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1. Field of the Invention
The present invention relates to a direct spray fuel injector, and more particularly, a direct spray fuel injector that is capable of efficiently suppressing and preventing bounce generated in a valve needle of a bundle of opening/closing valves when a spray hole of an injector for injecting a fuel under a high pressure is closed due to the bundle of opening/closing valves that opens and closes the spray hole of the injector.
2. Description of the Related Art
In general, most direct spray fuel injectors that directly inject a fuel into a combustion chamber of an engine recently operate and are controlled in an electronic manner. A representative example thereof may include an injector having an opening/closing valve structure marked by reference numeral 101 of FIG. 1.
The injector 101 includes a bundle of opening/closing valves 110 including a valve needle 105 that directly opens and closes a spray hole 113, an electromagnetic coil 107 that pulls the valve needle 105 when the spray hole 113 is opened, an armature 109 that pulls the valve needle 105 by gravity of the electromagnetic coil 107, and a pressurizing spring 111 that elastically pressurizes the valve needle 105 against the spray hole 113, as illustrated in FIG. 1.
Thus, the injector 101 according to the relate art closes the spray hole 113 due to a valve ball 125 when the valve needle 105 is pressurized toward the spray hole 113 together with a stop ring 115 pressurized by an elastic force of the pressurizing spring 111 in normal times when no injection operation is performed, as illustrated in FIGS. 1 and 2.
However, when the injector 101 operates so as to inject the fuel under the high pressure, first, the electromagnetic coil 107 of the bundle of opening/closing valves 110 is excited. Thus, the armature 109 is pulled by a magnetic force of the electromagnetic coil 107, compresses a buffer spring 120 against a stop sleeve 117, is lifted upwardly in the drawing and thus contacts the stop ring 115.
The armature 109 pulled by the electromagnetic coil 107 even after contacting the stop ring 115 compresses the pressurizing spring 111 through the stop ring 115 and is lifted, as illustrated in FIG. 3. Thus, the valve needle 105 is lifted together with the armature 109 and opens the spray hole 113 such that a high-pressure fuel filled in a housing 103 can be injected into the combustion chamber.
Then, when injection of the injector 101 is completed, in contrast, the electromagnetic coil 107 is demagnetized and thus gravity of the electromagnetic coil 107 that pulls the armature 109 disappears. Thus, the valve needle 105 intends to return to a normal state illustrated in FIG. 2 and to close the spray hole 113. However, the valve needle 105 is bounced due to an elastic repulsive force generated when the valve ball 125 and a valve seat around the spray hole 113 contact each other or a high spray pressure in the spray hole 113 and is again lifted upwardly in the drawing, as illustrated in FIG. 4. This is usually referred to as ‘bouncing’ of the valve needle 105. Further bounce of the valve needle 105 lifted in this way is suppressed and prevented when the stop sleeve 117 is pressurized downward by the armature 109 that descends downward in the drawing due to a restorative force of the buffer spring 120.
In this way, in the injector 101 according to the related art, the bundle of opening/closing valves 110 suppresses and prevents the bounce of the valve needle 105. Thus, a spring holder 118 that supports the buffer spring 120 needs to be additionally disposed at an opposite side to a side in which the stop sleeve 117 is formed, so as to elastically support the armature 109 due to the buffer spring 120. Also, the spring holder 118 needs to be fixed to a bottom surface of the armature 109 by welding. Due to the buffer spring 120 and the spring holder 118, an assembling structure of the injector 101 according to the related art is complicated, and the number of components required for the injector 101 according to the related art increases. Thus, manufacturing efficiency or economic feasibility of the injector 101 according to the related art is lowered. | {
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It is known in the art to which this invention pertains to electrodeposit upon a basis metal a metallic material exemplified by zinc, copper, nickel, nickel-iron or the like utilizing in the electroplating baths a polyethylenimine having the general empirical formula --[C.sub.2 H.sub.5 N].sub.x --, and a sulfonating agent for the polyethylenimine whereby there is obtained a reaction product which contains nitrogen substituted sulfamate groups as an integral part of the polymer chain. The nitrogen substituted sulfamate unit of the reaction product is represented by the formula: ##STR2## where, M = H, Li, Na, K or NH.sub.4. The ratio of these nitrogen substituted sulfamate units to amino units, --[CH.sub.2 CH.sub.2 N]--, in the reaction product is determined by the molar ratio of the polymer repeat unit, --[C.sub.2 H.sub.5 N]--, to sulfonating agent in the reaction.
The inventive concept set forth above, which is disclosed in commonly assigned application Ser. No. 603,563 filed Aug. 11, 1975, now U.S. Pat. No. 4,101,387, has fulfilled a need long existing in the art with respect to a bath composition which simply contains polyvinyl alcohol, an aromatic aldehyde and a chelating agent. It has now been discovered by applicant that markedly improved results by way of adhesion and simplicity of manufacturing techniques can be obtained when there is incorporated in the bath composition a sulfamalkylated polyamine of the structure earlier described. | {
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1. Field of the Invention
This invention relates to a saddle support for a bicycle saddle, more particularly to a saddle support which has solid metal reinforcing rods inserted fittingly into an intermediate section thereof in order to prevent breakage of the saddle support at the intermediate section.
2. Description of the Related Art
Referring to FIG. 1, a conventional bicycle seat (10) includes a bicycle saddle (11), a saddle support (12) to be mounted to the bottom side of the bicycle saddle (11), and a seat post (13) connected securely to the intermediate section (121) of the saddle support (12).
Referring to FIG. 2, the saddle support (12) has resilient properties so as to lessen the vibrations felt when the bicycle is in use. However, when the saddle support (12) bears a heavy load for a long period of time, the intermediate section (121) of the saddle support (12) breaks off easily at two end portions (122) that contact two ends of the seat post (13). | {
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This invention relates to plain bearings of the kind used in internal combustion engines. More particularly it relates to bearings for use as crankshaft (main) bearings and/or big end bearings.
Numerous metal and alloy combinations have been proposed. It is common practice to employ a strong backing material such as steel onto which is cast or otherwise affixed one or more primary layers of a bearing metal or alloy. It is common practice to provide the working face of the primary layer with an overlay coating of minimal thickness, to impart a degree of conformability and lubricity and also the ability to embed particulate debris which is generally found in engines and which can cause serious damage and/or premature wear problems, or even seizure.
For example, one well known bearing material is based on a steel backing layer onto which is cast a bronze layer, the latter serving as the primary layer referred to earlier. The primary layer is then given an electrodeposited overlay coating of lead and indium. (It will be understood that ancillary steps such as forming, shaping and machining to final dimensions may be required, but as these are all well known in the art, they need not be discussed in detail in this specification).
In addition to achieving wear resistance and conformability, a plain bearing for automotive engine use should also exhibit resistance to cavitation erosion due to the behaviour of the oil film under conditions of heat and cyclic pressures. Cavitation erosion is a particularly serious problem at very high engine speeds and loadings. High speed in this context means up to and in excess of 10,000 r.p.m. and engines capable of operation at such speeds are generally run using synthetic lubricants, the latter apparently considerably exacerbating the erosion problem.
The use of relatively exotic metals such as silver has been proposed; silver is/was used in certain aircraft engines. It is an excellent metal for bearing purposes, but is prone to seizure if run under unloaded conditions. It would normally be used in a relatively thick, monolithic layer.
A further problem for plain bearings in automotive engines arises from the surface finish of the shaft which the bearing supports, or with which the bearing working surface is in contact. Surface irregularities can and do cause damage to the bearing, especially during the xe2x80x9crunning-inxe2x80x9d phase of operation. To counter this it has been proposed to incorporate an amount of very fine, hard abrasive particles into the working surface of the bearing, more especially into the overlay coating. It is believed that such particles not only serve to xe2x80x9cpolishxe2x80x9d the shaft, but also to strengthen the soft overlay so that damage to it is greatly reduced. Titanium carbide is a known material for this purpose.
It is an object of the present invention to provide a bearing having improved performance at engine speeds in excess of 10,000 r.p.m.
According to a first aspect of the present invention, there is provided a bearing material comprising a metal having therein diamond particles.
In accordance with a second aspect of the present invention, a bearing comprises a strong backing, a layer of silver or a silver alloy and an overlay coating layer of a metal containing diamond particles.
A structural bronze bearing material layer may be interposed between the strong backing (normally of steel for example) and the silver layer. In that case, the silver may be applied over a nickel interlayer to improve adhesion and minimise the formation of undesirable intermetallic compounds. Such a nickel layer will, in fact, normally be used on top of bronze. The diamond-containing metal overlay layer may be silver, pure lead or a lead/indium mix, or it may be lead/tin or lead/tin/copper.
It will be appreciated that the invention in one embodiment may be regarded as comprising an overlay having two-layers, in which both layers may be principally of silver.
The second or outermost overlay layer adjacent a shaft journal in use is preferably applied by electroplating; it will be typically only about 1-5 microns thick, and the diamond particles should preferably be in the size range 0.1-2 microns. The underlying silver or silver alloy layer may be of the order of 5-20 microns thick, whilst the nickel interlayer (if used) will be typically 1-2 microns thick. The strong backing material may be of an appropriate thickness, but 1-2 mm would be suitable for many applications. The structural bronze layer (if used) may have a thickness in the range of 200-300 microns for example.
Suitable silver alloys may comprise silver and lead for example.
The diamond particles may be natural or synthetic and may be present in an amount of from about 0.1 volume % to 3 volume %. A more preferred range of diamond content may be from 0.25 to 1 volume %.
Surprisingly small amounts of diamond particles are effective. For example, 0.15% by weight (about 0.5% by volume) gave satisfactory results.
The performance of a bearing according to the present invention is good, especially at speeds in excess of 10,000 r.p.m. and under heavy loading. | {
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The present invention relates to a powdered niobium for a capacitor having a large capacity per unit weight and good specific leakage current property, a sintered body using the powdered niobium, a capacitor using the sintered body and production method of the capacitor.
Capacitors used for electronic instruments such as portable telephone and personal computer are demanded to be compact and have a large capacity. Among these capacitors, a tantalum capacitor is preferably used because it has a large capacity for the size and exhibits good performance. In this tantalum capacitor, a sintered body of powdered tantalum is generally used for the anode moiety. In order to increase the capacity of the tantalum capacitor, it is necessary to increase the weight of sintered body or to use a sintered body increased in the surface area by pulverizing the powdered tantalum.
The former method of increasing the weight of sintered body is naturally accompanied by enlargement of the capacitor size and the requirement for downsizing cannot be satisfied. On the other hand, in the latter method of pulverizing the powdered tantalum to increase the surface area, the pore size of tantalum sintered body is reduced or closed pores are increased at the stage of sintering, therefore, a cathode agent can be difficultly impregnated in the after process. As a means for solving these problems, a capacitor using a sintered body of a powdered material having a dielectric constant larger than the tantalum is being studied. Examples of such a material having a larger dielectric constant include niobium and titanium.
However, conventional capacitors using a sintered body of such a material are disadvantageous in that the specific leakage current property is greatly dispersed and not satisfied by any means. Using a powdered tantalum makes a sintered body. When a sintered body is electrolytically oxidized and then combined with counter electrode to manufacture a capacitor, it is nothing to satisfy the basis which the specific leakage current as a practical value is 10 nA/xcexcFxc2x7V and less. However, in capacitors using conventional powdered niobium and titanium, the specific leakage current values are greatly dispersed and there are many cases which exceed this value.
Furthermore, conventional capacitors using a sintered body of such a material are deficient in the high-temperature property and are not put into practical use. Because, when a sintered body is electrolytically oxidized and then combined with counter electrode to manufacture a capacitor, the high-temperature property usually falls within xc2x120% in the case of a sintered body using powdered tantalum, however, in some sintered bodies using conventional powdered niobium, the high-temperature property does not fall within xc2x120%.
Therefore, capacitors using a niobium sintered body and a titanium sintered body must be estimated to have low reliability also at room temperature and are duly judged deficient in the service life, thus cannot be used in practice.
As a result of extensive investigations, the present inventors have developed a powdered niobium for a niobium sintered body capable of providing a capacitor having a small dispersion in the specific leakage current value, and accomplished the present invention.
Furthermore, the present inventors have accomplished the present invention by findings which a capacitor having good high-temperature property is obtained when a crystal of a given niobium compound is comprised in a niobium sintered body.
Namely, the present invention relates to the following powdered niobium for capacitor, sintered body thereof, capacitor using the same and production method of the capacitor.
(1) A powdered niobium for a capacitor, containing elements such as iron, nickel, cobalt, silicon, sodium, potassium and magnesium, wherein an amount of each element is about 100 ppm by weight or less.
(2) A powdered niobium for a capacitor, containing elements such as iron, nickel, cobalt, silicon, sodium, potassium and magnesium, wherein the total amount of the elements is about 350 ppm by weight or less.
(3) A powdered niobium for a capacitor, containing elements such as iron, nickel, cobalt, silicon, sodium, potassium and magnesium, wherein an amount of each element is about 100 ppm by weight or less and the total amount of the elements is about 350 ppm by weight or less.
(4) The powdered niobium for a capacitor described in any one of the (1) to (3), which contains at least one of niobium nitride, niobium carbide and niobium boride.
(5) A sintered body for a capacitor using a powdered niobium described in any one of the (1) to (4).
(6) A niobium sintered body for a capacitor, comprising at least one of niobium monoxide crystal and a diniobium mononitride crystal.
(7) The niobium sintered body for a capacitor according to the (6), wherein the content of niobium monoxide crystal is from about 0.1 wt % to about 20 wt %.
(8) The niobium sintered body for a capacitor according to the (6), wherein the content of diniobium mononitride crystal is from about 0.1 wt % to about 20 wt %.
(9) A capacitor comprising one party electrode assigned to the niobium sintered body described in any one of the (5) to (8), other party electrode and a dielectric material interposed between two electrodes.
(10) The capacitor according to the (9), wherein the dielectric material is tantalum oxide, niobium oxide, polymer material, or ceramics compound.
(11) The capacitor according to the (10), wherein the dielectric material is niobium oxide formed by chemical forming on a niobium sintered body.
(12) A process for producing a capacitor, comprising preparing the second electrode opposing on the dielectric material, after forming the dielectric material on the niobium sintered body (first electrode) described in any one of the (5) to (8).
(13) The process for producing a capacitor according to the
(12), wherein the dielectric material is tantalum oxide, niobium oxide, polymer material, or ceramics compound.
(14) The process for producing a capacitor according to the
(13), wherein the dielectric material is niobium oxide formed on a niobium sintered body by chemical forming. | {
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A thorough background of the invention is set forth in U.S. patent application Ser. No. 10/931,288, incorporated by reference herein.
Briefly, automotive vehicles are equipped with seat belts and air bags as equipment for ensuring the safety of the passenger. In recent years, an effort has been underway to enhance the performance of the seat belt and/or the air bag by controlling these devices in accordance with the morphology, e.g., weight, of the occupant. For example, the quantity of gas used to deploy the air bag or the speed of deployment could be controlled. Further, the amount of pretension of the seat belt could be adjusted in accordance with the weight and posture of the passenger. To this end, it is necessary to know the weight of the passenger sitting on the seat by some technique. The position of the center of gravity of the passenger sitting on the seat could also be referenced in order to estimate the posture of the passenger.
As an example of a technique to determine the weight or the center of gravity of the passenger of this type, a method of measuring the seat weight including the passenger's weight by disposing the load sensors (load cells) at the front, rear, left and right corners under the seat and summing vertical loads applied to the load cells has been disclosed in the assignee's numerous patents and patent applications on occupant sensing.
Since a seat weight measuring apparatus of this type is intended for use in general automotive vehicles, the cost of the apparatus must be as low as possible. In addition, the wiring and assembly also must be easy. Keeping such considerations in mind, the object of the present invention is to provide a seat weight measuring apparatus having such advantages that the production cost and the assembling cost may be reduced. To provide new and improved vehicular seats in which the weight applied by an occupying item to the seat is measured based on capacitance between conductive and/or metallic members underlying the seat cushion.
A further object of an invention herein is to provide new and improved adjustment apparatus and methods that evaluate the occupancy of the seat and adjust the location and/or orientation relative to the occupant and/or operation of a part of the component or the component in its entirety based on the evaluated occupancy of the seat and on a measurement of the occupant's weight or a measurement of a force exerted by the occupant on the seat.
Definitions
Preferred embodiments of the invention are described below and unless specifically noted, it is the applicants' intention that the words and phrases in the specification and claims be given the ordinary and accustomed meaning to those of ordinary skill in the applicable art(s). If the applicants intend any other meaning, they will specifically state they are applying a special meaning to a word or phrase.
Likewise, applicants' use of the word “function” here is not intended to indicate that the applicants seek to invoke the special provisions of 35 U.S.C. §112, sixth paragraph, to define their invention. To the contrary, if applicants wish to invoke the provisions of 35 U.S.C. §112, sixth paragraph, to define their invention, they will specifically set forth in the claims the phrases “means for” or “step for” and a function, without also reciting in that phrase any structure, material or act in support of the function. Moreover, even if applicants invoke the provisions of 35 U.S.C. §112, sixth paragraph, to define their invention, it is the applicants' intention that their inventions not be limited to the specific structure, material or acts that are described in the preferred embodiments herein. Rather, if applicants claim their inventions by specifically invoking the provisions of 35 U.S.C. § 112, sixth paragraph, it is nonetheless their intention to cover and include any and all structure, materials or acts that perform the claimed function, along with any and all known or later developed equivalent structures, materials or acts for performing the claimed function.
“Pattern recognition” as used herein will generally mean any system which processes a signal that is generated by an object (e.g., representative of a pattern of returned or received impulses, waves or other physical property specific to and/or characteristic of and/or representative of that object) or is modified by interacting with an object, in order to determine to which one of a set of classes that the object belongs. Such a system might determine only that the object is or is not a member of one specified class, or it might attempt to assign the object to one of a larger set of specified classes, or find that it is not a member of any of the classes in the set. The signals processed are generally a series of electrical signals coming from transducers that are sensitive to acoustic (ultrasonic) or electromagnetic radiation (e.g., visible light, infrared radiation, capacitance or electric and/or magnetic fields), although other sources of information are frequently included. Pattern recognition systems generally involve the creation of a set of rules that permit the pattern to be recognized. These rules can be created by fuzzy logic systems, statistical correlations, or through sensor fusion methodologies as well as by trained pattern recognition systems such as neural networks, combination neural networks, cellular neural networks or support vector machines.
A trainable or a trained pattern recognition system as used herein generally means a pattern recognition system that is taught to recognize various patterns constituted within the signals by subjecting the system to a variety of examples. The most successful such system is the neural network used either singly or as a combination of neural networks. Thus, to generate the pattern recognition algorithm, test data is first obtained which constitutes a plurality of sets of returned waves, or wave patterns, or other information radiated or obtained from an object (or from the space in which the object will be situated in the passenger compartment, i.e., the space above the seat) and an indication of the identify of that object. A number of different objects are tested to obtain the unique patterns from each object. As such, the algorithm is generated, and stored in a computer processor, and which can later be applied to provide the identity of an object based on the wave pattern being received during use by a receiver connected to the processor and other information. For the purposes here, the identity of an object sometimes applies to not only the object itself but also to its location and/or orientation in the passenger compartment. For example, a rear facing child seat is a different object than a forward facing child seat and an out-of-position adult can be a different object than a normally seated adult. Not all pattern recognition systems are trained systems and not all trained systems are neural networks. Other pattern recognition systems are based on fuzzy logic, sensor fusion, Kalman filters, correlation as well as linear and non-linear regression. Still other pattern recognition systems are hybrids of more than one system such as neural-fuzzy systems.
The use of pattern recognition, or more particularly how it is used, is important to many embodiments of the instant invention. In the above-cited prior art, except that assigned to the current assignee, pattern recognition which is based on training, as exemplified through the use of neural networks, is not mentioned for use in monitoring the interior passenger compartment or exterior environments of the vehicle in all of the aspects of the invention disclosed herein. Thus, the methods used to adapt such systems to a vehicle are also not mentioned.
A pattern recognition algorithm will thus generally mean an algorithm applying or obtained using any type of pattern recognition system, e.g., a neural network, sensor fusion, fuzzy logic, etc.
