sealed system containing a bolus of liquid, the operator simply installs the disposable cartridge and initiates heating. There is no need to source liquid, fill the system, or purge gas from the system. This makes the apparatus much easier to use and improves patient safety by ensuring sterility of the system. Since the liquid is contained in a sealed system and is driven by pneumatic means, in the event of a balloon rupture only sterile liquid can be released into the uterus. The disposable component does not include valves or fluid pumping means and can therefore be manufactured for minimal cost.
A further object of the invention is to automate balloon inflation and control of balloon inflation pressure. The described apparatus provides improved control of balloon inflation pressure by modulating pneumatic pressure within a chamber external to the patient. This pressure can be readily monitored and automatically controlled with a high degree of accuracy to achieve the desired inflation pressure of the distal balloon during the treatment period, adapting quickly to changes in uterine volume due to relaxation or contraction of the associated musculature. By using pneumatic pressure to transfer liquid from the proximal flexible balloon into the distal flexible balloon and withdraw liquid from the distal flexible balloon, the system achieves a high degree of control and reduces user errors.
Yet another object of the invention is to provide a physical means to indicate when the proper depth of insertion of the balloon is achieved. The described apparatus uses a soft rubber flange (“cervical tab”) around the insertion catheter which is larger than the cervical opening. This prevents insertion of the catheter beyond a predetermined depth into the uterus. The apparatus is configured such that when the catheter is inserted until this cervical tab rests against the proximal cervical opening, the associated treatment balloon can deploy to treat the indicated range of uterine sizes and volumes. Before treatment, the operator confirms by examination that the uterine depth and volume fall within this predetermined range, then the operator simply inserts the balloon until the cervical tab rests against the cervix. The operator does not need to change the depth of insertion or manner of use for different patients. As a result, there is minimal risk of perforating the uterus and treatment methodology is greatly simplified for the user.
A further object of the invention is to provide a means of preventing any treatment to the cervical canal. This is achieved by a thermal insulating sheath, which surrounds the liquid delivery catheter. When the treatment balloon and liquid delivery catheter are inserted such that the cervical tab rests against the cervix, the insulating sheath located distal to the cervical tab is precisely positioned within the cervical canal. This sheath has thermal insulating capabilities, which limit the heat transfer between the liquid delivery catheter and the patient's cervix and prevents unwanted treatment of this area. | {
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Purchase planning for direct material requirements largely depends on the master planning systems. Master planning systems generate material requirements by considering demand/forecast for finished goods and exploding the bill of materials to generate projected requirements of raw material and sub-assembly quantities. The master planning systems may consider other factors some examples of which are inventory policies, supply lead times, supply lot-sizes, supplier capacities, on-hand inventory, supplier allocation policies, shipping and receiving calendars for generating the scheduled material requirements. These material requirements are then used for procurement.
However there are two groups of parameters that must be addressed by purchase planning systems. First, it must be able to model and address corporate policy guidelines, some examples of which are inventory levels, fulfillment rates, and approved vendor lists. Second, it must be able to model the contractual terms of the supply agreements with various vendors, some examples of which are obligations, rebates, volume based price breaks, and flex quantity limitations.
The currently existing systems that address master planning and supply chain planning do not adequately address the second groups of requirements above. On the other hand, the currently existing contract management systems do not go beyond modeling the supply contracts, and don't provide any planning capabilities to generate purchase schedules that are compliant with the contracts, as well as the corporate policies.
Therefore the existing systems do not adequately address all the operational constraints that are relevant for purchasing. Partial list of examples of such constraints that remain un-addressed by the existing systems are trading partner terms, conditions and agreements for supply contracts, enterprise business rules and various cost factors that form the landed cost for an item. Another problem that is inadequately addressed by the existing systems is that while the master planning is normally done on a continual basis, tactical and operational purchase planning is not necessarily kept in sync with the latest master planning data. Another example showing this would be the fact that the material requirement patterns change with each master-planning run, but these are not used to determine the best vendor quotas or business splits after each run of master-planning.