To “identify” as used herein will generally mean to determine that the object belongs to a particular set or class. The class may be one containing, for example, all rear facing child seats, one containing all human occupants, or all human occupants not sitting in a rear facing child seat, or all humans in a certain height or weight range depending on the purpose of the system. In the case where a particular person is to be recognized, the set or class will contain only a single element, i.e., the person to be recognized.
To “ascertain the identity of” as used herein with reference to an object will generally mean to determine the type or nature of the object (obtain information as to what the object is), i.e., that the object is an adult, an occupied rear facing child seat, an occupied front facing child seat, an unoccupied rear facing child seat, an unoccupied front facing child seat, a child, a dog, a bag of groceries, a car, a truck, a tree, a pedestrian, a deer etc.
An “object” in a vehicle or an “occupying item” of a seat may be a living occupant such as a human or a dog, another living organism such as a plant, or an inanimate object such as a box or bag of groceries or an empty child seat.
A “rear seat” of a vehicle as used herein will generally mean any seat behind the front seat on which a driver sits. Thus, in minivans or other large vehicles where there are more than two rows of seats, each row of seats behind the driver is considered a rear seat and thus there may be more than one “rear seat” in such vehicles. The space behind the front seat includes any number of such rear seats as well as any trunk spaces or other rear areas such as are present in station wagons.
An “optical image” will generally mean any type of image obtained using electromagnetic radiation including X-ray, ultraviolet, visual, infrared, terahertz and radar radiation.
In the description herein on anticipatory sensing, the term “approaching” when used in connection with the mention of an object or vehicle approaching another will usually mean the relative motion of the object toward the vehicle having the anticipatory sensor system. Thus, in a side impact with a tree, the tree will be considered as approaching the side of the vehicle and impacting the vehicle. In other words, the coordinate system used in general will be a coordinate system residing in the target vehicle. The “target” vehicle is the vehicle that is being impacted. This convention permits a general description to cover all of the cases such as where (i) a moving vehicle impacts into the side of a stationary vehicle, (ii) where both vehicles are moving when they impact, or (iii) where a vehicle is moving sideways into a stationary vehicle, tree or wall.
“Vehicle” as used herein includes any container that is movable either under its own power or using power from another vehicle. It includes, but is not limited to, automobiles, trucks, railroad cars, ships, airplanes, trailers, shipping containers, barges, etc. The term “container” will frequently be used interchangeably with vehicle however a container will generally mean that part of a vehicle that separate from and in some cases may exist separately and away from the source of motive power. Thus, a shipping container may exist in a shipping yard and a trailer may be parked in a parking lot without the tractor. The passenger compartment or a trunk of an automobile, on the other hand, are compartments of a container that generally only exists attaches to the vehicle chassis that also has an associated engine for moving the vehicle. Note, a container can have one or a plurality of compartments.
“Out-of-position” as used for an occupant will generally mean that the occupant, either the driver or a passenger, is sufficiently close to an occupant protection apparatus (airbag) prior to deployment that he or she is likely to be more seriously injured by the deployment event itself than by the accident. It may also mean that the occupant is not positioned appropriately in order to attain the beneficial, restraining effects of the deployment of the airbag. As for the occupant being too close to the airbag, this typically occurs when the occupant's head or chest is closer than some distance, such as about 5 inches, from the deployment door of the airbag module. The actual distance where airbag deployment should be suppressed depends on the design of the airbag module and is typically farther for the passenger airbag than for the driver airbag.
“Dynamic out-of-position” refers to the situation where a vehicle occupant, either driver or passenger, is in position at a point in time prior to an accident but becomes out-of-position, (that is, too close to the airbag module so that he or she could be injured or killed by the deployment of the airbag) prior to the deployment of the airbag due to pre-crash braking or other action which causes the vehicle to decelerate prior to a crash.
“Transducer” or “transceiver” as used herein will generally mean the combination of a transmitter and a receiver. In come cases, the same device will serve both as the transmitter and receiver while in others two separate devices adjacent to each other will be used. In some cases, a transmitter is not used and in such cases transducer will mean only a receiver. Transducers include, for example, capacitive, inductive, ultrasonic, electromagnetic (antenna, CCD, CMOS arrays), electric field, weight measuring or sensing devices. In some cases, a transducer will be a single pixel either acting alone, in a linear or an array of some other appropriate shape. In some cases, a transducer may comprise two parts such as the plates of a capacitor or the antennas of an electric field sensor. Sometimes, one antenna or plate will communicate with several other antennas or plates and thus for the purposes herein, a transducer will be broadly defined to refer, in most cases, to any one of the plates of a capacitor or antennas of a field sensor and in some other cases, a pair of such plates or antennas will comprise a transducer as determined by the context in which the term is used.
“Adaptation” as used here will generally represent the method by which a particular occupant or object sensing system is designed and arranged for a particular vehicle model. It includes such things as the process by which the number, kind and location of various transducers are determined. For pattern recognition systems, it includes the process by which the pattern recognition system is designed and then taught or made to recognize the desired patterns. In this connection, it will usually include (1) the method of training when training is used, (2) the makeup of the databases used, testing and validating the particular system, or, in the case of a neural network, the particular network architecture chosen, (3) the process by which environmental influences are incorporated into the system, and (4) any process for determining the pre-processing of the data or the post processing of the results of the pattern recognition system. The above list is illustrative and not exhaustive. Basically, adaptation includes all of the steps that are undertaken to adapt transducers and other sources of information to a particular vehicle to create the system that accurately identifies and/or determines the location of an occupant or other object in a vehicle.
For the purposes herein, a “neural network” is defined to include all such learning systems including cellular neural networks, support vector machines and other kernel-based learning systems and methods, cellular automata and all other pattern recognition methods and systems that learn. A “combination neural network” as used herein will generally apply to any combination of two or more neural networks as most broadly defined that are either connected together or that analyze all or a portion of the input data. “Neural network” can also be defined as a system wherein the data to be processed is separated into discrete values which are then operated on and combined in at least a two-stage process and where the operation performed on the data at each stage is in general different for each of the discrete values and where the operation performed is at least determined through a training process. The operation performed is typically a multiplication by a particular coefficient or weight and by different operation, therefore is meant in this example, that a different weight is used for each discrete value.
A “morphological characteristic” will generally mean any measurable property of a human such as height, weight, leg or arm length, head diameter, skin color or pattern, blood vessel pattern, voice pattern, finger prints, iris patterns, etc.
A “wave sensor” or “wave transducer” is generally any device which senses either ultrasonic or electromagnetic waves. An electromagnetic wave sensor, for example, includes devices that sense any portion of the electromagnetic spectrum from ultraviolet down to a few hertz. The most commonly used kinds of electromagnetic wave sensors include CCD and CMOS arrays for sensing visible and/or infrared waves, millimeter wave and microwave radar, and capacitive or electric and/or magnetic field monitoring sensors that rely on the dielectric constant of the object occupying a space but also rely on the time variation of the field, expressed by waves as defined below, to determine a change in state.
The “windshield header” as used herein generally includes the space above the front windshield including the first few inches of the roof.
A “sensor” as used herein can be a single receiver or the combination of two transducers (a transmitter and a receiver) or one transducer which can both transmit and receive.
The “headliner” is the trim which provides the interior surface to the roof of the vehicle and the A-pillar is the roof-supporting member which is on either side of the windshield and on which the front doors are hinged.
An “occupant protection apparatus” is any device, apparatus, system or component which is actuatable or deployable or includes a component which is actuatable or deployable for the purpose of attempting to reduce injury to the occupant in the event of a crash, rollover or other potential injurious event involving a vehicle
As used herein, an “occupant restraint device” generally includes any type of device which is deployable in the event of a crash involving the vehicle for the purpose of protecting an occupant from the effects of the crash and/or minimizing the potential injury to the occupant. Occupant restraint devices thus include frontal airbags, side airbags, seatbelt tensioners, knee bolsters, side curtain airbags, externally deployable airbags and the like.
As used herein, a “part” of the vehicle generally includes any component, sensor, system or subsystem of the vehicle such as the steering system, braking system, throttle system, navigation system, airbag system, seatbelt retractor, air bag inflation valve, air bag inflation controller and airbag vent valve, as well as those listed below in the definitions of “component” and “sensor”.
As used herein, a “sensor system” generally includes any of the sensors listed below in the definition of “sensor” as well as any type of component or assembly of components which detect, sense or measure something.
The term “gage” or “gauge” is used herein interchangeably with the terms “sensor” and “sensing device”.
References
References potentially relevant to the subject matter of the claimed invention and/or relevant to the disclosure herein are listed in U.S. patent application Ser. No. 10/931,288 incorporated by reference herein. | {
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1. Field of the Invention
The present invention relates to glow plugs used in assisting startup of a diesel engine.
2. Description of the Related Art
Conventionally, glow plugs used in assisting startup of a diesel engine include a tubular metallic shell and a heater mounted at the front end of an axial hole of the shell, and are configured such that a front end portion of the heater projects into the engine. Further, a bar-shaped center shaft, formed of metal, is inserted into the axial hole of the metallic shell. The center shaft is insulated from the metallic shell and is mounted such that one end portion of the center shaft projects from the rear end of the metallic shell. Two electrodes extend from the heater so as to supply electricity to the heater and are electrically connected to the metallic shell and the center shaft, respectively.
In a glow plug having such a structure, in order to maintain the axial hole of the metallic shell airtight, an O-ring is disposed between the wall surface of the axial hole and the center shaft at the rear end of the axial hole. Further, an insulating member is disposed between the wall surface of the axial hole and the center shaft, and the O-ring is pressed from the rear end side by an end surface of the insulating member. Thus, the O-ring is brought into close contact with the end surface of the insulating member, the wall surface of the axial hole, and the outer circumferential surface of the center shaft, so as to seal the interior of the axial hole. Reference is made, for example, to Japanese Patent Application Laid-Open (kokai) No. 2005-315474.
One problem that has occurred with current glow plug constructions is that glow plugs have been reduced in diameter so as to meet the recent demand for downsizing diesel engines, and the clearance space between the wall surface of the axial hole and the center shaft of each glow plug has decreased. Therefore, disposing an O-ring in the clearance space at the time of assembly of a glow plug is difficult. In addition, because the cross section of an O-ring perpendicular to the circumferential direction thereof is of a circular shape, when such an O-ring is disposed in the narrow clearance space between the wall surface of the axial hole and the center shaft, a portion thereof undergoes substantial local deformation, because the O-ring is sandwiched between the wall surface of the axial hole and the outer circumferential surface of the center shaft and is pressed by the insulating member. If the internal stress of the O-ring increases due to that deformation, the elastic force of the O-ring decreases, which reduces the degree of contact between the wall surface of the axial hole and the outer circumferential surface of the center shaft, and makes it difficult to maintain the axial hole airtight. | {
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The information age is characterized by the widespread availability of information made possible through network communication. However, the mass of available information often makes it difficult to extract data of interest. Because of the potentially laborious nature of extracting valuable data from large amounts of less valuable information, the labor is often referred to as “data mining”. Less valuable or irrelevant information is analogous to raw earth that must be sifted through in order to find valuable minerals, which are analogous to relevant information.
One way to extract information is to submit queries on databases. This method lends itself well to data that has identified properties that are monitored by the database. However, there is a wide variety of ways in which data can be stored. Some types of data, such as time series charts, are not quite as easy to sift through as they can often represent complex line representations that do not lend themselves well subject to database queries. | {
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Oxalic amides are usually widely concerned due to their various biological activities. For example, monomethyl oxalate can be used as chemical hybridization reagent for Cicer arietinum, and oxalate aryldiamide compounds are useful as glycogen phosphorylase inhibitors, or as a small molecule modulator that acts on the CD4-gp120 protein. Until recently, the team led by Dawei Ma uses oxalate 2,6-dimethylphenyl monoamide carboxylic acid as a ligand for copper-catalyzed C—N coupling reaction of aryl iodides and bromides with amines, thus opening up new uses of these compounds. However, this reaction is mainly applicable to the coupling reaction of aryl iodides and bromides.
The transition metal-catalyzed coupling reaction of aryl halides with suitable nucleophiles, such as amines, active methylene compounds, alkynes, phenols, alcohols, thiophenols, sodium sulfinics, sodium sulfides, phosphates and the like, is very efficient for the formation of C—N, C—C, C—O, C—S, and C—P bonds. Generally, due to the high reactivity of aryl iodides and aryl bromides, the corresponding coupling reaction proceeds well under the catalysis of transition metals such as palladium, copper and nickel. Aryl chlorides are cheaper and more readily available, and have more application prospects compared with aryl bromides (iodides). However, high energy of C—Cl bond makes the oxidative addition of transition metal to aryl chlorides hardly occur, and the coupling reaction is more difficult than that of aryl bromides and iodides. Palladium and nickel catalyzed C—N coupling reactions of aryl chlorides have been reported by using sterically hindered phosphine ligands. In 2005, Hartwig and coworkers described the coupling reaction of (hetero)aryl chlorides with primary amines was promoted by a large sterically hindered phosphine ligand with a ferrocene structure. The loading of catalysts and ligands in this system can even be reduced to one hundred thousandth molar equivalent. Such reaction can be accomplished at room temperature for some particular heteroaryl substrates. In addition, a wide range of functionalized (hetero)aryl chlorides were compatible for this transformation.
In 2011, Buchwald's group found that the use of different phosphine ligands allowed the coupling reaction of aryl chlorides with primary and secondary amines respectively. The system has a very wide compatibility with substrates. In addition to common aliphatic amines, the aromatic amines with heterocyclic rings also are suitable nucleophiles.
Although the catalysis of metallic palladium and nickel are highly efficient in the amination of aryl chlorides, there are still some problems in large-scale applications: 1. it is required to add large sterically hindered and complex phosphine ligands or N-heterocyclic carbenes ligands; 2. palladium catalyst is expensive, and for zero-valent nickel catalyzed reaction, the operation is quite harsh. In contrast, copper catalysts are cheap, stable and readily available, and the useful ligands are simple. However, the substrates of copper-catalyzed coupling reaction reported so far are mostly limited to aryl iodides and bromides.
In 2007, Pellón's group reported the coupling of 2-chlorobenzoic acid and aliphatic amines with assistance of ortho-substituent effect and ultrasound. Both primary and secondary amines can provide the corresponding coupling products in good yields. However, only aryl chlorides with ortho-carboxyl substituent are suitable for this transformation (Docampo, M. L.; Pellón, R. F.; Estevez-Braun, A.; Ravelo, A. G. Eur. J. Org. Chem. 2007, 4111.). This reaction should undergo a nucleophilic substitution process rather than a coupling reaction. In addition, the high reaction temperature is still required. A schematic of this reaction is shown in FIG. 1.
Another report on Ullmann coupling reaction of aryl chlorides came from Taillefer's group. They used 2,2,6,6-tetramethyl-3,5-heptanedione as a ligand to achieve C—O coupling of benzyl chlorides with phenols. However, the addition of large amount ligand as much as 0.8 equivalents made the reaction less economically (Xia, N.; Taillefer, M. Chem. Eur. J. 2008, 14, 6037.). A schematic of this reaction is shown in FIG. 2.
In summary, there is no catalytic system for copper-catalyzed coupling reaction of aryl chlorides in the art that enables the reaction to be carried out efficiently. | {
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Heretofore, as a kneading apparatus for kneading a material to be kneaded such as, for example, rubber or plastic, one disclosed in Patent Literature 1 has been known. This conventional kneading apparatus is a double-arm type and is driven by a drive apparatus disposed near the kneading apparatus.
More particularly, the kneading apparatus in question is provided with an externally projecting input shaft, while the drive apparatus is provided with an externally projecting output shaft. The input shaft of the kneading apparatus and the output shaft of the drive apparatus are coupled together through a coupling apparatus having gear coupling portions. With this coupling, power from the drive apparatus is transmitted to the kneading apparatus.
[Patent Literature 1]
Japanese Patent Laid-Open Publication No. 2004-313927 | {
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A known coil spring with press-fit end caps includes dead coil turns with radially inner surfaces fixed to the end caps. The fixed contact between the end caps and radially inner surfaces prevents the deal coil turns from expanding or contracting. Thus, the dead coil turns do not contribute to the spring rate of the coil spring. Further, press-fitting of end caps is not suitable for nitrided coil springs, due to cracking of coil turns due to pressure exerted by the end caps on the coil springs. | {
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The present invention relates to substituted phenolic thioethers and more particularly relates to the novel compounds of formula I which are specific 5-lipoxygenase inhibitors and are useful, for example, as anti-inflammatory and anti-allergy agents.
It is well recognized that arachidonic acid, an essential unsaturated fatty acid, is enzymatically oxygenated to various products, including, prostaglandins, thromboxanes, the 5-, 11-, 12- and 15-hydroxyeicosatetraenoic acids (HETEs, DIHETEs) and hydroperoxyeicosatetranenoic acids (HPETEs) and the leukotrienes, all of which have potent physiological effects. The leukotrienes, which are produced via the 5-lipoxygenase pathway, are the major contributors to the onset of the symptoms of asthma, and mediators for immediate hypersensitivity reactions, inflammation and other allergic responses.
Leukotrienes are found in inflammatory exudates and are involved in the process of cellular invasion during inflammation. The term "leukotrienes" is used as a generic term to describe a class of substances, such as slow-reacting substance (SRS) which is an important mediator in asthma and other hypersensitivity reactions. Immunologically generated SRS is usually referred to as slow-reacting substance of anaphylaxis (SRS-A). SRS-A consists of leukotrienes (LT) known as A.sub.4, B.sub.4, C.sub.4, D.sub.4, and E.sub.4. LTC.sub.4 is at least 100 times more potent than histamine in causing long lasting bronchoconstricting effects. The leukotrienes also increase vascular permeability and cause decreased cardiac output and impaired ventricular contraction. LTB.sub.4 may be an important mediator of inflammation in, for example, inflammatory bowel disease.
Chemotaxis is a reaction by which the direction of migration of cells is determined by substances in their environment. It is one of the major processes bringing leukocytes from the blood to an inflammatory site, whether the inflammation is caused by an infectious agent, allergic challenge, or other pro-inflammatory stimuli. LTB.sub.4 is not only chemotactic for neutrophils and monocytes, but is also highly active in stimulating eosinophil locomotion. LTB.sub.4 also stimulates calcium influx and aggregation of polymorphonuclear leukocytes and LTB.sub.4 may, thus, play an important role in mediating both acute and chronic inflammation.
Rheumatoid spondylitis is characterized by an acute neutrophil flareup in the joint which is associated with elevated levels of LTB.sub.4. LTB.sub.4 is also present in gouty effusions; and exposure to urate crystals is known to stimulate LTB.sub.4 production by neutrophils. Accordingly, the 5-lipoxygenase inhibitors of the present invention through inhibition of neutrophil attraction and activation in arthritic joints should reduce the protease and oxidative burden believed responsible for joint destruction in arthritic diseases.
Aspirin and the other non-steroidal anti-inflammatory agents (NSAIDs) such as indomethacin, ibuprofen, fenoprofen, and the like, inhibit the synthesis of prostaglandins via the cyclooxygenase pathway of arachidonic acid metabolism. These prostaglandin synthetase inhibitors generally exhibit anti-inflammatory, anti-pyretic and analgesic activity, and are widely used in the treatment of arthritis. The non-steroidal anti-inflammatory agents can lead to the formation of additional pro-inflammatory derivatives of arachidonic acid produced through the 5-lipoxygenase pathway which play a role in immediate hypersensitivity reactions and also have pronounced inflammatory effects. Administration of the NSAIDs alone can produce allergic reactions including bronchospastic reactivity; skin rashes; syndrome of abdominal pain, fever, chills, nausea and vomiting; and anaphylaxis. For this reason, aspirin and the other non-steroidal anti-inflammatory agents (NSAIDs) are generally contraindicated for patients suffering from asthma or who have previously exhibited allergic sensitivity to aspirin or other NSAIDs. Co-administration of the 5-lipoxygenase inhibitors of this invention with cyclooxygenase inhibitors may mitigate the untoward side effects of the latter and allow the increased advantageous use of such cyclooxygenase inhibitors.