Purchase decisions are complex and involve multiple parameters. If these parameters are not considered, possible cost saving opportunities are lost. In addition there could be penalties that could have been avoided or reduced using intelligent planning. For example consider a simple case of two vendors. If there is a contractual obligation to buy a certain quantity of material by a certain week from the first supplier then it may not be an effective decision to buy anything from the second supplier in that week. However, a hard coded allocation solution will automatically decide to buy from the first as well as second vendor based on vendor quota rules and may incur a penalty for not meeting the obligations from the first supplier.
Therefore, an ideal purchase-planning tool should include capabilities to model all the parameters mentioned and other similar parameters all of which are not covered above. It should leverage optimization technologies to minimize the overall cost of direct material purchasing while ensuring complete compliance to the trading partner terms and conditions as well as the corporate business rules. The tool should also provide a system for evaluating the effect of such terms and/or business rules on the overall purchasing costs. The tool should provide simulation capabilities to actually influence the development of supply channel network so as to best meet the purchasing requirements of an enterprise. | {
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As a time code signal used in the transmission of a picture signal, there is an LTC (linear time code) signal, which is recorded on a voice frequency band after being subjected to bi-phase mark modulation. Time code signals are transmitted in synchronization with picture signals.
In a time code signal, an error (change in data content) may be generated by a reading failure or transmission failure when the time code signal is regenerated from a regenerating device or the signal is transmitted. Such an error causes a deterioration in the precision of the time code signal. For this reason, it is necessary to detect the generation of the error in the time code signal with high accuracy. When the error can be detected, the use of the time code signal can be stopped. The location of the error can also be restored by applying a given processing to the time code signal.
Hitherto, however, the method or structure for detecting an error generated in time code signals has not been carried out at all, and effective proposals have not yet been made.
Accordingly, a main object of the present invention is to provide a method and a device for transmitting a time code signal which can detect an error generated during the transmission of the time code signal effectively. | {
"pile_set_name": "USPTO Backgrounds"
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1. Field of the Invention
This disclosure relates to an electronic device and, more particularly to a portable electronic device.
2. Description of the Related Art
A processor of an electronic device can generate heat in operation. While the heat generated by the processor cannot be dissipate, the electronic device may work in unstable state. Thus, the electronic device needs a heat dissipation module to enhance the heat dissipation effect.
With the development of science, more portable electronic, devices such as a notebook, a tablet computer or a smartphone are commonly used in daily life. Since the development trend of appearance of portable electronic device is miniaturization in which the inner space of the portable electronic is limited so as to the space used to heat dissipate of the heat dissipation module is limited the same. | {
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1. Field of the Invention
The present invention relates generally to fluid reaction surfaces, and more specifically to a gas turbine blade with tip cooling.
2. Description of the Related Art including information disclosed under 37 CFR 1.97 and
A gas turbine engine includes a turbine section with a plurality of rotor blade stages. A compressor supplies compressed air to a combustor to produce a hot gas flow through the turbine resulting in the generation of mechanical power. The rotating blades of the turbine form a seal between the blade tips and the outer shroud wall of the turbine. Thus, a seal is formed between two relatively rotating members of the turbine.
Leakage across this seal reduces the engine efficiency. Also, the leakage is hot gas flowing between the tip and the shroud. This hot gas flow on the tip will cause heating of the blade tip resulting in excessive wear or damage to the tip and shroud.
Rubbing of the tip against the shroud is also a problem because of thermal expansion of the blade from the heat load and from the centrifugal force developed in the blade from the rotation thereof. Squealer tips have been developed to provide a tip seal and to limit the amount of blade material that can rub. Cooling of the squealer tip is necessary to prevent the tip from overheating. Leakage in to the squealer tip cavity of the hot gas flow will cause the balder tip region to overheat.