Prior to the recognition of the significance of the 5-lipoxygenase pathway of arachidonic acid metabolism in allergic reactions and inflammation, the search for effective therapeutic agents was based primarily on those agents which treated the symptoms of allergy and inflammation. There has since been effort to develop new drugs which selectively block the formation of the mediators of these conditions, and the present invention provides new chemical entities which are inhibitors of the 5-lipoxygenase pathway and are useful in the treatment of asthma, rheumatoid arthritis, psoriasis, and other allergic, hypersensitivity, and inflammatory conditions.
See Bengt Samuesson, "Leukotrienes: Mediators of Immediate Hypersensitivity Reactions and Inflammation", Science, Vol. 220, pp. 568-575 (May 1983); Michael K. Bach, "Inhibitors of Leukotriene Synthesis and Action", The Leukotrienes, Chemistry and Biology, pp 163-194 (Academic Press, Inc., 1984); C. W. Lee et al., "Human Biology and Immunoreactivity of Leukotrienes", Advances in Inflammation Research, Volume 6, pp 219-225 (Raven Press, New York 1984); Editorial, "Leukotrienes and other Lipoxygenase Products in the Pathogenesis and Therapy of Psoriasis and Dermatoses", Arch. Dermatol, Vol. 119, pp 541-547 (July, 1983); Robert A. Lewis et al., "A Review of Recent Contributions on Biologically active Products of Arachidonate Conversion", Int. J. Immunopharmac., Vol. 4, No. 2, pp 85-90 (1982); Michael K. Bach, Biochemical Pharmacology, Vol. 23, No. 4, pp 515-421 (1984); and E. L. Becker, Chemotactic Factors of Inflammation, pp 223-225 (Elsevier Science Publishers V.B., Amsterdam, 1983); P. Sharon, and W. F. Stenson, Gastroenterology, Vol. 84, 454 (1984); and Musch, M. W. et al., Science, Vol. 217, 1255 (1982).
The present invention provides compounds which block the 5-lipoxygenase metabolic pathway and, therefore, block the formation of the leukotrienes responsible for allergy and inflammation, and represent therapeutic agents which are useful in the treatment of allergic and hypersensitivity reactions and inflammation, alone, or also may be utilized in combination with other lipoxygenase inhibitors or with cyclooxygenase inhibitors such as the non-steroidal anti-inflammatory agents.
Various thioether compounds have been described previously. For example, European Patent Application publication No. 0131221 discloses compounds of the formula ##STR2## in which Ar is phenyl or phenyl substituted by one to three of varied substituents, for example, alkyl, alkoxy, hydroxy, etc.; Q is oxygen, sulfur or an NH group; A is straight or branched chain, optionally substituted, alkylene and R is hydrogen or straight or branched alkyl, optionally substituted by alkoxy, hydroxyl, carboxyl, alkoxycarbonyl, etc.; and n is 0, 1 or 2. The disclosed compounds are indicated to have anti-inflammatory and anti-allergic properties through inhibition of undefined anaphylactic and anaphylactoid reactions, although no test data are provided. The preferred compounds are stated to be those in which Q represents oxygen and n is O without mention of any preference among the numerous possible substituents for R or substituted phenyl as Ar. In contrast to the invention disclosed in the foregoing publication, the compounds of the present invention all have a sulfur atom at the position corresponding to Q as well as having di(tertiary)-alkyl or diphenyl groups as substituents on the phenol moiety corresponding to the substituted Ar group in the above publication which, as described therein, amy or may not comprise a phenol. Moreover, it is noted that the compounds of the present invention have been found to possess specificity for the inhibition of 5-lipoxygenase which is an important distinctive property not attributed to the compounds in the foregoing publication. Those of ordinary skill in the art will appreciate that the compounds of formula I of this invention, including their surprising specific 5-lipoxygenase inhibitory properties, are, therefore, not specifically described in the aforementioned EPA publication No. 0131221.
U.S. Pat. Nos. 4,029,812, 4,076,841 and 4,078,084 disclose compounds of the formula ##STR3## comprising 2-(3,5-di-tert-butyl-4-hydroxy-phenyl)thio carboxamides. The compounds are indicated to be useful in lowering serum cholesterol and triglyceride levels.
A series of thioethers, useful as, for example, polyfunctional antioxidants for polymers, and biologically active substances, obtained by the nucleophilic addition of thiols, including 3,5-di-tert-butyl-4-hydroxythiophenol, and hydrogen sulfide to acrylate derivatives have been described. See Medvedev et al., Khimiya; Khimicheskaya Tekhnologiya, Volume 20, (1977), pp. 568-574. The compounds resulting from the foregoing process have the general formulas RS(CH.sub.2).sub.n X and S(CH.sub.2 CH.sub.2 X).sub.2 in which R is 3,5-di-tert-butyl-4-hydroxyphenyl and X represents, for example, --C.tbd.N, NH.sub.2, CH(OH)CH.sub.2 Cl, OH, COCl and various carboxy, carboxylate and amide functions. Compounds of formula I according to the present invention or 5-lipoxygenase activity for structurally related compounds are not disclosed.
U.S. Pat. No. 4,153,803 discloses cholesterol-lowering phenoxyalkanoic acid esters of the formula ##STR4## wherein, when Y is sulfur, X is hydrogen, benzyl, benzyloxy or benzylthio or substituted derivatives thereof; R is hydrogen, halogen, hydroxy, alkyl or alkoxy, A.sup.1 and A.sup.2 are hydrogen or alkyl and Z is amine or azacyclohydrocarbonyloxy. | {
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The invention relates to a device for contact-free data gathering from a thermal machining system with at least one machining tool and one workpiece.
A workpiece such as a metal plate or the like can be cut into the desired shape with a cutting torch or a laser cutting head by means of which a cutting beam is aimed at the surface and it then cuts through the workpiece.
In general, the cutting torch is mounted in a mobile holder so that the cutting torch can move along the workpiece in the desired pattern. The distance between the torch nozzle and the workpiece must be constant so that an optimal cutting of the workpiece is achieved and maintained. If the distance between the torch nozzle and the workpiece is too small, then uneven spots in the workpiece can cause contact with the tip of the torch, thereby extinguishing the flame and interrupting the cutting of the workpiece. If the distance is too great, this can impair the cutting quality and the cut will be interrupted. In the case of laser cutting, great distance changes cause a shift in the position of the focal point in the metal and it is no longer possible to cut.
It is known that distances to workpieces are measured with capacitive measuring methods and that the holder of the cutting torch is kept at a constant height above the surface of the workpiece via a closed control circuit (West German patent no. DE 26 41 851 A1, East German patent no. DD 225 651 A1).
In the case of capacitive distance measurement, sensor elements are used in the vicinity of the torch nozzle, and these sensor elements are designed in the shape of a ring, horseshoe or plate. Since they are located in the hot or spraying area of the cutting beam, they only have a short service life and must be replaced at regular intervals.
In order to obtain an adequately strong measuring signal with the known models, as a rule, annular sensor elements with large diameters are used, which are disadvantageous whenever the end edge of the workpiece runs close by or whenever workpieces have already been cut out of the workpiece plate in the immediate vicinity, so that the sensor element is no longer positioned completely above the surface of the workpiece. This leads to erroneous measuring signals.
In the case of devices with an oscillator circuit and a frequency-determining capacity with a subsequent PLL circuit or the like, LC combinations are also necessary in the vicinity of the sensor elements. In actual practice, this calls for a positioning of electronic components in the hot area of the cutting process and a large diversity of parts for the different machines and torch models. Moreover, due to the high-voltage ignition systems used, high field strengths and severe electromagnetic interferences occur. The interference contours at the torch are increased. Thus, although the known devices fulfill the required functions in all kinds of different systems, the mechanical, electrical and electronic complexity is very great. Individual mechanical and electrical design elements of the thermal machining system lead to changeable parasitic capacities which enter into the distance measurements; these elements include factors such as the size of the torch carriage, the type, size and shape of the cutting torch, the type of the nozzles and nozzle caps, type of gas, marking tools, torch holders, distance to adjacent torches when the height of the individual torch shifts as well as, in the case of multiple torch aggregates, additional mounted elements in the vicinity of the torch and process fluctuations typical in actual practice with electric arcs as well as with autogenic and laser processes as well as the cable lengths used, whose capacity and plug-and-socket connections in the measuring circuit and transition resistances, for example, in slip rings with infinitely rotatable aggregates.
Moreover, it is also known that thermal influences have an impact on electronic components in the vicinity of the torch as well as on the capacity of cables and plug-and-socket connections and, especially in the case of frequency-based devices, these influences can lead to drifting during operation. The dynamic range of such devices is currently only a distance of a few millimeters from the nozzle to the sheet (workpiece) and calls for a complex and precise adjustment of the sensor elements.
An arrangement to compensate for interfering emissions of electromagnetic high-frequency vibrations with contact-free sensing devices is described in German patent no. DE 30 42 781 A1.
Moreover, a device for contact-free determination of the position and/or the dielectric properties of objects is known for use in an annealing furnace; this device sensitively detects any interference in an electrical alternating field. It consists of an arrangement of three electrical conductors, two of which are operated as field-generated transmission electrodes with a low-frequency, opposite-phase alternating voltage, whereas the third conductor serves as a current-sensitive measuring electrode. The results of frequency-sensitive and phase-positive processing of the measuring signals is a high measuring sensitivity and a great insensitivity to electrical interference effects (European patent no. EP 0 038 551 B1).
In this context, the direction-dependence of the two transmission electrodes is detrimental during cutting processes since such processes also involve cutting in a plane in any desired direction at any time. The distorting effect of cut joints on the measured value is especially great when the cut is made in the direction of the sensor electrodes. Furthermore, installing two transmission electrodes in the vicinity of the torch entails great mechanical difficulties.
Moreover, an inductive device is known which consists of at least one receiving coil and at least one primary excitation coil connected to a HF generator for inducing voltage values which can be predetermined in the undisturbed state and which have opposite polarity in the receiving coil. In order to compensate for errors and deviations in the induction in the receiving coil, there is at least one additional excitation coil which generates a compensation field or compensation voltages in the receiving coil (European patent no. EP 0 300 974 A1).
In addition to the physically differing signal stabilities and interference voltage distances that exist for the various measuring methods, the state of the art makes it possible to achieve the necessary functions in the different systems, but the influences stemming from the occurrence of plasma and thus of differing conductivities and parasitic capacities in the area of the sensor elements or of the measuring electrodes lead to complicated subsequent electronic correction measures of the distance signal. The actual measurement distance between the sensor elements and the workpiece is affected. The autogenic flame, the plasma light arc or the laser beam, etc., influence and distort the measured values of capacitive sensor systems in various ways, depending on the process and on the process state.
The result is that there are large differences between the positions of the tools to the sheet metal which can be achieved with and without plasma. The effect is negative for the cutting process as well as for the automation of the machine.
In most cases, during the individual cutting phases, an incorrect distance measurement which is detrimental to the cutting quality and consequently an incorrect height of the nozzle above the sheet has to be accepted as a compromise. In order to avoid cutting interruptions during autogenic welding as a result of flashbacks, for example, excessive distances often have to be maintained during the cutting operation, with the result that the quality of the cut deteriorates and the effectiveness of the process decreases or else the cutting speed is too low. Conversely, if the distances are too great, an inadequate power density can interrupt the cutting process.
Furthermore, a state of the art is known in which the capacitive annular distance sensor is arranged concentrically around the torch nozzle, and its distance to the workpiece is greater than that of the torch nozzle. In addition to detecting the distance, this sensor ring also serves to detect a collision of the sensor ring and the workpiece if the sensor comes into lateral contact with the workpiece in the case of a horizontal movement path. An interactive electronic system evaluates the contact and activates the subsequent control steps in order to move the torch with the torch nozzle out of the danger zone.
The lower torch nozzle is not protected by the state of the art, especially in the case of a vertical movement path. | {
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The invention relates to a process for the linearization and characterization of an image producing RGB or CMYK device according to the preamble of the independent claim.
The invention relates to the field of graphic processing and especially to the image producing devices used in its workflows, especially printers.
The typical graphic processing workflow includes the use of different image producing devices and offers the user the possibility to produce, look at, correct and output, especially print, images. The workflow normally extends from an image capturing step with input devices such as digital cameras and scanners to an observation step with display devices such as, for example a monitor, to an output step with output devices such as, for example, a printer. The user thereby aims in the output step for images which either come as close as possible to the underlying original or which are (according to individual conceptions) perceived as “nice” or “pleasing”.
Because of the technological differences between the image producing devices (for example CCD, Filter, Inkjet, others), the need exists to first adjust the devices involved to a common colour description language. One of the most important points is thereby the linearization and characterization of each image producing device involved.
The linearization is most of the time carried out by the device manufacturer, requires special knowledge and requires a lot of time. The ICC (International Colour Committee) has defined what is to be understood under characterization: an ICC colour profile is assigned to each image producing device which describes the colour capabilities/limitations of the device.
The generation of an ICC profile for an image producing device is a relatively lengthy process which includes amongst other things the reproduction (for example printing) of a colour test chart with a respective device as well as the colorimetric evaluation of the many hundred individual test fields on the reproduced colour test chart. Standard colour test charts set by the ICC are often used, but special colour test charts of the manufacturers of profile generation software are also used. Common colour test charts are, for example, the IT8.73 (928 measurement fields) and the ECI2002 (1440 measurement fields). The working with such large colour test charts is very time consuming and costly for the normal (for example private) user. | {
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I. Field and Purview
The present invention concerns heat-inhibition with respect to a motor, and the same in connection with a heated instrument.
II. Art with Problems
In kinematic viscosity baths, a tank of mineral oil is heated to provide control for samples immersed therein for determination of kinematic viscosity, and the mineral oil is stirred to provide uniform heating of the samples. It is a simple device, indeed, and owing to its simplicity and the nature of testing involved in the art, economy is a prime consideration in providing the baths.
In prior baths, the rather inexpensive stirring motor, which was mounted directly to a top panel on the kinematic viscosity bath cabinet, would fail prematurely owing to overheating from transfer of heat from the bath during testing. One solution is to purchase and install another model of motor rated to withstand the 150-degree C. temperature of the test, but such an alternate motor involves a roughly five- to ten-fold increase in cost compared to the more economically priced motor. Thus, the consideration of economy in providing the test would be lost.
It would be desirable to ameliorate if not overcome the same. | {
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During the steel making processes, a large amount of steel-making slag is generated. Although the steel-making slag contains, for example, P and metal components such as Fe and Mn, it also contains a large amount of CaO, which leads to expansion and collapse. This has restricted the steel-making slag to be used as, for example, a material for roadbed or aggregate. However, in recent years, resources have been increasingly recycled, and a large number of methods for recovering the valuable substances from the steel-making slag has been disclosed.
Patent Document 1 discloses a method of processing iron and steel slag, which includes adding iron and steel slag generated during melting and making iron and steel, to molten iron and steel liquid in the smelting furnace, further adding heat and reducing agents, moving Fe, Mn, and P to the molten liquid while altering the iron and steel slag to obtain altered slag, and then, moving Mn and P in the molten liquid into the slag. However, this processing method requires batch processing to be continuously applied several times until a slag with predetermined components can be obtained, and hence, results in poor working efficiency.
Patent Document 2 discloses a method, which includes: supplying steel slags having iron oxide contents of more than 5 wt % onto a steel bath having a carbon content of less than 1.5 wt %; then introducing carbon or carbon carriers to carbonize the steel bath to obtain the steel bath having a carbon content of more than 2.0 wt %; and then performing reduction processing.
However, with the method described in Patent Document 2, the concentration of C (carbon concentration) in the molten iron is set to less than 1.5 wt % at the time of inserting the molten slag to suppress the discharge of the large amount of gas, and the concentration of C is increased to more than 2.0 wt % at the time of performing smelting reduction, thereby performing desired reduction. Thus, a process of de-carbonization in conjunction with an increase in temperatures and a process of addition of carbon for reduction are repeated, which results in batch processing. As a result, working efficiency deteriorates. It should be noted that, since the method described in Patent Document 2 increases the concentration of C to more than 2.0 wt % at the time of performing the reduction processing, it is considered that this method promotes the reduction reaction mainly through the reaction between slag and metal.
Further, in the method described in Patent Document 2, the carbon material is used as the heat source as well as the reducing agent, and hence, the amount of exhaust gas increases. Thus, it is assumed that the thermal efficiency deteriorates, and the amount of dust generated increases.
Non-Patent Document 1 discloses results of reduction tests in which steel-making slag powder, carbon material powder, and slag-modifying agent powder are inserted through a hollow electrode into an electric furnace. However, in the reduction tests described in Non-Patent Document 1, the test is performed in an electric furnace by processing the cold steel-making slag, which has been solidified and crushed, and hence, the energy-consumption rate is large.
Further, Patent Document 3 discloses a technique of recovering valuable metals by reducing molten slags generated during smelting of non-ferrous metals using carbonaceous reducing agents in an open-type direct-current electric furnace to separate it into a metal phase and a slag phase. However, the method described in Patent Document 3 also involves a batch process with an electric furnace using the cold slag as the target of the processing, and hence, the energy-consumption rate is large.
As described above, these methods of recovering valuable components from the slags each have a problem of poor working efficiency or large energy-consumption rate. | {
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As is well known, fluid dynamic bearing devices have features in, for example, their high speed rotation, high rotational accuracy, and quietness. Thus, the fluid dynamic bearing devices are suitably used as bearing devices for motors to be mounted to various electrical apparatus such as information apparatus, for example, as bearing devices for spindle motors to be built in disk drives such as HDDs, for fan motors to be built in PCs and other devices, or for polygon scanner motors to be built in laser beam printers (LBPs).
For example, in Patent Literature 1, there is disclosed a fluid dynamic bearing device (spindle motor) including a bearing sleeve made of sintered metal, a rotary member including a shaft portion inserted along an inner periphery of the bearing sleeve, and a hub portion arranged on an axially outer side with respect to one end surface of the bearing sleeve, and a radial bearing portion and a thrust bearing portion configured to support the rotary member in a non-contact manner respectively in a radial direction and a thrust direction. Along with rotation of the rotary member, a radial bearing gap of the radial bearing portion is formed between an inner peripheral surface of the bearing sleeve and an outer peripheral surface of the shaft portion opposed to the inner peripheral surface of the bearing sleeve, and a thrust bearing gap of the thrust bearing portion is formed between the one end surface of the bearing sleeve and an end surface of the hub portion opposed to the one end surface of the bearing sleeve. In this fluid dynamic bearing device, the bearing sleeve is fixed to an inner periphery of a housing having a bottomed cylindrical shape. An opening portion of the housing is formed between an outer peripheral surface of the housing and an inner peripheral surface of the hub portion, and is sealed by a sealing gap that retains an oil surface of lubricating oil. With this configuration, leakage of the lubricating oil to an outside can be prevented as much as possible, thereby being capable of stably maintaining desired bearing performance. | {
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Loss prevention is a continuing problem in the retail industry. Current anti-theft systems involve locking up merchandise behind counters, far away from related merchandise, or locking up the merchandise in secure cabinets, closer to the place where related merchandise is generally stored.
There are disadvantages to each of these methods. When merchandise is stored in a secured location away from the point of storage of related items, sales of the secured merchandise decrease because customers are less likely to go out of their way to locate a sales associate to retrieve the merchandise. Also, sales of related items that would otherwise be situated in proximity to the secured merchandise decrease as well because the customer is not drawn to their location.
Therefore, although common anti-theft systems may be effective at preventing loss, they also have the significantly negative impact of reducing sales.
Accordingly, there exists a need in the art for an anti-theft system for retail stores that will deter theft without discouraging the sale of the merchandise and related items. Additionally, the anti-theft system should be able to be retrofitted onto existing retail displays to keep the cost of installation and the shelving downtime required for installation as low as possible.
The invention provides such an anti-theft system. This and other advantages of the invention, as well as additional inventive features, will be apparent from the description of the invention provided herein. | {
"pile_set_name": "USPTO Backgrounds"
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1. Field of the Invention
This invention relates to novel polynucleotides identified and sequenced which encode a carboxylesterase enzyme, polypeptides encoded by these polynucleotides and vectors and host cells comprising these vectors which express the enzyme. This enzyme is capable of metabolizing chemotherapeutic prodrugs and inactive metabolites into active drug. The instant invention thus relates to compositions comprising these polynucleotides and methods for sensitizing selected tumor cells to a chemotherapeutic prodrug by transfecting the tumor cells with a polynucleotide placed under the control of a disease-specific responsive promoter. Sensitized tumor cells can then be contacted with a chemotherapeutic prodrug to inhibit tumor cell growth. Compositions of the present invention can also be used in combination with chemotherapeutic prodrugs to purge bone marrow of tumor cells. The invention further includes novel drug screening assays for identifying chemotherapeutic prodrugs that are activated by this enzyme.
2. Background of the Invention
Cancer is a disease resulting from multiple changes at the genomic level. These changes ultimately lead to the malfunction of cell cycle machinery and finally to autonomous cell proliferation. Neoplastic transformation involves four types of genes: oncogenes, tumor-suppressor genes, mutator genes, and apoptotic genes. Different types of cancer can involve alteration of any one or any combination of these genes.
Proto-oncogenes of the myc family are overexpressed in many different types of human tumors including tumors of the breast, colon, cervix, head and neck, and brain. Many solid tumors amplify or overexpress c-myc, with up to a 50-fold increase in c-myc RNA in tumor cells relative to normal cells having been reported (Yamada, H. et al. 1986. Jpn. J. Cancer Res. 77:370-375). For example, three of the six most common solid tumors, including up to 100% of colon adenocarcinomas, 57% of breast cancers, and 35% of cervical cancers, demonstrate increased levels of c-myc protein. Enforced expression of c-myc in nontumorigenic cells causes immortalization but not transformation; however, elevated levels of c-myc protein are rare in benign cancers and normal differentiated tissue. While solid tumors can oftentimes be removed surgically, overexpression of c-myc has been linked with amplification of the c-myc gene and correlated with poor prognosis and an increased risk of relapse (Nagai, M. A. et al. 1992. Dis. Colon Rectum 35:444-451; Orian, J. M. et al. 1992. Br. J. Cancer 66:106-112; Riou, G. et al. 1987. Lancet 2:761-763; Field, J. K. et al. 1989. Oncogene 4:1463-1468).
Another member of the myc oncogene family, N-myc, has been linked with development of neuroblastomas in young children. Overexpression of this member of the myc family of proto-oncogenes has also been correlated with advanced stages of disease and poor prognosis (Brodeur, G. M. et al. 1997. J. Ped. Hematol. Oncol. 19:93-101). Primary tumors for this specific condition usually arise in the abdomen and as many as 70% of patients have bone marrow metastases at diagnosis (Matthay, K. E. 1997. Oncology 11:1857-1875). Treatment of children with Stage 4 disease using surgery, chemotherapy, and purged autologous or allogeneic marrow transplant produces a progression-free survival rate of 25 to 49% in patients four years post transplant (Matthay, K. K. et al. 1994. J. Clin. Oncol. 12:2382-2389). Most relapses after autotransplant occur at sites of bulk disease and/or previously involved sites. Estimates of the rate of local recurrence vary depending upon the study. However, recurrence of tumor at an original site has been estimated to occur in approximately 25% of high risk neuroblastoma patients.
Further, definitive evidence from gene marking studies indicates that autologous marrow, free of malignant cells by standard clinical and morphologic criteria, contributes to relapse at both medullary and extramedullary sites (Rill, D. R. et al. 1994. Blood 84:380-383). In a recent pilot clinical study, bone marrow involvement at diagnosis correlated with specific relapse at that site in children receiving autologous purged marrow (Matthay, K. K. et al. 1993. J. Clin. Oncol. 11:2226-2233). Accordingly, improvements in surgery, detection of tumor margins, development of new anticancer drugs or application of novel therapies are required to prevent local tumor regrowth. In particular, more effective treatment strategies are needed for elimination of xe2x80x9cminimal residual diseasexe2x80x9d or xe2x80x9cMRDxe2x80x9d which results from the presence of a small number of tumor cells at the site of disease after treatments such as tumor resection or purging bone marrow of tumor cells.
CPT-11 (irinotecan, 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin) is a prodrug currently under investigation for the treatment of cancer that is converted to the active drug known as SN-38 (7-ethyl-10-hydroxy-camptothecin) (Tsuji, T. et al. 1991. J. Pharmacobiol. Dynamics 14:341-349; Satoh, T. et al. 1994. Biol. Pharm. Bull. 17:662-664). SN-38 is a potent inhibitor of topoisomerase I (Tanizawa, A. et al. 1994. J. Natl. Cancer Inst. 86:836-842; Kawato, Y. et al. 1991. Cancer Res. 51:4187-4194), an enzyme whose inhibition in cells can result in DNA damage and induction of apoptosis (Hsiang, Y. -H. et al. 1989. Cancer Res. 49:5077-5082). The specific enzyme responsible for activation in vivo of CPT-11 has not been identified, although serum or liver homogenates from several mammalian species have been shown to contain activities that convert CPT-11 to SN-38 (Tsuji, T. et al. 1991. J. Pharmacobiol. Dynamics 14:341-349; Senter, P. D. et al. 1996. Cancer Res. 56:1471-1474; Satoh, T. et al. 1994. Biol. Pharm. Bull. 17:662-664). Uniformly, these activities have characteristics of carboxylesterase (CE) enzymes (Tsuji, T. et al. 1991. J. Pharmacobiol. Dynamics 14:341-349; Senter, P. D. et al. 1996. Cancer Res. 56:1471-1474; Satoh, T. et al. 1994. Biol. Pharm. Bull. 17:662-664). In fact, SN-38 can be detected in the plasma of animals and humans minutes after the administration of CPT-11 (Stewart, C. F. et al. 1997. Cancer Chemother. Pharmacol. 40:259-265; Kaneda, N. et al. 1990. Cancer Res. 50:1715-1720; Rowinsky, E. K. et al. 1994. Cancer Res. 54:427-436), suggesting that a CE enzyme present in either serum or tissues can convert the camptothecin analog to its active metabolite.
CEs are ubiquitous serine esterase enzymes that are thought to be involved in the detoxification of a variety of xenobiotics. CEs are primarily present in liver and serum, however, the physiological role of this class of enzymes has yet to be identified. A recent biochemical analysis of 13 CEs compared their ability to metabolize CPT-11 to SN-38. While the efficiency of conversion varied between enzymes, those isolated from rodents were the most efficient (Satoh, T. et al. 1994. Biol. Pharm. Bull. 17:662-664). The amino acid sequence of a rabbit liver CE has been disclosed (Korza, G. and J. Ozols. 1988. J. Biol. Chem. 263:3486-3495). In addition, there are currently 13 CDNA sequences encoding CE in the GenBank and EMBL databases, including a rat serum and rat liver microsomal CE. Interestingly, CEs purified from human tissues demonstrated the least efficient conversion of CPT-11 to SN-38, with less than 5% of the prodrug being converted to active drug (Leinweber, F. J. 1987. Drug Metab. Rev. 18:379-439; Rivory, L. P. et al. 1997. Clin. Cancer Res. 3:1261-1266).
In addition to metabolism to SN-38, in humans CPT-11 is also metabolized to a compound known as APC (Haaz, M. C. et al. 1998. Cancer Res. 58:468-472). APC has little, if any, anti-tumor activity and is not converted to an active metabolite in humans (Rivory, L. P. et al. 1996. Cancer Res. 56:3689-3694).
In preclinical studies, CPT-11 administered to immune-deprived mice bearing human tumor xenografts produces complete regression of glioblastomas, rhabdomyosarcomas (RMS), neuroblastomas, and colon adenocarcinomas (Houghton, P. J. et al. 1995. Cancer Chemother. Pharmacol. 36:393-403; Houghton, P. J. et al. 1993. Cancer Res. 53:2823-2829). However, maintenance of tumor regression in studies with CPT-11 appears to be dependent upon drug scheduling, suggesting that viable tumor cells survive therapy (i.e., minimal residual disease (MRD)). These studies also showed a steep dose-response relationship between dose of drug administered and induction of tumor regression. For example, 20 mg of CPT-11/kg/day given daily for 5 days for two weeks produced complete regression of Rh18 RMS xenografts, while 10 mg/kg/day given on the same schedule produced only partial tumor regression. Similar effects were seen when mice bearing SJGC3A colon adenocarcinoma xenografts were treated with 40 mg CPT-11/kg compared to a 20 mg/kg dose.
Early clinical trials with CPT-11 indicate that the prodrug also has anti-tumor activity in vivo against many different types of solid tumors in humans. However, myelosuppression and secretory diarrhea limit the amount of drug that can be administered to patients. Accordingly, before this promising anti-cancer agent can be used successfully, these dose-limiting toxicities must be overcome.
The development of new effective treatment strategies for cancer is dependent upon the availability of specific drug screening assays. Specific drug screening assays can involve isolated target tissue models, i.e., isolated heart, ileum, vasculature, or liver from animals such as rabbits, rats, and guinea pigs, wherein the target tissue is removed from the animal and a selected activity of that target tissue is measured both before and after exposure to the candidate drug. An example of a selected activity measured in drug screening assays to identify new cancer agents is the activity of enzymes such as topoisomerase I or II, which are known to modulate cell death. Such assays can also be used to screen for potential prodrugs which are converted to the active metabolite in selected tissues or to identify selected tissues capable of converting prodrug to its active metabolite.
However, any molecular event that is shown to be modified by a novel class of compounds can be developed as a screening assay for selection of the most promising compounds for therapeutic development. In fact, in recent years the idea of modulating cells at the genomic level has been applied to the treatment of diseases such as cancer. Gene therapy for treatment of cancer has been the focus of multiple clinical trials approved by the National Institutes of Health Recombinant DNA Advisory Committee, many of which have demonstrated successful clinical application (Hanania et al. 1995. Am. Jour. Med. 99:537-552; Johnson et al. 1995. J. Am. Acad. Derm. 32(5):689-707; Barnes et al. 1997. Obstetrics and Gynecology 89:145-155; Davis et al. 1996. Current Opinion in Oncology 8:499-508; Roth and Cristiano 1997. J. Natl. Canc. Inst. 89(1):21-39). To specifically target malignant cells and spare normal tissue, cancer gene therapies must combine selective gene delivery with specific gene expression, specific gene product activity, and, possibly, specific drug activation. Significant progress has been made in recent years using both viral (retrovirus, adenovirus, adeno-associated virus) and nonviral (liposomes, gene gun, injection) methods to efficiently deliver DNA to tumor sites. Genes can be transfected into cells by physical means such as scrape loading or ballistic penetration, by chemical means such as coprecipitation of DNA with calcium phosphate or liposomal encapsulation; or by electro-physiological means such as electroporation. The most widely used methods, however, involve transduction of genes by means of recombinant viruses, taking advantage of the relative efficiency of viral infection processes. Current methods of gene therapy involve infection of organisms with replication-deficient recombinant viruses containing the desired gene. The replication-deficient viruses most commonly used include retroviruses, adenoviruses, adeno-associated viruses, lentiviruses and herpes viruses. The efficacy of viral-mediated gene transfer can approach 100%, enabling the potential use of these viruses for the transduction of cells in vivo.
Adenovirus vector systems in particular have several advantages. These include the fact that non-dividing cells can be transduced; transduced DNA does not integrate into host cell DNA, thereby negating insertional mutagenesis; the design of adenoviral vectors allows up to 7 kb of foreign DNA to be incorporated into the viral genome; very high viral titers can be achieved and stored without loss of infectivity; and appropriate plasmids and packaging cell lines are available for the rapid generation of infectious, replication-deficient virus (Yang, N. S. 1992. Crit. Rev. Biotechnol. 12:335-356). The effectiveness of adenoviral-mediated delivery of genes into mammalian cells in culture and in animals has been demonstrated.
To increase the specificity and safety of gene therapy for treatment of cancer, expression of the therapeutic gene within the target tissue must also be tightly controlled. For tumor treatment, targeted gene expression has been analyzed using tissue-specific promoters such as breast, prostate and melanoma specific promoters and disease-specific responsive promoters such as carcinoembryonic antigen, HER-2/neu, Myc-Max response elements, DF3/MUC. Dachs, D. U. et al. 1997. Oncol. Res. 9(6-7):313-25. For example, the utility of herpes simplex virus thymidine kinase (HSV-TK) gene ligated with four repeats of the Myc-Max response element, CACGTG (SEQ ID NO:22), as a gene therapy agent for treatment of lung cancer with ganciclovir was examined in c-, L- or N-myc-overexpressing small cell lung cancer (SCLC) cell lines (Kumagai, T. et al. 1996. Cancer Res. 56(2):354-358). Transduction of the HSV-TK gene ligated to this CACGTG (SEQ ID NO:22) core rendered individual clones of all three SCLC lines more sensitive to ganciclovir than parental cells in vitro, thus suggesting that a CACGTG-driven HSV-TK gene may be useful for the treatment of SCLC overexpressing any type of myc family oncogene. Additional experiments with c-myc have focused on the use of the ornithine decarboxylase (ODC) promoter gene. Within the first intron of the ODC gene are two CACGTG xe2x80x9cE boxesxe2x80x9d that provide binding sites for the c-myc protein when bound to its partner protein known as max. Mutation of the E box sequence results in the inability of c-myc to transactivate the ODC promoter. Previous reports indicate that reporter constructs containing the ODC promoter fused upstream of the chloramphenicol acetyltransferase gene immediately adjacent to the second exon were activated in cells that overexpress c-myc (Bello-Fernandez, C. et al. 1993. Proc. Natl Acad. Sci. USA 90:7804-7808). In contrast, transient transfection of promoter constructs in which the E boxes were mutated (CACGTG (SEQ ID NO:22) to CACCTG (SEQ ID NO:25) demonstrate significantly lower reporter gene activity. These data suggest that it is possible to activate transcription of specific genes under control of the c-myc responsive ODC promoter. In the case of N-myc, N-myc protein is a basic helix-loop-helix (BHLH) protein that can dimerize with proteins of the same class. N-myc dimerizes with the BHLH protein max to form a complex that binds to the CACGTG motif present in gene promoters, such as ODC, resulting in transactivation and expression of specific genes containing this sequence (Lutz, W. et al. 1996. Oncogene 13:803-812). Studies in a neuroblastoma cell line and tumors have shown that binding of N-myc to its consensus DNA binding sequence correlates with N-myc expression, data that indicate that the level of N-myc in neuroblastoma cells is a determining factor in expression of proteins under control of promoters containing the CACGTG sequence (Raschella, G. et al. 1994. Cancer Res. 54:2251-2255). Inhibition of expression of the c-myc gene via antisense oligonucleotides as a means for inhibiting tumor growth has also been disclosed (Kawasaki, H. et al. 1996. Artif. Organs 20(8):836-48).
In the present invention, polynucleotides encoding carboxylesterase enzymes or active fragments thereof and polypeptides encoded thereby which are capable of metabolizing the chemotherapeutic prodrug CPT-11 and its inactive metabolite APC to active drug SN-38 are disclosed. Use of these enzymes in combination with APC renders this inactive metabolite a useful chemotherapeutic prodrug. It has also been found that compositions comprising a polynucleotide of the present invention and a disease-specific responsive promoter can be delivered to selected tumor cells to sensitize the tumor cells to the chemotherapeutic prodrug CPT-11, thereby inhibiting tumor cell growth.
An object of the present invention is to provide polynucleotides encoding carboxylesterases capable of metabolizing a chemotherapeutic prodrug and inactive metabolites thereof to active drug.
Another object of the present invention it to provide polypeptides encoded by these polynucleotides.
Another object of the present invention is to provide vectors comprising these polynucleotides and host cells containing these vectors which express carboxylesterases.
Another object of the present invention is to provide a composition comprising a polynucleotide encoding a carboxylesterase and a disease-specific responsive promoter of selected tumor cells or a promoter such as CMV.
Another object of the present invention is to provide a method for sensitizing tumor cells to a chemotherapeutic prodrug which comprises transfecting selected tumor cells with a composition comprising a polynucleotide encoding carboxylesterase and a disease-specific responsive promoter of the selected tumor cells.
Another object of the present invention is to provide a method of inhibiting growth of selected tumor cells which comprises sensitizing selected tumor cells to a chemotherapeutic prodrug metabolized to active drug by a carboxylesterase and administering a chemotherapeutic prodrug.
Another object of the present invention is to provide a method of using APC as a prodrug in the treatment of cancer.
Another object of the present invention is to provide drug screening assays for identification of compounds activated by carboxylesterases.
Yet another object of the present invention is to provide a modified ornithine decarboxylase promoter which upregulates target protein expression in tumor cells that over-express myc proteins. | {
"pile_set_name": "USPTO Backgrounds"
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Tropical rust is a fungal disease caused by the pathogen Physopella zeae (Mains) Cummins & Ramachar (syn. Angiopsora zeae Mains), previously classified as Angiopsora zeae Mains (Donald G. White, ed. 1999. Compendium of corn diseases. Third edition. APS Press, ISBN 0-89054-234-1). Tropical rust can spread very rapidly, killing the plant in a short time.
Disease management strategies include crop rotation, destruction of old maize residues by tillage, and fungicide application, all of which are aimed at reducing the fungal inoculum. However, the most effective and most preferred method of control for tropical rust is the planting of resistant hybrids.
The methods of controlling tropical rust by reducing fungal inoculum require additional time and resources on the part of the farmer, and in addition, can have detrimental effects on the environment. This makes the planting of resistant hybrids even more attractive to farmers and the general public. Thus, it is desirable to provide compositions and methods for identifying and selecting maize plants with enhanced resistance to tropical rust. | {
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Most major segments of the integrated circuit industry have alternate sourcing. For example a purchaser can buy SRAMs, DRAMs, and microprocessors from more than one source (i.e., a company with IC fabrication facilities). Customers have always found it desirable to have alternate sourcing available for an assured supply and lower cost by virtue of the competition among the alternate sources.
In the early eighties, the leading ASIC vendors were vertically integrated, i.e. they provided the three key technologies required for successful ASICs. These key technologies are the CAD (Computer Aided Design), the ASIC technology (The ASIC products itself; the methodologies for design, simulation, and test; and guaranteeing that the silicon works to customer specifications), and the silicon fabrication facilities to manufacture the ASICs. These ASIC vendors guaranteed the ASICs would function properly and reliably only if the ASICs were produced using that vendor's CAD, ASIC Technology, and silicon fabrication facilities and process.
Thus, in this prior art system, once a customer decides on a specific ASIC vendor, the customer is locked into using and relying on that ASIC vendor. Once the ASIC goes to production the customer is dependent on that single silicon fabrication source. Any problems with this fabrication facility, process, or company will directly impact the production of the ASICs, upon which the customer's systems are based. In such a situation the customer can go to another ASIC vendor to obtain a newly designed ASIC chip to serve the same purpose, but this is costly, time consuming, and the newly designed ASIC chip may not perform the same.
In the mid 1980's CAD companies, such as Cadence, took advantage of the customer's desire for alternate sourcing by offering a set of CAD tools that offered the customers some independence from the ASIC vendors, as their CAD tools were suitable for use with any number of ASIC vendors. Customers quickly embraced this "open" CAD concept.
This open CAD concept was a step in the direction of alternate sourcing ASICs, but ASIC vendors still required the use of their specific ASIC Technology which was integrated to their silicon fabrication process. The precise timing models in the library of ASIC technology must represent the behavior of the ASIC devices when fabricated by the ASIC vendor. An ASIC vendor is only able to guarantee accurate timing in the ASICs manufactured by themselves, and cannot guarantee the ASIC will function the same if it is fabricated using another vendor's ASIC technology or fabrication process.
For many years, ASIC vendors have been porting libraries of their proprietary ASIC products to various software tools available from different CAD companies. This provides the systems designer with a wide choice in these front end tools. However, this approach does not provide the flexibility of allowing the systems designer to choose different semiconductor fabrication facilities and guarantee the same high performance, and in some cases even the same functionality, since different vendors, different fabrication processing techniques, etc. result in variations in device performance.