U.S. Pat. No. 4,247,254 issued to Zelahy on Jan. 27, 1981 entitled TURBOMACHINERY BLADE WITH IMPROVED TIP CAP discloses a squealer tip for a turbine blade with cooling holes on the tip cal to inject cooling air into the cavity formed within the sidewalls of the squealer tip.
U.S. Pat. No. 5,511,946 issued to Lee et al on Apr. 30, 1996 entitled COOLED AIRFOIL TIP CORNER discloses a blade with a tip corner on the trailing edge having cooling holes that cross each other for improved cooling of the tip.
U.S. Pat. No. 5,660,523 issued to Lee on Aug. 26, 1997 entitled TURBINE BLADE SQUEALER TIP PERIPHERY END WALL WITH COOLING PASSAGE ARRANGEMENT discloses a turbine blade squealer tip with a cooling passages that cross one another to provide a larger cooling surface area and thereby more effective convective cooling that do separate single holes. The crossing cooling holes also cause for a more turbulent flow within the holes.
U.S. Pat. No. 6,932,571 B2 issued to Cunha et al on Aug. 23, 2005 entitled MICROCIRCUIT COOLING FOR A TURBINE BLADE TIP discloses a turbine blade with a tip having a microcircuit that traverses the tip between a suction sidewall and a pressure sidewall. | {
"pile_set_name": "USPTO Backgrounds"
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The present invention relates to footwear soles and more particularly to adjustable footwear sole constructions.
The design and manufacture of footwear is complicated by the fact that different people have different footwear needs. For example, some individuals prefer a firmer, more unyielding sole, while others prefer a softer, more cushioning sole. With some people this is simply an aesthetic desire, but for others it can result from physical factors, such as those associated with foot shape, skeletal alignment and other anatomical issues. Anatomical issues cause some individuals to suffer from a tendency to pronate (roll their feet inward when striding) and others to have the opposite tendency to supinate (roll their feet outward when striding). One method for addressing these issues is to stiffen the sole in select regions to provide increased resistance against the undesired motion. For example, pronation can be addressed by providing a dual-density midsole with a higher density region along the medial side of the sole. Similarly, supination can be addressed by providing a dual-density midsole with a higher density region along the lateral side of the sole
In an effort to address the needs of different consumers, a variety of footwear products have been developed with a customizable sole construction. For example, in one conventional product, the sole defines a void adapted to receive one of a variety of different cushioning inserts. With this product, the wearer is provided with different cushioning inserts that meet different cushioning/support needs. The wearer customizes the sole by inserting the appropriate cushioning insert into the void. The insert may be replaced with alternative inserts in the future as desired to alter the characteristics of the sole. Though providing some degree of customization, this solution requires the manufacture and supply of a plurality of inserts. This can increase cost of manufacture and assembly. Further, the consumer is required to save and store the various inserts to permit future adjustment. Additionally, the number of adjustment settings is a function of the number of inserts supplied with the shoe, which has led to relatively limited adjustability in sole constructions of this type. | {
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The subject matter described herein generally relates to the monitoring of the Quality-of-Experience (QoE) of a mobile user of a wireless network without introducing any additional packets or requiring user feedback.
Wireless networks are expanding their offerings of live or near-live multimedia services, including mobile video calls, voice and/or video conferencing, video streaming, mobile informational devices (for example, mobile telemedicine video carts), and service appliances. In addition, the availability of fourth generation wireless networks (4G), which enable high bandwidth and latency sensitive applications over wireless, is increasing. Quality-of-Service (QoS) parameters, such as packet delay, loss, and jitter, provided by the underlying network to the service flow varies with time. In addition, the QoE is sensitive to even small changes in the QoS parameter values. As such, in order to provide satisfactory multimedia service, it is important to continuously monitor the QoE perceived by the mobile user.
Existing QoE metrics for multimedia services can be categorized in multiple ways. For example, QoE metrics for multimedia services can be categorized according to service type, such as whether the application is utilizing voice (mean opinion scores [MoS]) or video (peak signal-to-noise ratio PSNR). QoE metrics can be categorized subjectively through evaluation by actual users of a particular service (MoS) or through objective quality metrics, such as analytical models like PSNR. QoE metrics for can be categorized based on how much reference information is required about the original (reference) multi-media flow (for example, full-reference, reduced-reference and no-reference). QoE metrics for can be categorized based on whether spatial or temporal distortions (initial buffering time, stalls) are measured, whether user feedback is required, and/or whether probes (QoE robots) or new messages are utilized. QoE metrics for can be categorized based on location of the QoE module (at the source, end-user or in the network), and whether live QoE monitoring or offline QoE computation is employed.
The monitoring and management of Quality-of-Experience (QoE) is important to high-level wireless communication networks, such as the fourth generation wireless network (4G). This is due to such networks volume intensive rich media services, scarce wireless resources, the pack value per wireless bit, and prioritizing among sessions to increase value per wireless bit. Wireless communication networks, such as 4G networks, are higher bandwidth compared to 3G networks, due primarily to the ability to provide, among other services, rich media services, data downloads, and multiple sessions simultaneously. As such, bottlenecks will occur between network base stations and end users devices. Thus, there is a need for specific intervention to manage such services, as the challenge to the wireless link becomes the bottleneck created by supporting all of a network's mobile users.
In existing systems, wireless links have a fixed number of transmission slots. In addition, wireless conditions can vary depending on, among other conditions, geographic area, number of users, and data load. Furthermore, services delivered on wireless links, such as media services, may not be provided at a constant rate and network base stations may not have the same data and connection capabilities. Thus, a need exists for an intelligent mechanism to manage and alleviate any such network bottlenecks.
Existing solutions for remote monitoring of QoE of a mobile user either modify existing messages or introduce new packets or messages, while other existing solutions are application specific. In addition, such solutions are not easy to deploy and are not scalable when continuous monitoring of QoE of a large number of mobile users is required. Furthermore, certain existing solutions are based on non-standard protocols and, as such, are unable to support diverse end-user equipment and applications. | {
"pile_set_name": "USPTO Backgrounds"
} |
Although it will be apparent that its usefulness is not limited thereto, the invention has particular applicability to steam systems wherein it is desirable to separate condensed vapor and other materials from the working vapor.
During warmup in a steam supply system, large amounts of condensate, air and other gases are invariably found in the system and should be separated from the working vapor quickly for operational efficiency. Even after warm-up, some of the undesirable products are produced. Condensate formation is in large part due to pipe heat losses which result from heat radiation, convection and conduction through the pipe walls and occurs whether or not the pipes are insulated. Condensate is also formed due to the performance of work in the various applications of the system and is found in the dead-end sections of piping. No matter how formed, it causes a number of undesirable effects such as reduced system capacity for steam flow, water hammer, erosion due to the friction of fluid flow, corrosion due to dissolved oxygen and the presence of carbonic acid and damage to machinery due to high moisture content of the steam. In addition, the condensate, air, CO.sub.2 and non-condensable vapors, reduce the heat transfer and have other undesirable side effects. In addition, dirt, rust and scale invariably accumulate, particularly when the system has been shut down for any appreciable period of time. As is recognized by those skilled in the art, it is fundamental that for efficient operation, all of these components should be removed from the system with a minimum loss of vapor and with the condensate preferably being returned to the feed tank for redelivery to the steam generating equipment.
According to conventional practice, steam traps of various classes are used in drain lines at points throughout the steam system where condensate may be found so as to remove the condensate and other materials as described above. One class of steam trap commonly employed is the thermostatic trap. These usually have a bellows or a bi-metallic element which fully or partially opens a valve to allow the passage of the condensate and undesirable gases when the temperature at the thermostatic element is below a predetermined value hereinafter termed the actuating temperature.