As in any market, customers desire an "alternate sourcing" of their ASICs. Today there is no method or system for the true alternate sourcing of ASICs. There have been attempts to provide alternate sourcing of ASICs by two ASIC vendors teaming up to second source products using as identical ASIC architecture and fabrication processes as possible. However, even in these instances Where two or more vendors are actively pursuing identical fabrication techniques in each of their fabrication facilities, fabrication processes change over time due to different product priorities, yield enhancement techniques, use of different manufacturing equipment, etc., and thus device performance variations will increase over time. None of these attempts to second source ASICs have worked well over time. So, in spite of good intentions, alternate sourcing quickly becomes incompatible.
In array based products, such as gate arrays and embedded arrays, alternate sourcing generally does not exist. The main technical reason is the large number of macrocell library elements, which could number more than 100. These are based on a fixed primitive cell with predetermined transistor widths. It is impractical for a designer to adjust the width of each transistor to compensate for performance differences of different semiconductor processes for all the macrocells in the library. This is the main technical reason that alternate sourcing in ASICs does not exist. The only possible exception is if two companies agreed on the same architecture, library, design, methodology, design tools, same place and route software and methodology, and same semiconductor process technology. Because of customer insistence, there have been such attempts at alternate sourcing. However, different companies have different priorities and the semiconductor process technology tends to quickly drift apart and the alternate sourcing begins to fail.
At present, when a second source is needed, systems companies have no choice but to do an almost total redesign of the ASIC. Even then the ASIC components obtained from two separate ASIC vendors may or may not work the same on the customer's systems. The problem is that the second vendor's ASIC has a different architecture, different library elements, different timing performance, different methodology, different place and route, as well as a different fabrication process. The success rate of second sourcing leaves a lot to be desired.
In order to develop confidence that an ASIC will perform as desired or expected, the designer needs to perform accurate gate level simulation, including timing. Since each ASIC vendor has libraries with different timings and possibly different functional library elements, the systems customer now must select one ASIC vendor to which the simulation will be directed. Once the ASIC vendor selection is made, the simulation, place and route, timing adjustments for wire routing, and manufacturing will take a significant amount of time and effort. It is costly for the customer to duplicate this time and effort for an alternate source. The customer is in effect, due to time and cost constraints, locked in a sole sourced situation, meaning the customer can only buy from this one ASIC vendor.
In order for a customer to obtain a second source, the customer needs to duplicate the simulation on a different library, perform a different place and route which will provide different wire induced delays, and manufacture the gate array (generally a different architecture) on a different fabrication process. The odds are not good that the second sourced ASIC device will work the same after going through so many steps, each of them different from one another.
This situation increases the cost of the ASICs, but more importantly, a single source may not be able to meet demand. A single sourced vendor could have a yield problem resulting in an insufficient supply of ASICs, which in turn may stop production of the customer's electronic system which incorporates the ASIC. Or if the system sells much better than expected, a single source vendor most likely will not be able to increase production quickly enough to meet the customers demand for the ASICs.
FIG. 1 is a flow chart of a prior art attempt to provide alternate sourcing of a given basic circuit design from a plurality of vendors. As shown in FIG. 1, a first step 201 is to define a device specification, including the system behavior and timing desired. Step 202 is a synthesis step, during which equivalent logic is synthesized into different libraries of different alternate sources. This results in a netlist for each source's library which is simulated for timing and functionality in steps 203-1 and 203-2. The results of step 202 are suitable for application to a plurality of ASIC vendors parameters, by simulation steps 203-1 and 203-2, in order to verify by simulation of gate level implementations of the specified functionality and timing specifications the expected operation of ASIC devices produced by each vendor. These simulation steps need to be done at least once per vendor because the primitive library elements are logically different and have different speeds.
This prior art also requires a duplication in the place and route steps 204-1 and 204-2, during which devices and interconnects are defined in accordance with each vendor's parameters. Place and route must be uniquely performed for each ASIC vendor in steps 204-1 and 204-2 because this step significantly impacts timing. Most likely the two vendors use different place and route algorithms. So step 204-2 must be redone until the timing can match the timing of the first source which utilized a different place and route step 204-1. Fabrication steps 205-1 and 205-2 are then performed by each vendor, in accordance with specific layout steps performed for that vendor. Thus, it is shown in the prior art flow chart of FIG. 1 that a number of steps required in order to allow each ASIC vendor to fabricate devices which are intended to be functionally identical are not themselves identical, and due to the variations in these steps are likely to lead to supposedly functionally identical ASICs from two vendors which, unfortunately, are all too often not as functionally identical as one would need or desire. For example, simulation steps 204-1 and 204-2 are performed according to the individual vendor parameters, and place and route algorithms result in a difference in location of various devices within each ASIC and different electrical interconnect lengths as well. Thus, in addition to the fact that a number of steps must be duplicated specifically for each vendor, the net result is a set of devices available from a plurality of vendors which all too often have significant disparities in operating characteristics. | {
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1. Field of the Invention
The present invention relates to an antenna device that can be tuned to wideband frequencies.
2. Description of the Related Art
A known antenna device 10 is described with reference to FIGS. 4 and 5. A conductor 12 made of a fine metal wire is spirally wound around a ferrite magnetic core 14. Ends of the conductor 12 form connection terminals 16 and 18. The conductor 12 includes a plurality of divided conductor portions 12′, and the conductor portions 12′ are connected to one another by a plurality of capacitance elements 20. As shown in FIGS. 4 and 5, the antenna device 10 is such that the capacitance elements 20 are physically distributed in the conductor 12 to have a closed loop form. The antenna device 10 responds to a particular frequency (see, for example, Japanese Unexamined Patent Application Publication No. 51-83755 (FIGS. 1 and 3) and its corresponding U.S. Pat. No. 3,946,397).
The known antenna device resonates with a particular frequency. Thus, when the known antenna device receives over wide bands, its reception sensitivity in frequencies other than the particular frequency decreases. | {
"pile_set_name": "USPTO Backgrounds"
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1. Field of the Invention
The present invention relates to a method and system for management of data and, more particularly, to a method and system for monitoring and determining whether all the data sent by the sender has been received by the receiver.
2. Description of the Related Art
In computer network systems, data is commonly transmitted in discrete units referred to as data blocks or packets. In accordance with data transmission protocols such as the Internet protocol (IP), transmission control protocol (TCP), small computer system interface (SCSI) protocol, and internet small computer system interface (iSCSI) protocol, for example, control for the transmission and receipt of each block or packet is performed by processing information contained in the “header” of each block or packet. As used hereinafter the term “packet” will refer to a discrete unit of data, including a block of data, or any other unit or discrete quantity of data that is or can be transmitted in accordance with data transmission protocols known in the art.
FIG. 1 illustrates a block diagram of a computer network 10 having server computer 12 having central processing unit (CPU) 14. The server 12 further includes host server memory 16 coupled to the CPU 14 via peripheral component interconnect (PCI/PCIX) bus interface 18. The host memory 16 stores data and programs that are used by the CPU 14 and can comprise a ROM, hard disk drive (HDD), EEPROM, Flash or other types of nonvolatile memory known in the art. It is understood that the server 12 inherently includes other well-known components/devices, such as volatile memory (e.g., RAM, DRAM, SRAM), cache, floppy disk drive, compact disk drive, etc. which are not illustrated in FIG. 1.
The CPU 14 is further coupled to a host bus adapter (HBA) card 20 via the PCI/PCIX interface 18. The HBA card2O is in turn coupled to a network communications medium 26 (e.g., Internet/world wide web, LAN, WAN, fiber channel, etc.) via a physical connection port 22, also referred to herein as medium access control (MAC) port or interface 22. The HBA 20 further includes a local memory 24, otherwise referred to herein as a network interface buffer (NIB) 24, for storing data handled and processed by a microprocessor (not shown) within the HBA 20.
Generally, HBA's are well-known peripheral devices that handle data input/output (I/O) operations for host devices and systems (e.g., servers). In simple terms, a HBA provides I/O processing and physical connectivity between a host device (e.g., server 12) and one or more external devices 28, which may be a data storage device or a remote personal computer. The external device 28 may be “connected” to the host device via the communications medium 26 using a variety of known “direct attached” or networking technologies, including TCP/IP, Fiber channel, SCSI, iSCSI, VI/IP or FICON. Thus, the communication medium 26 may comprise the world wide web (a.k.a., the “Internet”), a fiber channel fabric, or other known computer networking communications medium (e.g., LAN, WAN, etc.), which operates according to known communication protocols.
When the server 12 is communicating with the external device 28, data packets are transmitted between the server 12 and the external device 28 in accordance with one or more predetermined protocols, depending on the type of communication medium 26 that is employed, to provide “connectivity” (either physical and/or wireless) between the server 12 and the external device 28. For example, if the server 12 is communicating with the external device 28 via the Internet, various protocol “layers” are typically utilized to control, monitor and route the data so that it is reliably and efficiently received by its intended recipient in a useable format. FIG. 2 illustrates some well known protocol layers that are used to format and transmit data between a first device and a second device via the world wide web (a.k.a., “Internet”). As shown in FIG. 2, these various protocols include a physical layer 30 (a.k.a., a medium access control (MAC) layer 30), an IP layer 32, a TCP layer 34, and an iSCSI layer 36.
The medium access control (MAC) protocol 30 is used to provide a physical layer or “data link layer” for Ethernet LAN systems. The MAC protocol encapsulates or “packetizes” data to be transmitted and adds a header to the data (also referred to as the “payload”). The header information contains protocol control information and typically includes at least the following three parts: (1) a destination address, which specifies either a single recipient node (unicast mode), a group of recipient nodes (multicast mode), or the set of all recipient nodes (broadcast mode); (2) a source address, which is set to the sender's globally unique node address; and (3) a protocol type field, which provides service access point (SAP) information to identify the type of network protocol being carried (e.g. the values 0x0800 is used to identify the IP network protocol, other values are used to indicate other network protocols). The MAC protocol 30 also adds cyclic redundancy check (CRC) data at the end of the packet or frame to provide error detection in case line errors (or transmission collisions in Ethernet) result in corruption of the MAC frame. Any frame with an invalid CRC is discarded by the MAC receiver without further processing. The MAC protocol is well known in the art and, therefore, further details regarding additional functions and characteristics of the MAC protocol are not provided herein.
The Internet Protocol (IP) layer 32 is the method or protocol by which data is sent from one computer to another via the Internet. Each computer (known as a host) on the Internet has at least one IP address that uniquely identifies it from all other computers and devices on the Internet. When you send or receive data (for example, an e-mail note or a Web page), the message gets divided into packets. Each of these packets contains both the sender's Internet address and the receiver's address. The IP program layer 32 generates these addresses for each packet of data and stores them in the header of each packet. Based on a destination address, a packet is sent first to a gateway computer that understands a small part of the Internet. The gateway computer reads the destination address and forwards the packet to an adjacent gateway that in turn reads the destination address and so forth across the Internet until one gateway recognizes the packet as belonging to a computer within its immediate neighborhood or domain. That gateway then forwards the packet directly to the receiving computer whose address is specified.
Because a message is divided into a number of packets, each packet can, if necessary, be sent by a different route across the Internet. Packets can arrive in a different order than the order they were sent in. The Internet Protocol just delivers them. It's up to another protocol, the Transmission Control Protocol (TCP) to put them back in the right order. In essence, the IP is a connectionless protocol, which means that there is no continuing connection between the end points that are communicating. Each packet that travels through the Internet is treated as an independent unit of data without any relation to any other unit of data. The task of arranging the packets in the right order at the receiving end is performed by the TCP—the connection-oriented protocol that keeps track of the packet sequence in a message.
The TCP layer 34 comprises a set of rules used along with the IP protocol to send data in the form of message units between computers over the Internet. While IP takes care of handling the actual delivery of the data, TCP takes care of keeping track of the individual units of data (packets) that a message is divided into for efficient routing through the Internet. For example, when an HTML file is sent from a Web server, the TCP program layer in that server divides the file into one or more packets, numbers the packets, and then forwards them individually to the IP protocol program layer. Although each packet has the same destination IP address, it may get routed differently through the network. At the receiving end (e.g., a client computer executing complementary program), TCP reassembles the individual packets and presents them to the client as a single file in accordance with pre-specified conditions that are well known in the art (e.g., time based, setting of a “push flag,” etc.).
TCP is known as a connection-oriented protocol, which means that a connection is established and maintained until such time as the message or messages to be exchanged by the application programs at each end have been exchanged. TCP is responsible for ensuring that a message is divided into the packets that IP manages and for reassembling the packets back into the complete message at the other end. The TCP layer 34 does this by generating a TCP sequence number for each packet of data received by the iSCSI layer 36 (discussed in further detail below). At the receiving device, a corresponding TCP program layer 34 receives the packets and reads the TCP sequence numbers to verify that all expected TCP sequence numbers are accounted for.
The small computer system interface (SCSI) protocol is a collection of American National Standards Institute (ANSI) standards and proposed standards that define the operation and architecture of I/O buses that provide connectivity between storage subsystems or devices and host systems (e.g., servers) through host bus adapters (HBAs). Originally intended primarily for use with small (desktop and desk-side workstation) computers, SCSI has been extended to serve most computing needs, and is arguably the most widely implemented I/O bus protocol in use today.
The iSCSI protocol layer 36 is the Internet SCSI protocol layer, which is an IP-based storage networking standard for linking data storage facilities and other devices over the Internet, developed by the Internet Engineering Task Force (IETF). By carrying SCSI commands over IP networks, iSCSI is used to facilitate data transfers over intranets and to manage storage over long distances. The iSCSI protocol is among the key technologies expected to help bring about rapid development of the storage area network (SAN) market, by increasing the capabilities and performance of storage data transmission. Because of the ubiquity of IP networks, iSCSI can be used to transmit data over local area networks (LANs), wide area networks (WANs), or the Internet and can enable location-independent data storage and retrieval.
In accordance with the iSCSI protocol layer 36, when an end user or application sends a request, the operating system of the end user computer generates the appropriate SCSI commands and data request, which then go through further TCP, IP and encapsulation processing, as discussed above. As further discussed above, a packet header is added by the MAC protocol layer 30 before the resulting IP packets are transmitted over an Ethernet connection (e.g., MAC physical layer). When a packet is received, it is decrypted (if it was encrypted before transmission), and disassembled, separating the SCSI commands and request. The SCSI commands are sent on to the SCSI controller, and from there to the SCSI storage device. Because iSCSI is bi-directional, the protocol can also be used to return data in response to the original request. iSCSI is a well known protocol for managing the transmission of data over IP networks. A number of vendors, including Cisco, IBM, and Nishan have introduced iSCSI-based products (such as switches and routers). Other methods, such as Fibre Channel over IP (FCIP) are also known.
The iSCSI protocol layer 36 also plays an important role in ensuring that all the data packets transmitted by a source application program is received by the intended receiving device at the specified destination address. The iSCSI layer 36 does this by generating an an iSCSI sequence number for each set of data that is to encapsulated in a single packet, wherein one or more packets comprise a “message” or complete set of data transmitted by an application program executed by the source device (e.g., server 12). A respective iSCSI sequence number, along with the TCP sequence number mentioned above, is contained in the header portion of each packet. The iSCSI sequence number provides additional assurance beyond that provided by the TCP sequence number by ensuring that all packets that were intended to be transmitted by an application program are in fact received by the receiving device at the destination address. The TCP sequence number alone cannot ensure this because the TCP program layer 34 sequentially assigns a TCP sequence number to each packet of data as it is received from the iSCSI layer, not knowing (and not caring) whether some packets failed to be successfully forwarded by the iSCSI layer 36 to the TCP layer 34.
FIG. 3 illustrates a block diagram representation of a data packet 40. The packet 40 includes a payload portion 42 which contains the user data being transmitted to the receiving device. The packet 40 further includes a header portion 43, which includes an IP header portion 44, a TCP header portion 45 and an iSCSI header portion 46. As discussed above, the IP header portion 44 includes the source and destination IP addresses, the TCP header portion 45 includes the TCP sequence number, and the iSCSI header portion 46 includes the iSCSI sequence number. It is understood that other data may be contained in these header portions as is necessary to carry out various transmission control and tracking functions, and functions such as timing, etc., that are known in the art in accordance with these various protocols. The packet 40 further includes a CRC data portion 48 appended to a tail end of the packet 40. Such CRC data portions and their functionality are well known in the art.
When the packet 40 is received by a receiving device, a corresponding TCP layer program 34 executed by the receiving device verifies that all expected TCP sequence numbers are accounted for. Similarly, a corresponding iSCSI layer program 36 verifies that all expected iSCSI sequence numbers are accounted for. The TCP sequence numbers ensure that no data was lost during transmission over the Internet 26, while the iSCSI sequence numbers ensures that no data was lost during iSCSI layer 36 processing. For example, the TCP layer 34 expects to receive TCP sequence numbers in order. Otherwise, the received packets are held in the TCP layer until contiguous packets with contiguous TCP sequence numbers are received. Peer applications, such as iSCSI, can transmit its packets in any order. Thus, for example, while the iSCSI layer may transmit packets with sequence numbers i1, i2, i4, i6, i3 and i5, these packets would be labeled in the TCP layer s t1, t2, t3, t4, t5 and t6. Therefore, because the iSCSI layer can transmit packets in any order, some mechanism is needed to keep track of what has been received and if any gaps exist.
Since packets of data can arrive out of order at the receiving device, each packet must be tracked to determine whether all expected packets in a “set” (e.g., a complete message) has been safely received. What is interesting about this problem is that initially it's a sparse data management problem that evolves into a non-sparse data management problem. At the beginning of the data transmission process, the amount of data received by the receiving device is “sparse.” However, as more and more packets are received, the amount of data becomes “non-sparse.” Previously existing methods for determining whether all the data has actually been received include the use of “linked lists” or “bit-vectors.” These existing techniques that utilize either a linked list or a bit vector to keep track of received data do not manage both sparse and non-sparse data efficiently.
A linked list allocates memory space for each element it is “tracking” wherein each element is typically referred to as a “linked list element” or “node.” The list gets its overall structure by using pointers to connect all its nodes together like the links in a chain. Each node contains two fields: a “data” field to store whatever element type the list holds (e.g., sequence no.) and a “next” field which is a pointer used to link one node to the next node. Each node is allocated an address in the memory. As each packet of data is received by the receiving device (e.g., a HBA), firmware or software executed by a processor in the receiving device creates a new node, which contains the packet sequence no. (e.g., iSCSI sequence no.) and a pointer value that points to the next closest node in the linked list. When a new node is created, the software or firmware determines where in the linked list the new node must be inserted and thereafter adjusts pointer values for adjacent nodes as necessary. A linked list can efficiently store received sequence numbers, if the packets to be tracked are contiguous. However, searching the linked-list requires linear searching of the list and, therefore, is not well-suited for high-speed or real time input/output (I/O) data processing applications. Additionally, when a large number of packets are received the memory requirements for storing a node for each packet can become significant.
Bit vectors are also well known in the art. Instead of creating a node for each packet sequence number, bit vectors allocate a bit in memory space for each sequence number. As each expected packet sequence number is received by the receiving device, firmware or software executed by the receiving device sets a corresponding bit in the bit vector to indicate that the corresponding packet has been received. Since this technique requires a bit for every packet to be tracked, it requires a potentially large memory allocation. Additionally, since each bit must be read to determine whether all packets are accounted for, the use of bit vectors can be relatively slow and not well-suited for high-speed, high-bandwidth I/O processing applications.
Thus, there is a need for a more efficient and faster method and system for managing data so as to keep track of data packets received by a receiving device and indicate when one or more packets are missing. Furthermore, there is a need for a method and system than can efficiently monitor and manage the receipt of data when it is sparse as well as when it is non-sparse. | {
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1. Field of the Invention
This invention relates to an apparatus and a method for sensing the position of a device on a cassette, more particularly for sensing the position of the cassette handling apparatus on a cassette holding liquid sterilant.
2. Description of the Related Art
U.S. Pat. No. 4,643,876, incorporated herein by reference, discloses a sterilization system in which a vaporizable germicide, such as hydrogen peroxide, is introduced into an evacuated sterilization chamber. The vaporizable germicide vaporizes and is allowed to disperse throughout the chamber and onto the items to be sterilized. After a desired period of time electrical energy is applied to an electrode to form a plasma to complete the sterilization cycle.