During the warmup stage of operation, when the temperature is well below the actuating temperature, the bellows or bimetallically controlled valve is in the open position and will pass the large amounts of condensate and other products present in the drain line. Once the warmup stage is passed, the preselected actuating temperature is reached and the thermostatic element closes the valve until condensate accumulates, at which point a condition of temperature imbalance develops, cooling the thermostatic element and causing the valve to open when the temperature is below the actuating temperature. It should be noted that in a typical installation the thermostatically operated trap cycles between the open and closed position on a regular basis. By way of example, it is not uncommon for such a trap to open and close 75,000 or more times a year. This continuous cycling leads to wear due to the constant operation of the thermostatically operated valve in seating and unseating as well as to fluid friction. This wear rapidly becomes appreciable during prolonged periods of operation. In relatively short periods of time the wear leads to leakage which is in addition to the normal seat leakage caused by mismatching of parts. Thus, cyclic operation soon leads to an appreciable loss of steam and reduction in the efficiency of the system. Even though a trap might be capable of blocking almost all vapor when it is new, it becomes a source of gradually increasing vapor leakage during its life span.
A further problem which is more acute in the case of bellows-type thermostatically operated traps, is that the bellows are subject to fatigue stressing as they are cycled and to damage by pressure surge and water hammer. Eventually failure of the bellows will occur if the traps are not replaced on a regular basis. When the bellows-type fails it fails in the open position, causing large amounts of steam to escape from the system until the source of the problem is located and corrected.
Although bimetallic type traps are not as subject to pressure surge or water hammer damage, these traps are affected by hysterisis losses with use so that their response characteristics change over a period of time.
The cyclic nature of the operation is also a cause of pressure and temperature fluctuations in the system and is thus a source of system inefficiency. In addition, these fluctuations create turbulence around the valve which contributes to valve wear.
One answer to many of the foregoing problems is the use of continuous drain orifice assembly of the kind shown in U.S. Pat. No. 3,877,895 owned by the assignee of this application and in U.S. Pat. No. 3,715,870. This assembly is a continuous condensate removal device with an orifice sized to pass the condensate produced in the system with a stable but nominally small steam loss. It is an effective and highly efficient condensate removal device when employed in a steam system in locations where the condensate load is predictable and load fluctuations are not a problem.
During warm-up and in certain other operations where condensate load fluctuates over a wide range, a thermostatic steam trap is more effective in that it is capable of automatically passing the large amounts of condensate produced under these conditions. However, for the reasons expressed above, the thermostatic steam trap is not as effective a device as a continuous drain orifice once the system has stabilized. | {
"pile_set_name": "USPTO Backgrounds"
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The present invention relates to an electronic device assembly, and more particularly to an electronic device assembly including a first substrate and a second substrate mounted on the first substrate.
An example of a conventional electronic device is disclosed in U.S. Pat. No. 5,203,075.
Referring to FIG. 10 of the above reference, a semiconductor device 43 is mounted on a flexible substrate 31. The flexible substrate 31 is connected to a substrate 13 via solder.
Referring to FIGS. 6 and 9 of the reference, a solder member 32 and a solder paste 27 connect the flexible substrate 31 and the substrate 13. Part of the solder member 32 is positioned in a through-hole provided in the flexible substrate 31.
The aforementioned structure has the following problems.
First, the solder connection is susceptible to failure because it is not protected from mechanical stress.
Specifically, the solder connection is apt to fall off, be broken, or be short circuited with the adjacent solder connection. This problem becomes serious when a relatively heavy device such as a heat sink is mounted on the flexible substrate. The failure of the solder connection is also caused by thermal cycling (i.e., repetitive heating and cooling).
Second, the solder is further susceptible to failure because it is not protected from air humidity (e.g., the moisture in the air).
Third, it is difficult to control the gap precisely between the flexible substrate 31 and the substrate 13 because it is difficult to keep the flexible substrate 31 flat. If the gap between the flexible substrate 31 and the substrate 13 is uneven, the reliability of the solder connection decreases. | {
"pile_set_name": "USPTO Backgrounds"
} |
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