This system has been successfully commercialized as the STERRAD(copyright) Sterilization System and is available from Advanced Sterilization Products, a Division of Ethicon, Inc., Irvine, Calif. The system is used in hospitals and other environments where it is operated repeatedly throughout the day by personnel having a widely varying range of understanding of the apparatus. In order to insure safeguards in the event of operator error, the system employs an automated delivery system for delivering the liquid vaporizable germicide to the sterilization chamber. Measured portions of the liquid germicide, for example hydrogen peroxide, are provided in rupturable cells within a rigid cassette housing. The cassette and operation of the delivery system are more fully described in the Williams et al. patents, U.S. Pat. No. 4,817,800 issued Apr. 4, 1989; U.S. Pat. No. 4,913,196 issued Apr. 3, 1990; U.S. Pat. No. 4,938,262 issued Jul. 3, 1990; and U.S. Pat. No. 4,941,518 issued Jul. 17, 1990, all of which are incorporated herein by reference. In the above-referenced patents, the operator manually grasps the cassette housing and inserts it into the sterilizer. When spent, the cassette is ejected.
Prior methods of sterilization utilized heat, steam, or toxic, flammable chemicals, such as ethylene oxide. Heat or steam can damage delicate medical equipment. Use of toxic chemicals for sterilization poses risks to workers. Sterilization of equipment with hydrogen peroxide and plasma with the cassette system provide many advantages over the prior sterilization systems. The hydrogen peroxide and plasma kill a wide range of bacteria, viruses, and spores at low temperatures, minimizing the chance of damaging delicate temperature-sensitive instruments. Further, hydrogen peroxide decomposes to water and oxygen after exposure to plasma, avoiding the need to dispose of any toxic byproducts. Finally, the cassette isolates the operator from the liquid hydrogen peroxide in the cells in the cassette.
U.S. Pat. No. 5,882,611 issued Mar. 16, 1999 and U.S. Pat. No. 5,887,716 issued Mar. 30, 1999 to Williams et al., herein incorporated by reference, describe an improved cassette and delivery system, in which the cassette is encased in a protective sleeve. The sleeve isolates the cassette from the operator""s hands during all stages of handling and absorbs any drops of liquid hydrogen peroxide which might be left on the exterior of the spent cassette, protecting the operator from contact with any sterilant which escapes from the cassette. The delivery system automatically extracts the cassette from the sleeve, delivers the liquid germicide to the sterilization chamber, and reinserts the spent cassette into the sleeve, all without any handling by the operator. Further, the delivery system checks the cassette before processing to insure that the cassette is not already used or that the cassette is expired.
Although the delivery system described in U.S. Pat. No. 5,882,611 offers many advantages over the previous delivery systems, opportunities for improvement remain. The delivery system is complex and expensive. Further, the delivery system depends on a timer to determine which cell is in the injector rather than directly sensing the position of the cassette in the delivery system.
There is thus a need for a delivery system which is simpler and less expensive than the previously described systems while retaining the advantage of minimizing operator handling. Further, there is a need for a delivery system in which the position of the delivery system and injection system on the cassette may be determined with more certainty than simply relying on a timer.
The cassette sensing mechanism and delivery system of the present invention provide a positive indication of the location of the cassette in the delivery and injection system. Further, the delivery system is far less complex than the previous delivery system. Finally, the delivery system of the present invention retains the advantages of the prior delivery and injection system in extracting the cassette from a sleeve, delivering the liquid sterilant to the sterilization chamber, and reinserting the spent cassette into the sleeve without the requirement for operator intervention.
One aspect of the invention involves a sensing mechanism for detecting the unevenness of a surface on a device, where there is at least a first path and a second path on the surface. The sensing mechanism contains at least one connector, a first pawl, a second pawl, and a sensor mounted on the first pawl or the second pawl. The first end of the first pawl is connected to the connector in a manner allowing movement of the first pawl and the second end of the first pawl contacts a portion of the first path on the surface. The first end of the second pawl is connected to the connector in a manner allowing movement of the second pawl and the second end of the second pawl contacts a portion of the second path. The sensor detects the position of the first pawl relative to the second pawl.
Advantageously, the first path and said second path are noncoincident. Preferably, the device is a cassette. In an embodiment, the cassette contains germnicide. Advantageously, the germicide contains hydrogen peroxide. Preferably, the connector is a pivot, where the first pawl and said second pawl rotate about the pivot. Advantageously, the movement of the first pawl and the second pawl is due to gravity. In another embodiment, the movement of the first pawl and the second pawl is due to one or more springs.
The unevenness of the surface may be on the top, bottom, or side of the device. The sensor may be a photoelectric sensor, an electromechanical sensor, or a proximity sensor. Advantageously, the first path is adjacent to second path. Preferably, the mechanism also contains a control unit.
Another aspect of the invention involves a sensing mechanism for detecting the position of a cassette having a first path and a second path, where the first path has at least one groove and the second path is relatively smooth. The mechanism includes at least one connector, a first pawl, a second pawl, and a sensor mounted on the first pawl or the second pawl. The first end of the first pawl is connected to the connector in a manner allowing movement of the first pawl and the second end of the first pawl contacts a portion of the first path on the surface. The first end of the second pawl is connected to the connector in a manner allowing movement of the second pawl, while the second end of the second pawl contacts a portion of the said second path. The sensor detects the position of the first pawl relative to the second pawl, to detect the position of the cassette.
Preferably, the cassette contains germicide. Advantageously, the germicide is hydrogen peroxide. Preferably, the connector is a pivot, where the first pawl and said second pawl rotate about the pivot. In an embodiment, the movement of the pawls is due to gravity. In another embodiment, the movement of the pawls is due to a moving mechanism, such as a hydraulic mechanism, pneumatic mechanism, or one or more springs.
Another aspect of the invention involves a method for positioning a cassette for injection of germicide to a sterilization system. The method includes providing a cassette with a surface having a first path and a second path, where the first path has at least one groove and the second path is relatively smooth. The method also includes providing a sensing mechanism having at least one connector, two pawls connected to the connector in a manner allowing movement of the pawls, and a sensor mounted on one of the pawls. The method also includes inserting the cassette into the sensing mechanism in the sterilization system. The end of one pawl contacts a portion of the first path on the surface of the cassette and the end of the other pawl contacts a portion of the second path on the surface of the cassette. The relative position of the two pawls is determined with the sensor, thereby determining the position of the end of the pawl on the first path on the surface of the cassette. The method also includes moving the cassette until the pawl contacts the groove in the first path on the surface of the cassette, positioning the cassette for injection of germicide into said sterilization system.
Advantageously, the determining and moving steps are repeated. Preferably, the cassette contains germicide. In an embodiment, the method also includes injecting the germicide into the sterilization system. Preferably, the sensor is a photoelectric sensor, an electromechanical sensor, or a proximity sensor. Advantageously, the first path and the second path are noncoincident. Preferably, the germicide is hydrogen peroxide. | {
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In recent years, from the demands for faster operation and miniaturization of semiconductor devices, a wiring referred to as a redistribution layer formed on a first pad electrode which is a part of an uppermost layer wiring of a multilayer wiring layer on a semiconductor substrate has been used. The redistribution layer is mainly composed of a thick copper film formed by, for example, the plating method in order to reduce the wiring resistance. Apart of an upper surface of the redistribution layer is a region to be connected to an external connection terminal formed of a bump electrode, a bonding wire, or the like, and constitutes a second pad electrode. Then, the second pad electrode is electrically connected to a printed circuit board or the like.
For example, Patent Document 1 (Japanese Patent Application Laid-Open Publication No. 2009-194144) describes a technique for forming a redistribution layer on a multilayer wiring layer. | {
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This invention pertains to the art of methods and apparatuses for storage of unvulcanized tire treads, sidewalls, and other tire components, and more specifically to an improved method and apparatus to remove an unvulcanized tread from a storage device.
It is known in the art to store unvulcanized tire treads in storage devices commonly known as xe2x80x9cbear trapsxe2x80x9d which have a series of planar elements upon which the treads are stored. Previously, treads removed from such storage devices were removed manually by a human tire builder.
Depending on the size of the tire tread, the task of removing the tread from the storage device could be one of the most distasteful and uncomfortable in the entire tire building process. For example, for truck tires and for aircraft tires, the associated treads in their unvulcanized state can approach one hundred pounds in weight and can be up to twelve feet long. In addition, the treads are xe2x80x9cbookedxe2x80x9d or stored upside down so that a sticky, tacky layer of rubber is upward. Manually manipulation of the tire treads is physically taxing for the tire builder. In addition, certain non-uniformities and undesirable qualities could be imparted to the tire tread, and eventually to the tire, through manual handling of the unvulcanized tread.
The present invention contemplates a new and improved method and apparatus for removing unvulcanized tire treads from the storage devices. The method and apparatus is simple in design, effective in use, and overcomes the foregoing difficulties in others while providing better and advantageous overall results.
In accordance with the present invention, a new and improved method and apparatus for removing unvulcanized tire treads from a storage device is provided.
More particularly in accordance with the invention, the apparatus includes a frame, an arm movably mounted on the frame, the arm having a horizontal axis, a first translation means for translating the arm along the vertical axis of the frame, a gripping means for gripping the associated tire tread, a second horizontal translation means for translating the gripping means along the horizontal axis of the arm.
According to another aspect of the invention, the apparatus includes a frame with a vertical axis and an arm assembly movably mounted on the frame. The arm assembly has a horizontal axis, a vertical moving means for moving the arm assembly along the vertical axis, a first horizontal moving means for moving the arm assembly along the horizontal axis, a gripping means for gripping the associated tire tread, translation means for translating the gripping means about the horizontal axis, and a second horizontal moving means for moving the gripping means horizontally along the horizontal axis.
One advantage of the present invention is the provision of a new apparatus which can effectively remove tire treads from a storage device, and invert the treads, and place them on an appropriate conveyor for further processing.
Another advantage of the present invention is the fact that such removal includes the step of inverting, thereby in a single step removing the tread from the storage device and inverting it for application to the tire.
Another advantage of the present invention is the labor savings, increase in job satisfaction, and the easing of strain on the tire builders body by automating the difficult task of lifting and positioning an unvulcanized tire tread.
Another advantage of the invention is that the above-recited advantages are accomplished by an apparatus with relatively few moving parts.
Still other benefits and advantages of the invention will become apparent to those skilled in the art to which it pertains upon a reading and understanding of the following detailed specification. | {
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1. Field of the Invention
The invention is related to ultracapacitors also known as supercapacitors. The applications of the ultracapacitors may include hybrid/electric vehicles, spacecrafts, uninterrupted power supplies and memory backup power supplies. Also, the invention is related to transition metal nitrides and their synthesis methods. The forms that the transition metal nitrides may take thin film layers, micrometer-sized particles, and nanometer-sized particles. The applications may include a thin film as a wear protective layer, particles for ultracapacitors, particles of catalysts, particles as an additive of a wear-resistant coating, and magnets.
2. Description of the Existing Technology and some of its Problems
Ultracapacitors store energy using either ion adsorption (electric double layer capacitors, EDLCs) or fast surface redox (reduction-oxidation) reactions (pseudo-capacitors). The ultracapacitors can store several magnitudes of higher electric charges than the conventional capacitors. Compared with the conventional batteries, the ultracapacitors can be charged-discharged much faster because it does not involve chemical redox reactions. In addition, due to extremely low internal resistance, it can supply much higher current than the conventional batteries. Although the total energy density is about one order of magnitude lower than that of the conventional batteries, the unique characteristics of the ultracapacitors found their applications in memory back-ups, booster power supplies for hybrid/electric vehicles, and temporary power supplies for short power outage. For weight-sensitive applications such as hybrid/electric vehicles, aircrafts, and spacecrafts, ultracapacitors with higher energy density is required. Ultracapacitors having comparable energy density with the conventional batteries are strongly demanded recently.
The ultracapacitors are conventionally constructed with carbon-based electrodes; however, due to low specific capacitance of carbon-based electrodes, the energy density is more than one order of magnitude lower than that of the conventional batteries. The specific energy density is proportional to the specific capacitance, therefore, it is very important to increase the specific capacitance of the electrodes. Similar to the conventional capacitors, the specific capacitance is proportional to the specific surface area and the dielectric constant, thus many improvements have been made to improve the electrodes.
For example, the US patent (US 2008 0180881 A1)[1] discloses extremely large specific surface area (1500 m2/g) by utilizing nano-sized porous carbon structure. However, the specific capacitance is as low as the order of 100 F/g. In the US patent (US 2011-0149473 A1)[2], the specific capacitance is increased by adding nano-sized particle having high dielectric constant onto the carbon-based electrodes. Although this approach is effective to increase the specific capacitance, the carbon-based electrode has a disadvantage of inherently low specific capacitance. Alternative material such as metal oxide is explored, and ruthenium oxide (RuO2) is reported to have high specific capacitance of 600 F/g [3]. However, due to extremely high cost of Ru, this is not preferable for a practical use. In contrast, metal nitride is reported to have high specific capacitance. Vanadium nitride recorded the specific capacitance as high as 1340 F/g [4]. Also, US patent (US 2010-0019207 A1)[5] disclosed high specific capacitance of ternary transition metal nitride, i.e. mixture of transition metal nitrides.
Although transition metal nitride has a great potential to improve the performance of ultracapacitors, its synthesis is challenging due to its chemical stability. The Ref. 4 and 5 discloses a synthesis method of transition metal nitride using chloride precursors. However, the method may leave halide impurities, which potentially causes corrosion of the support metals for electrodes, the electric terminals or the housing. To achieve reliable ultracapacitors with transition metal nitride, a synthesis method which does not involve a halide element is preferred.
Historically, transition metal nitride has been used as wear-resistant coatings and thermal barriers, due to its strong mechanical and thermal property. Along with the development of structural and mechanical engineering, the coatings and barriers are required to cover complicated and fine structures. In other words, the surface area relative to its volume is becoming larger in recent years.
It is also reported that transition metal nitride is useful as a functional material for ultracapacitors, catalysts, and magnet. To use transition metal nitride as ultracapacitor, catalysts, or magnets, it is important to increase the surface area of the material. Nanotechnology using nano-sized particles has a potential of obtaining superior characteristics due to extremely large surface area relative to its weight. Functional materials requiring large surface area such as ultracapacitors and catalyst receives tremendous benefit from nanotechnology.
With increasing demand of covering small-sized material with large surface area, the existing synthesis method is facing several challenges. Since transition metal is more readily oxidized than nitridized, synthesis of transition metal nitride requires elimination of oxygen and moisture. Synthesis methods typically involve vapor phase reaction in vacuum/air tight reactors. To form a nitride layer on transition metal parts, physical vapor deposition or plasma deposition are used. However, these methods are unable to coat complicated structure having deep blind holes because vapor phase reactant does not reach the bottom surface of the deep holes.
In the case of particle synthesis, vapor phase method is even less efficient because of extremely high surface area to cover. When the particles have size less than 10 nm or specific surface area larger than 10 m2/g, it becomes challenging for the gaseous agents to cover the entire surface. For example, vanadium nitride nanoparticles are synthesized using VCl4 as precursor. The VCl4 is dissolved and stirred in anhydrous chloroform inside a glovebox. The solution is then transferred to an Ar-filled glove bag, where the dissolved chloride is reacted with anhydrous ammonia gas over solution for 8 hours. The as-prepared powder is collected by evaporating the solvent at 100° C. under continuous NH3 gas flow. Final heat treatment for nitridization is conducted under an anhydrous ammonia atmosphere with a heating and cooling rate of 5° C./min. The temperature for heat treatment is 400° C. [4]. As shown in this example, the final heat treatment involves vapor phase reaction with constant ammonia flow at high temperature. A high temperature such as this can cause sintering, resulting in larger particle size than what would be achieved using a lower-temperature process. Also, this process may leave chlorine impurities in the synthesized transition metal nitride.
The challenges in the existing synthesis methods of transition metal nitride are summarized as follows: (1) the existing methods use vapor phase reaction which is unable to cover surfaces of complicated structures or small particles; (2) the existing methods require constant flow of source gas such as ammonia or nitrogen; (3) some existing methods use metal halide precursors, which leaves halogen impurities unfavorable to ultracapacitor applications; (4) some existing methods requires multiple steps to obtain transition metal nitride; (5) some existing methods requires high temperature which causes larger particle size. | {
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In machine learning and pattern recognition, a feature may be a measured property or quantity of a phenomenon being observed. Features are usually numeric, but structural features such as strings and graphs are used in syntactic pattern recognition. Feature extraction is typically performed on an input data set and the results provided to recognition/selection hardware for further processing. For example, to perform character recognition, features applied to, for example, a neural network may include histograms that count the number of black pixels along horizontal and vertical directions, number of internal holes, and/or stroke detection. For speech recognition, features for recognizing phonemes can include noise ratios, length of sounds, relative power, and/or filter matches. For spam detection, features may include the presence or absence of certain email headers, the email structure, the language, the frequency of specific terms, and/or the grammatical correctness of the text. For computer vision applications, possible features include edges and objects. | {
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Compositing and effects applications (such as Shake® by Apple Computer, Inc.) receive and process multimedia items (e.g., text, image, video, audio, etc.) to produce a multi-layered composited output. Such applications can import and composite multimedia items and allow transformations of multimedia items that change characteristics (e.g., position, size, shape, and rotation) using transformations such as pan/move, rotate, scale, etc. A graphical user interface (GUI) used in these applications display multimedia items in a three dimensional (3D) workspace and allows a user to select and manipulate the displayed multimedia items. Keyboards or cursor controlling devices (e.g., computer mouse) are used to interact with the GUI to select and manipulate multimedia items in the 3D workspace. | {
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1. Field of the Invention
The present invention relates to a method for forming an article of manufacture that is an explosives testing standard that may be molded variously to achieve different sizes and configurations while having uniform texture and predetermined density.
2. Description of the Prior Art
The prior art reveals relatively little attention toward construction of testing standards to evaluate the penetration of shaped charge jets into porous rock as would be characteristic of oil well perforators. U.S. Pat. No. 4,152,941 relates to measuring of the fracture toughness of rock in a simulated environment wherein a rock specimen is pressurized internally while simultaneously exerting increasing external horizontal stress. This is a destructive testing procedure which is effected to derive data relative to the actual rock while the environment is that which is simulated. The U.S. Pat. No. 1,684,739 relates to a zircon refractory including granular zircon and an organic binder that has been shaped and fired as desired. The zircon is shaped under considerable pressure and then fired at very high temperatures in order to form a stable refractory material.
U.S. Pat. No. 1,886,249 relates to the use of zircon sand and a suitable binder to form cores for molds. The binder material may be an organic material such as flour and dextrine mixed with water to provide sufficient plasticity and binding strength for the zircon sand to hold its shape. U.S. Pat. No. 2,647,397 relates to a method for forming a test specimen of standardized type as compacted in a cylindrical mold to form a solid of particular hardness characteristics. In this case, the compacted material undergoing compression is also the material that is being tested for certain green characteristics such as strength, deformation and permeability. | {
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The following description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art, or relevant, to the presently described or claimed inventions, or that any publication or document that is specifically or implicitly referenced is prior art.
Glucose is the primary source of energy for the human body. Absorbed from the intestine it is metabolized by energy production (by conversion to water and carbon dioxide), conversion to amino acids and proteins or keto-acids, and storage as glycogen. Glucose metabolism is regulated by complex orchestration of hormone activities. While all dietary sugars are broken down into various carbohydrates, the most important is glucose, which is metabolized in nearly all cells of the body. Glucose enters the cell by facilitated diffusion (glucose transport proteins). This facilitated transport is stimulated very rapidly and effectively by an insulin signal, pursuant to which glucose transport into muscle and adipose cells is increased up to twenty fold. After glucose is transported into the cytoplasm, insulin then directs the disposition of it by conversion of glucose to glycogen, to pyruvate and lactate, and to fatty acids.
Diabetes mellitus is heterogeneous group of metabolic disorders, connected by raised plasma glucose concentration and disturbance of glucose metabolism with resulting hyperglycemia. The hyperglycemia in diabetes mellitus generally results from defects in insulin secretion, insulin action, or both. Although its etiology has been clouded, the World Health Organization (WHO) has set forth a classification scheme for diabetes mellitus that includes type 1 diabetes mellitus, type 2 diabetes mellitus, gestational diabetes, and other specific types of diabetes mellitus. Former terms like IDDM (insulin-dependent diabetes mellitus), NIDDM (non-insulin dependent diabetes mellitus), and juvenile-onset diabetes mellitus or adult-onset diabetes mellitus are no longer primarily used to describe those conditions.
The terms “insulin-dependent diabetes” (IDDM) or “juvenile-onset diabetes” previously encompassed what is now referred to as type 1 diabetes. Type 1 diabetes results from an autoimmune destruction of the insulin-secreting β-cells of the pancreas. There are several markers of this autoimmune destruction, detectable in body fluids and tissues, including islet cell autoantibodies, autoantibodies to insulin, autoantibodies to glutamic acid decarboxylase (GAD65), and autoantibodies to the tyrosine phosphatases IA-2 and IA-2β. While genetic factors are strongly implicated, the concordance rate in twin studies is under 50% and supports a role for environmental factors, which are said to include viral infections. The autoimmune process typically begins many years before clinical detection and presentation. The rate of β-cell destruction is quite variable, being rapid in some individuals (mainly infants and children) and usually slow in adults.
The terms “non-insulin-dependent diabetes mellitus” (NIDDM) or “adult-onset diabetes” previously encompassed what is now referred to as type 2 diabetes mellitus. The disease usually develops after 40 years of age. It is much more common that type 1 diabetes and comprises approximately 90% of all individuals with diabetes. Type 2 patients are usually older at the onset of disease, and are characterized by various symptoms. Insulin concentrations are mostly increased but they can be normal or decreased. Obesity is common. Diet and exercise regimens leading to weight reduction can ameliorate hyperglycemia. Oral hypoglycemic drugs are also used in an effort to lower blood sugar. Nevertheless, insulin is sometimes required to correct hyperglycemia, particularly as patients grow older or as their β-cells fail.
Two groups of disorders may be said to typify type 2 diabetes mellitus. The first one is a decreased ability of insulin to act on peripheral tissues, usually referred to as “insulin resistance.” Insulin resistance is defined as a decreased biological response to normal concentrations of circulating insulin and represents the primary underlying pathological process. The second is the dysfunction of pancreatic β-cells, represented by the inability to produce sufficient amounts of insulin to overcome insulin resistance in the peripheral tissues. Eventually, insulin production can be insufficient to compensate for the insulin resistance due to β-cell dysfunction. The common result is a relative deficiency of insulin. Data support the concept that insulin resistance is the primary defect, preceding the derangement of insulin secretion. As with type 1 diabetes, the basis of the insulin resistance and insulin secretion defects is believed to be a combination of environmental and genetic factors.
Gestational diabetes mellitus is usually asymptomatic and not necessarily life threatening to the mother. The condition is associated with an increased incidence of neonatal morbidity, neonatal hypoglycemia, macrosomia and jaundice. Even normal pregnancies are associated with increasing insulin resistance, mostly in the second and third trimesters. Euglycaemia is maintained by increasing insulin secretion. In those women who are not able to increase the secretion of insulin, gestational diabetes develops. The pathophysiology of gestational diabetes mellitus is not well known but is said to include family history of diabetes mellitus, obesity, complications in previous pregnancies and advanced maternal age.
Other specific types of diabetes mellitus are heterogeneous, with the following representing the largest groups: genetic defects of β-cell function; genetic defects in insulin action; diseases of the exocrine pancreas (e.g., pancreatitis, traumalpancreatectomy, neoplasia, cystic fibrosis, hemochromatosis, and others); other endocrinopathies (e.g., acromegaly, Cushing's syndrome, glucagonoma, pheochromocytoma, hyperthyroidism, somatostatinoma, aldosteronoma, and others); drug- or chemical-induced diabetes mellitus (e.g., from vacor (an acute rodenticide released in 1975 but withdrawn as a general-use pesticide in 1979 because of severe toxicity, exposure to vacor causing destruction of the beta cells of the pancreas and diabetes mellitus in survivors), pentamidine, nicotinic acid, glucocorticoids, thyroid hormone, diazoxide, beta-adrenergic agonists, thiazides, phenyloin, alfa-interferon, and others); infection-induced diabetes mellitus (e.g., from congenital rubella, cytomegalovirus, and others); rare forms of immune-mediated diabetes; and, other genetic syndromes sometimes associated with diabetes (e.g., Down syndrome, Klinefelter's syndrome, Turner's syndrome, Wolfram syndrome, Friedreich's ataxia, Huntington's chorea, Lawrence-Moon Beidel syndrome, Myotonic dystrophy, Porphyria Prader-Willi syndrome, and others). The etiology and pathophysiology are very different, mostly complicated or connected to insulin secretion and action derangement, as well as signal transduction inside the cells disarrangement. See “The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus: Committee Report 2001,” American Diabetes Association, Diabetes Care 1997; 20:1183-97 (revised 1999; republished January 2002); Lernmark A., “Type I Diabetes,” Clin. Chem. 45 (8B): 1331-8 (1999); Lebowitz R E., “Type 2 Diabetes: An Overview,” Clin. Chem. 45 (8B): 1339-45 (1999). The vast majority of cases of diabetes fall into two broad etiopathogenetic categories, type 1 diabetes (characterized by an absolute deficiency of insulin secretion) and the much more prevalent type 2 diabetes (characterized by a combination of resistance to insulin action and an inadequate compensatory insulin secretory response), Sixteen million people in the United States are estimated to have diabetes, and more than 90% of these patients have type 2 diabetes. National Center for Health Statistics. Health United Stats. Washington, D.C.: Government Printing Office, 1998. The World Health Organization estimates that the number of diabetic adults will more than double globally, from 143 million in 1997 to 300 million in 2025, largely because of dietary and other lifestyle factors.
Diabetes mellitus is a chronic condition characterized by the presence of fasting hyperglycemia and the development of widespread premature atherosclerosis. Patients with diabetes have increased morbidity and mortality due to cardiovascular diseases, especially coronary artery disease. Vascular complications in diabetes may be classified as microvascular, affecting the retina, kidney and nerves and macrovascular, predominantly affecting coronary, cerebrovascular and peripheral arterial circulation. Thus, the chronic hyperglycemia of diabetes is associated with long-term damage, dysfunction, and failure of various organs, especially the eyes, kidneys, nerves, heart, and blood vessels and long-term complications of diabetes include retinopathy with potential loss of vision; nephropathy leading to renal failure; peripheral neuropathy with risk of foot ulcers, amputation, and Charcot joints; and autonomic neuropathy causing gastrointestinal, genitourinary, and cardiovascular symptoms and sexual dysfunction. Glycation of tissue proteins and other macromolecules and excess production of polyol compounds from glucose are among the mechanisms thought to produce tissue damage from chronic hyperglycemia. Patients with diabetes have an increased incidence of atherosclerotic cardiovascular, peripheral vascular, and cerebrovascular disease. Hypertension, abnormalities of lipoprotein metabolism, and periodontal disease are often found in people with diabetes.
Chronic hyperglycemia results in hyperglycosylation of multiple proteins and is the hallmark of diabetes. Hyperglycosylated proteins have altered function resulting in a spectrum of effects. Epidemiological studies have confirmed that hyperglycemia is the most important factor in the onset and progress of diabetes complications, both in insulin-dependent and non-insulin-dependent diabetes mellitus. Mechanisms connecting hyperglycemia with complications of long-term diabetes have been investigated indicating the involvement of nonenzymatic glycation processes. The nonenzymatic glycation process in one in which glucose is chemically bound to amino groups of proteins, but without the help of enzymes. It is a covalent reaction where, by means of N-glycoside bonding, sugar-protein complex is formed through a series of chemical reactions described by Maillard. In Maillard reactions, sugar-protein complexes are formed (Amadori rearrangement) and represent an early product of nonenzymatic glycation and an intermediary that is a precursor of later compounds. Numerous intermediary products are then formed, followed by complex product polymerization reactions resulting in heterogeneous structures called advanced glycation end products (AGE). It was believed that the primary role in Maillard reactions was exclusively played by high glucose concentration. However, recent data show that, in spite of the fact that sugars are the main precursors of AGE compounds, numerous intermediary metabolites including α-oxoaldehydes also participate in nonenzymatic glycation reactions. Such intermediary products are generated during glycolysis (methylglyoxal) or in the polyolic pathway, and they can also be formed by autooxidation of carbohydrates (glyoxal). Alpha-oxoaldehydes modify AGEs surprisingly fast, in contrast to classical Maillard reactions which are slower.
Glycation has both physiological and pathophysiological significance. In physiological conditions glycation can be detected in the aging process, and the reactions are significantly faster and more intensive with frequently increased glucose concentrations. In diabetology the importance of these processes is manifest in two essential issues, the effect of protein glycation on the change of protein structure and function, and the use of glycated proteins level as a parameter of integrated glycemia. A classical example of nonenzymatic glycation is the formation of glycated hemoglobin (HbA1c). The degree of nonenzymatic glycation being directly associated with blood glucose levels, the percentage of HbA1c in diabetes can be very increased. HbA1c was the first studied glycated protein, but it was soon discovered that other, various structural and regulatory proteins, are also subject to nonenzymatic glycation forming glycation end-products.
Protein modification with AGE is irreversible, there being no enzymes in the organism able to hydrolyze AGE compounds, which consequently accumulate during the life span of a protein on which they had were formed. Examples include all types of collagen, albumin, basic myelin protein, eye lens proteins, lipoproteins and nucleic acid. AGEs change the function of many proteins and contribute to various late complications of diabetes mellitus. The major biological effect of excessive glycation include the inhibition of regulatory molecule binding, crosslinking of glycated proteins, trapping of soluble proteins by glycated extracellular matrix, decreased susceptibility to proteolysis, inactivation of enzymes, abnormalities of nucleic acid function, and increased immunogenicity in relation to immune complexes formation.
It has also been reported that AGEs progressively accumulate on the tissues and organs that develop chronic complications of diabetes mellitus like retinopathy, nephropathy, neuropathy and progressive atherosclerosis. Immunohistochemical methods have demonstrated the presence of different AGE compounds in glomeruli and tubuli cells in both experimental and human diabetic nephropathy. The AGE role in atherosclerosis may also be significant. For instance, reticulated and irreversible low-density lipoprotein (LDL) from the circulation binds to AGE-modified collagen of blood vessel walls. In the majority of blood vessels such reticular binding delays normal outflow of LDL particles which penetrate vessel walls and thus enhance the deposit of cholesterol in the intima. This is followed by an accelerated development of atherosclerosis.
The level of AGE proteins reflects kinetic balance of two opposite processes, the rate of AGE compound formation and the rate of their degradation by means of receptors. AGE receptors participate in the elimination and change of aged, reticular and denaturated molecules of extracellular matrix as well as all other AGE molecules. However, in diabetes mellitus AGE protein accumulation may exceed the ability of their elimination due to chronic hyperglycemia and excessive glycation. AGE receptors were first detected on macrophage cells, and AGE protein binding to macrophage cell receptors is believed to cause a cascade of events in the homeostasis of blood vessel walls and their milieu by mediation of cytokines and tissue growth factors. At least four different AGE receptors have been described, among which two belong to the group of receptor scavengers. One of them is very similar, if not identical, to the receptor that internalizes altered LDL particles. Receptors on endothelium cells differ and these cell membrane sites bind AGE-ligands (denoted “RAGE” receptors). They belong to immunoglobulin receptor family and are prevalent in tissues. Binding of AGE compounds to RAGEs leads to cellular stress. It is not currently known whether variations in AGE level explain differences in susceptibility to develop complications, but it has been theorized that gene diversity in AGE receptors could offer an explanation.
Hyperglycemia induces a large number of alterations in vascular tissue that potentially promote accelerated atherosclerosis. Currently, in addition to the nonenzymatic glycosylation of proteins and lipids, two other major mechanisms have emerged that encompass most of the pathologic alterations observed in the vasculature of diabetic animals and humans: oxidative stress, protein kinase C (PKC) activation. Importantly, these mechanisms are not independent. For example, hyperglycemia-induced oxidative stress promotes the formation of AGEs and PKC activation, and both type 1 and type 2 diabetes are independent risk factors for coronary artery disease (CAD), stroke, and peripheral arterial disease. Schwartz C J, et al., “Pathogenesis of the atherosclerotic lesion. Implications for diabetes mellitus,” Diabetes Care 15:1156-1167 (1992); Stamler 3, et al., “Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial.” Diabetes Care 16:434-444 (1993). Atherosclerosis accounts for virtually 80% of all deaths among North American diabetic patients, compared with one-third of all deaths in the general North American population, and more than 75% of all hospitalizations for diabetic complications are attributable to cardiovascular disease. American Diabetes Association, “Consensus statement: role of cardiovascular risk factors in prevention and treatment of macrovascular disease in diabetes,” Diabetes Care 16:72-78 (1993).
The decline in heart disease mortality in the general U.S. population has been attributed to the reduction in cardiovascular risk factors and improvement in treatment of heart disease. However, patients with diabetes have not experienced the reduction in age-adjusted heart disease mortality that has been observed in nondiabetics, and an increase in age-adjusted heart disease mortality has been reported in diabetic women. Gu K, et al., “Diabetes and decline in heart disease mortality in U.S. adults,” JAMA 281:1291-1297 (1999). Studies have also shown that diabetic subjects have more extensive atherosclerosis of both coronary and cerebral vessels than age- and sex-matched nondiabetic controls. Robertson W B, Strong J P, “Atherosclerosis in persons with hypertension and diabetes mellitus,” Lab Invest 18:538-551 (1968). It has also been reported that diabetics have a greater number of involved coronary vessels and more diffuse distribution of atherosclerotic lesions. Waller B F, et al., “Status of the coronary arteries at necropsy in diabetes mellitus with onset after age 30 years. Analysis of 229 diabetic patients with and without clinical evidence of coronary heart disease and comparison to 183 control subjects,” Am J Med 69:498-506 (1980). Large studies comparing diabetics with matched controls have also shown that diabetic patients with established CAD undergoing cardiac catheterization for acute myocardial infarction, angioplasty, or coronary bypass have significantly more severe proximal and distal CAD. Granger C B, et al., “Outcome of patients with diabetes mellitus and acute myocardial infarction treated with thrombolytic agents. The Thrombolysis and Angioplasty in Myocardial Infarction (TAMI) Study Group,” J Am Coll Cardiol 21:920-925 (1993); Stein B, et al., “Influence of diabetes mellitus on early and late outcome after percutaneous transluminal coronary angioplasty,” Circulation 91:979-989 (1995); Barzilay J I, et al., “Coronary artery disease and coronary artery bypass grafting in diabetic patients aged > or =65 years [report from the Coronary Artery Surgery Study (CASS) Registry],” Am J Cardiol 74:334-339 (1994)). Postmortem and angioscopic evidence also shows a significant increase in plaque ulceration and thrombosis in diabetic patients. Davies M J, et al., “Factors influencing the presence or absence of acute coronary artery thrombi in sudden ischaemic death,” Eur Heart J 10:203-208 (1989); Silva J A, et al. “Unstable angina. A comparison of angioscopic findings between diabetic and nondiabetic patients,” Circulation 92:1731-1736 (1995).
CAD is not confined to particular forms of diabetes, and is prevalent in both type 1 and type 2 diabetes. In type 1 diabetes, an excess of cardiovascular mortality is generally observed after the age of 30. Krolewski A S, et al., “Magnitude and determinants of coronary artery disease in juvenile-onset, insulin-dependent diabetes mellitus,” Am J Cardiol 59:750-755 (1987). CAD risk was reported in this study to increase rapidly after age 40, and by age 55, 35% of men and women with type 1 diabetes die of CAD, a rate of CAD mortality that far exceeded that observed in an age-matched nondiabetic cohort. Id. Diabetic nephropathy in type 1 diabetics also increases the prevalence of CAD. Nephropathy leads to accelerated accumulation of AGEs in the circulation and tissue and parallels the severity of renal functional impairment. Makita Z, et al., “Advanced glycosylation end products in patients with diabetic nephropathy,” N Engl J Med 325:836-842 (1991). In diabetic patients reaching end-stage renal disease, overall mortality has been reported to be greater than in nondiabetic patients with end-stage renal disease. The relative risk for age-specific death rate from myocardial infarction among all diabetic patients during the first year of dialysis is reportedly 89-fold higher than that of the general population. Geerlings W, et al., “Combined report on regular dialysis and transplantation in Europe, XXI,” Nephral Dial Transplant 6[Suppl 4]:5-29 (1991). It has also been reported that the most common cause of death in diabetic patients who have undergone renal transplantation is CAD, accounting for 40% of deaths in these patients. Lemmers M J, Barry J M, “Major role for arterial disease in morbidity and mortality after kidney transplantation in diabetic recipients,” Diabetes Care 14:295-301 (1991).
With regard to people with type 2 diabetes, CAD is the leading cause of death, regardless of duration of diabetes. Stamler J, et al., “Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial,” Diabetes Care 16:434-444 (1993); Donahue R P, Orchard T J, “Diabetes mellitus and macrovascular complications. An epidemiological perspective,” Diabetes Care 15:1141-1155 (1992). The increased cardiovascular risk is said to be particularly striking in women. Barrett-Connor E L, et al., “Why is diabetes mellitus a stronger risk factor for fatal ischemic heart disease in women than in men? The Rancho Bernardo Study,” JAMA 265:627-631 (1991).
The degree and duration of hyperglycemia are the principal risk factors for microvascular complications in type 2 diabetes. The Diabetes Control and Complications Trial Research Group, “The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus,” N Engl J Med 329:977-986 (1993). However, it has also been said that there is no clear association between the extent or severity of macrovascular complications and the duration or severity of the diabetes, and an increased prevalence of CAD is apparent in newly diagnosed type 2 diabetes subjects has been reported. Uusitupa M, et al., “Prevalence of coronary heart disease, left ventricular failure and hypertension in middle-aged, newly diagnosed type 2 (non-insulin-dependent) diabetic subjects,” Diabetologia 28:22-27 (1985). It has also been reported that even impaired glucose tolerance carries an increased cardiovascular risk despite minimal hyperglycemia. Fuller J H, et al., “Coronary-heart-disease risk and impaired glucose tolerance. The Whitehall study,” Lancet 1:1373-1376 (1980).
Insulin resistance is a common condition and, associated with genetic predisposition, sedentary lifestyle, and aging, it is exacerbated and produced by obesity. Thus, even in the absence of diabetes, insulin resistance is reportedly a major risk factor for CAD. Lempiainen P, et al., “Insulin resistance syndrome predicts coronary heart disease events in elderly nondiabetic men,” Circulation 100:123-128 (1999). Impaired insulin action coupled with compensatory hyperinsulinemia leads to a number of proatherogenic abnormalities referred to as insulin resistance syndrome, and the association of insulin resistance with several established atherogenic risk factors apparently promotes atherosclerosis many years before overt hyperglycemia ensues. Ferrannini E, et al., “Insulin resistance in essential hypertension,” N Engl J Med 317:350-357 (1987); Zavaroni I, et al., “Risk factors for coronary artery disease in healthy persons with hyperinsulinemia and normal glucose tolerance,” N Engl J Med 320:702-706 (1989); Peiris A N, et al., “Adiposity, fat distribution, and cardiovascular risk,” Ann Intern Med 110:867-872 (1989); Reaven G M, “Role of insulin resistance in human disease (syndrome X): an expanded definition,” Annu Rev Med 44:121-131 (1993).
Dyslipidemia associated with insulin resistance entails elevated very-low-density lipoprotein (VLDL)-triglyceride levels, low high-density lipoprotein (HDL) levels, delayed postprandial clearance of triglyceride-rich lipoprotein remnants, and the presence of the very atherogenic, small, dense LDL particles. Grundy S M, “Hypertriglyceridemia, atherogenic dyslipidemia, and the metabolic syndrome,” Am J Cardiol 81:18B-25B (1998). This atherogenic lipoprotein phenotype is the most common lipoprotein abnormality seen in patients with CAD and is said to impart a risk for CAD at least equal to that of isolated moderate to severe hypercholesterolemia. Austin M A, et al., “Atherogenic lipoprotein phenotype. A proposed genetic marker for coronary heart disease risk,” Circulation 82:495-506 (1990). Insulin-resistant subjects also exhibit endothelial dysfunction and a hypercoagulable state, and chronic subclinical inflammation has emerged as part of the insulin-resistance syndrome. C-reactive protein, a marker of inflammation associated with cardiovascular events, is independently related to insulin sensitivity. Festa A, et al., “Chronic subclinical inflammation as part of the insulin resistance syndrome: the Insulin Resistance Atherosclerosis Study (IRAS),” Circulation 102:42-47 (2000). The proatherogenic metabolic risk factors in insulin-resistance subjects worsen continuously across the spectrum of glucose tolerance. Meigs J B, et al., “Metabolic risk factors worsen continuously across the spectrum of nondiabetic glucose tolerance. The Framingham Offspring Study,” Ann Intern Med 128:524-533 (1998). Whether compensatory hyperinsulinemia promotes atherosclerosis in insulin-resistant subjects is not clear.
The atherogenic risk factor profile observed in insulin-resistance patients accounts for only a portion of the excess risk for CAD in patients with type 2 diabetes, indicating that hyperglycemia itself plays a central role in accelerating atherosclerosis in these patients. Thus, insulin-resistant individuals who go on to develop type 2 diabetes become exposed also to the atherogenic effects of hyperglycemia. Furthermore, while the threshold above which hyperglycemia becomes atherogenic is unknown, it may be in the range defined as impaired glucose tolerance. Gerstein H C, Yusuf S, “Dysglycaemia and risk of cardiovascular disease,” Lancet 347:949-950 (1996). Various population-based studies in patients with type 2 diabetes are reported to have shown a positive association between the degree of glycemic control and CAD morbidity and mortality in middle-aged and elderly type 2 diabetic subjects. Turner R C, et al., “Risk factors for coronary artery disease in non-insulin dependent diabetes mellitus: United Kingdom Prospective Diabetes Study (UKPDS: 23),” BMJ316:823-828 (1998); Kuusisto Jr, et al., “NIDDM and its metabolic control predict coronary heart disease in elderly subjects,” Diabetes 43:960-967 (1994); Laakso M, “Hyperglycemia and cardiovascular disease in type 2 diabetes,” Diabetes 48:937-942 (1999).
The metabolic abnormalities associated with types 1 and 2 diabetes also result in profound changes in the transport, composition, and metabolism of lipoproteins. Lipoprotein metabolism is said to be influenced by several factors including type of diabetes, glycemic control, obesity, insulin resistance, the presence of diabetic nephropathy, and genetic background. Ginsberg H N, “Lipoprotein physiology in nondiabetic and diabetic states. Relationship to atherogenesis,” Diabetes Care 14:839-855 (1991). Abnormalities in plasma lipoprotein concentrations are commonly observed in diabetic individuals and reportedly contribute to the atherosclerotic process. The level of glycemic control is the major determinant of lipoprotein levels in type 1 diabetic patients. Garg A, “Management of dyslipidemia in IDDM patients,” Diabetes Care 17:224-234 (1994). In well- to moderately-controlled diabetes, lipoprotein levels are usually within the normal range, while in poorly controlled type 1 diabetic patients, triglycerides are markedly elevated, LDL is modesty increased (usually when HbA1c is greater than 11%), and HDL levels are decreased.
In contrast to type 1 diabetes, the pathophysiology of dyslipidemia in type 2 diabetes results from a complex relationship between hyperglycemia and the insulin-resistance state. The typical lipoprotein profile associated with type 2 diabetes includes high triglycerides, low HDL levels, and normal LDL levels, the most consistent change reportedly being an increase in VLDL-triglyceride levels. Syvanne M, Taskinen M R, “Lipids and lipoproteins as coronary risk factors in non-insulin-dependent diabetes mellitus,” Lancet 350:SI20-SI23 (1997); Ginsberg H N, “Diabetic dyslipidemia: basic mechanisms underlying the common hypertriglyceridemia and low HDL cholesterol levels,” Diabetes 45[Suppl 3]:S27-S30 (1996). HDL levels are typically approximately 25% to 30% lower than in nondiabetic subjects and are commonly associated with other lipid and lipoprotein abnormalities, particularly high triglyceride levels.
Hypertriglyceridemia in type 2 diabetes results from high fasting and postprandial triglyceride-rich lipoproteins, especially VLDL. Type 2 diabetic subjects with hypertriglyceridemia have both overproduction and impaired catabolism of VLDL. Increased VLDL production is almost uniformly present in patients with type 2 diabetes and hypertriglyceridemia. Increased VLDL production in diabetes is a consequence of an increase in free fatty acid mobilization (because maintenance of stored fat in adipose tissue depends on the suppression of hormone-sensitive lipase by insulin) and high glucose levels. Because free fatty acid availability is a major determinant of VLDL production by the liver, VLDL overproduction and hypertriglyceridemia occur.
The rest of the dyslipidemic phenotype that characterizes insulin resistance and type 2 diabetes (low HDL and small, dense LDL)—which has been termed atherogenic lipoprotein phenotype (Austin M A, et al, “Atherogenic lipoprotein phenotype. A proposed genetic marker for coronary heart disease risk,” Circulation 82:495-506 (1990))—follows once VLDL secretion increases, mainly through the action of cholesteryl ester transfer protein and lipoprotein compositional changes that occur in plasma. Ginsberg H N, “Insulin resistance and cardiovascular disease,” J Clin Invest 106:453-458 (2000). Increased fatty acid flux to the liver also results in the production of large triglyceride-rich VLDL particles because the size of VLDL is also mainly determined by the amount of triglyceride available. VLDL size is an important determinant of its metabolic fate and large triglyceride-rich VLDL particles may be less efficiently converted to LDL, thereby increasing direct removal from the circulation by non-LDL pathways. In addition, overproduction of large triglyceride-rich VLDL is said to be associated with the atherogenic small, dense LDL subclass.
In type 2 diabetic subjects with more severe hypertriglyceridemia, VLDL clearance by lipoprotein lipase (LPL)—the rate-limiting enzyme responsible for the removal of plasma triglyceride-rich lipoproteins—is also reported to be impaired. Syvanne M, Taskinen M R, “Lipids and lipoproteins as coronary risk factors in non-insulin-dependent diabetes mellitus,” Lancet 350:SI20-SI23 (1997). LPL requires insulin for maintenance of normal tissue levels, and its activity is low in patients with poorly controlled type 2 diabetes. The result is enzymatic activity insufficient to match the overproduction rate, with further accumulation of VLDL triglyceride.
Triglyceride concentrations are associated with premature CAD, and studies have shown that triglyceride-rich lipoproteins play an important role in the progression of atherosclerosis. Hodis H N, “Myocardial ischemia and lipoprotein lipase activity,” Circulation 102:1600-1601 (2000). Furthermore, in contrast to the controversy regarding hypertriglyceridemia as a risk factor for coronary heart disease (CHD) in the nondiabetic population, several studies indicate that elevated triglyceride levels are independently associated with increased CHD risk in diabetic patients. Hypertriglyceridemia in diabetic patients often correlates with LDL density and subclass (i.e., small, dense LDL) and decreased levels of HDL2, which appear to increase overall risk synergistically. Havel R J, Rapaport E, “Management of primary hyperlipidemia,” N Engl J Med 332:1491-1498 (1995).
Characterized by increased VLDL production and impaired removal, it has been reported that patients with type 2 diabetes exhibit excessive postprandial lipemia and impaired remnant clearance. Exaggerated postprandial lipemia resulting from impaired remnant clearance is a factor in atherogenesis, involving endothelial dysfunction and enhanced oxidative stress. Karpe F, “Postprandial lipoprotein metabolism and atherosclerosis,” J Intern Med 246:341-355 (1999); Zilversmit D B, “Atherogenesis: a postprandial phenomenon,” Circulation 60:473-485 (1979); Patsch J R, et al., “Relation of triglyceride metabolism and coronary artery disease. Studies in the postprandial state,” Arterioscler Thromb 12:1336-1345 (1992); Plotnick G D, et al., “Effect of antioxidant vitamins on the transient impairment of endothelium-dependent brachial artery vasoactivity following a single high-fat meal,” JAMA 278:1682-1686 (1997). Postprandial lipemia consists of a heterogeneous group of triglyceride-rich particles of different composition and origin. Although 80% of the increase in postprandial triglyceride levels is accounted for by chylomicrons (which carry a large number of triglyceride molecules), the number of endogenous (liver-derived) VLDL constitutes over 90% of the triglyceride-rich particles in the postprandial state. Delayed VLDL clearance results in the accumulation of partially catabolized VLDL remnants that are reduced in size and enriched in cholesteryl ester, and evidence is said to indicate that these small, cholesteryl ester-enriched VLDL particles are atherogenic.
As in nondiabetic subjects, low high-density lipoprotein (HDL) levels are said to be powerful indicators of CHD in diabetic patients. Decreased HDL levels in diabetes result from decreased production and increased catabolism of HDL and are closely related to the abnormal metabolism of triglyceride-rich lipoproteins. In insulin-resistant patients with or without overt type 2 diabetes, the composition of LDL particles is altered, resulting in a preponderance of small, triglyceride-enriched and cholesterol-depleted particles (phenotype B). A preponderance of small, dense LDL particles is related to many characteristics of insulin-resistance syndrome, and in nondiabetic subjects, LDL subclass phenotype B is associated with other components of insulin-resistance syndrome, including central obesity, hypertension, glucose intolerance, and hyperinsulinemia. Selby J V, et al., “LDL subclass phenotypes and the insulin resistance syndrome in women,” Circulation 88:381-387 (1993); Reaven G M, et al., “Insulin resistance and hyperinsulinemia in individuals with small, dense low density lipoprotein particles,” Clin Invest 92:141-146 (1993); Haffner S M, et al., “LDL size in African Americans, Hispanics, and non-Hispanic whites: the insulin resistance atherosclerosis study,” Arterioscler Thromb Vasc Biol 19:2234-2240 (1999).
The formation of small, dense LDL in diabetes occurs in a similar fashion to the increased formation of small and dense HDL3. Cholesteryl ester transfer protein mediates the exchange of triglyceride from VLDL for cholesteryl ester in LDL. If sufficient LDL cholesteryl ester is replaced by triglyceride from VLDL, then when the particle comes into contact with hepatic lipase hydrolysis of newly acquired triglyceride in LDL and HDL by HTGL in turn decreases the size of LDL particles. Packard C J, Shepherd J, “Lipoprotein heterogeneity and apolipoprotein B metabolism,” Arterioscler Thromb Vase Biol 17:3542-3556 (1997). Small, dense LDL has also been said to be associated with CAD risk independently of the absolute concentrations of LDL cholesterol or other CAD risk factors, small, dense LDL particles being more susceptible to oxidative modification. Tribble D L, et al., “Oxidative susceptibility of low density lipoprotein subfractions is related to their ubiquinol-10 and alpha-tocopherol content,” Proc Natl Acad Sci USA 91:1183-1187 (1994). They are also particularly prone to induce endothelial dysfunction. Anderson T J, et al., “Endothelium-dependent coronary vasomotion relates to the susceptibility of LDL to oxidation in humans,” Circulation 93:1647-1650 (1996). In addition, there is enhanced arterial wall penetration by small LDL particles. Nielsen L B, “Transfer of low density lipoprotein into the arterial wall and risk of atherosclerosis,” Atherosclerosis 123:1-15 (1996).
Glycosylation occurs both on the apoB and phospholipid components of LDL, and is said to result in profound functional alternations in LDL clearance and susceptibility to oxidative modification, Bucala R, et al., “Identification of the major site of apolipoprotein B modification by advanced glycosylation end products blocking uptake by the low density lipoprotein receptor,” J Biol Chem 270:10828-10832 (1995); Bucala R, et al., “Lipid advanced glycosylation: pathway for lipid oxidation in vivo,” Proc Natl Acad Sci USA 90:6434-6438 (1993). Clinical studies have reportedly shown an increased level of AGEs on LDL obtained from diabetics compared with healthy individuals. Bucala R, et al., “Modification of low density lipoprotein by advanced glycation end products contributes to the dyslipidemia of diabetes and renal insufficiency,” Proc Natl Acad Sci USA 91:9441-9445 (1994). Glycosylation of LDL apoB occurs mainly on a positively charged lysine residue within the putative LDL receptor binding domain, which is essential for the recognition of LDL by the LDL receptor. Id. LDL glycosylation increases with glucose levels and impairs LDL receptor-mediated LDL clearance.
Another atherogenic effect of glycation is to increase LDL susceptibility to oxidative modification. Advanced glycosylation of an amine-containing phospholipid component of LDL is accompanied by progressive oxidative modification of unsaturated fatty acid residues. Thus, glycation is said to also confer increased susceptibility of LDL to oxidative modification, which has been considered a critical step in its atherogenicity. Lyons T J, “Glycation and oxidation: a role in the pathogenesis of atherosclerosis,” Am J Cardiol 71:26B-31B (1993); Bowie A, et al., “Glycosylated low density lipoprotein is more sensitive to oxidation: implications for the diabetic patient?,” Atherosclerosis 102:63-67 (1993).
Cholesterol lowering using agents such as pravastatin have been reported to reduce the absolute risk of coronary events for diabetic patients. Goldberg R B, et al., “Cardiovascular events and their reduction with pravastatin in diabetic and glucose-intolerant myocardial infarction survivors with average cholesterol levels: subgroup analyses in the Cholesterol and Recurrent Events (CARE) trial,” Circulation 98:2513-2519 (1998). However, the absolute clinical benefit achieved by cholesterol lowering may be greater in diabetic than in nondiabetic patients with CAD because diabetic patients have a higher absolute risk of recurrent CAD and higher case fatality rates, or because LDL cholesterol in diabetic patients is more atherogenic. Aronson D, et al., “Mechanisms determining course and outcome of diabetic patients who have had acute myocardial infarction,” Ann Intern Med 126:296-306 (1997).
The American Diabetes Association recommendations for the management of hyperlipidemia in patients with diabetes generally follow the guidelines of the National Cholesterol Education Program with several differences. American Diabetes Association. Position statement. “Management of dyslipidemia in adults with diabetes,” Diabetes Care 21:179-182 (1998). Non-pharmacologic strategies to treat dyslipidemia in diabetics include dietary modification (similar to those recommended by the National Cholesterol Education Program), weight loss, physical exercise, and improved glycemic control. Id. In patients with type 1 diabetes, optimal glycemic control should result in normal or below normal lipoprotein levels and prevent the atherogenic state associated with lipoprotein glycosylation. Improved diabetic control in type 2 diabetes is beneficial but not always associated with reversal of lipoprotein abnormalities.
Improved glycemic control using pharmacologic agents such as sulfonylureas, insulin, metformin (N,N-dimethylimidodicarbonimidic diamide hydrochloride), or thiazolidinediones can also help. The magnitude of improvement in triglycerides generally correlates with the change in glucose levels rather than the mode of therapy. However, agents that improve insulin sensitivity such as metformin and thiazolidinediones can also lead to lower triglycerides. In addition, “perfect” glycemic control is not attained in many type 2 diabetic patients, and relatively recent publications have argued against the relevance of the traditional classification to primary and secondary CHD prevention in the setting of diabetes. Haffner S M, “Management of dyslipidemia in adults with diabetes,” Diabetes Care 21:160-178 (1998); Haffner S M, et al. “Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction,” N Engl J Med 339:229-234 (1998). The rationale stems from both the high event rates in diabetic patients without clinical evidence of CAD (presumably because of the high rates of subclinical atherosclerosis), as well as the worse prognosis in diabetic patients who have had a clinical event compared with nondiabetic subjects, leading to the suggestion that LDL cholesterol should be lowered to less than 100 mg per dL in diabetic subjects without prior CAD. Id.
Endothelial cells situated at the vessel wall-blood interface participate in a number of important homeostatic and cellular functions that protect from atherosclerosis and intraluminal thrombosis. Endothelial dysfunction can promote both the formation of atherosclerotic plaques and the occurrence of acute events and, in diabetes, is said to entail profound perturbations in several critical functions of the endothelium that contribute to the initiation and progression of the atherosclerotic process, as well as to the occurrence of clinical events. It is believed that diabetes results in weakened intercellular junctions, and that AGEs diminish endothelial barrier function. The endothelial lining of the large arteries is of the continuous type characterized by tight junctions in the lateral borders, which restrict the movement of macromolecules from reaching the subendothelial space.
Leukocyte adhesion to the vascular endothelium also contributes to diabetic complications. Among the earliest events in atherogenesis is the binding of mononuclear leukocytes to the endothelium with subsequent entry into the vessel wall. This is mediated through the expression of inducible adhesion molecules on the endothelial cell surface. Hyperglycemia stimulates the expression of vascular cell adhesion molecule-1 (VCAM-1) and E selectin. In addition, AGE interaction with the AGE receptor has been reported to result in the induction of oxidative stress and, consequently, of the transcription factor NF-kappaB and VCAM-1. Thus, early events in the atherosclerosis process in diabetes may be mediated through enhanced adhesive interactions of monocytes with the endothelial surface.
Impaired endothelium-dependent relaxation, which is mediated through the release of endothelium-derived relaxing factor (EDRF), is also reportedly a consistent finding in animal models and in human diabetes and occurs in a variety of vascular beds, including the coronary arteries. Impaired endothelium-dependent relaxation has been demonstrated in both type 1 and type 2 diabetes in the absence of clinical complications, while endothelium-independent vasodilation is preserved, and impaired endothelium-dependent relaxation can be demonstrated in insulin-resistant subjects with normal glucose tolerance. De Vriese A S, et al., “Endothelial dysfunction in diabetes,” Br J Pharmacal 130:963-974 (2000). Thus, hyperglycemia is recognized as the primary mediator of diabetic endothelial dysfunction. Williams S B, et al., “Acute hyperglycemia attenuates endothelium-dependent vasodilation in humans in vivo,” Circulation 97:1695-1701 (1998). Similar to the mechanism of endothelial dysfunction observed in hypercholesterolemia, hyperglycemia-induced endothelial dysfunction is thought to result primarily from increased generation of oxygen free radicals that inactivate EDRF. Insulin resistance is also said to contribute to endothelial dysfunction in diabetic patients. Steinberg H O, et al., “Obesity/insulin resistance is associated with endothelial dysfunction. Implications for the syndrome of insulin resistance,” J Clin Invest 97:2601-2610 (1996).
Diabetes is also said to be characterized by a variety of individual alterations in the coagulation and fibrinolytic systems that combine to produce a prothrombotic state. These alterations include increased platelet functional behavior, increased levels of several coagulation components, and impaired fibrinolysis. The coagulation and fibrinolytic systems are said to be especially important in atherosclerosis because of the substantial contribution that mural thrombosis may make to the later stages of plaque progression, and because thrombotic occlusion plays a vital role in the development of clinical events. In the vast majority of cases, the fundamental mechanism in the development of potentially life-threatening events such as unstable angina or myocardial infarction is thrombosis arising at sites of plaque disruption.
Platelet hyperaggregability, including the presence of spontaneous platelet aggregation and increased platelet aggregability induced by conventional stimuli, also increases the risk for cardiovascular events. Platelets from diabetic subjects exhibit enhanced adhesiveness and hyperaggregability, and shear-induced platelet adhesion and aggregation are also increased in diabetic patients. Knobler H, et al., “Shear-induced platelet adhesion and aggregation on subendothelium are increased in diabetic patients,” Thromb Res 90:181-190 (1998). von Willebrand factor (vWF) is involved in the initial adhesion of platelets to the subendothelium of injured vessel wall and is among the most important adhesive molecules mediating hemostatic interactions between platelets and vessel wall components. Synthesized and secreted by endothelial cells, high circulating levels of vWF are considered markers of endothelial dysfunction. In diabetic patients plasma concentrations of vWF are elevated and are closely associated with the presence of vascular complications and endothelial dysfunction. Stehouwer C D, et al., “Urinary albumin excretion, cardiovascular disease, and endothelial dysfunction in non-insulin-dependent diabetes mellitus,” Lancet 340:319-323 (1992). Epidemiologic data have also demonstrated a relation between plasma vWF and insulin-resistance syndrome. Conlan M G, et al., “Associations of factor VIII and von Willebrand factor with age, race, sex, and risk factors for atherosclerosis. The Atherosclerosis Risk in Communities (ARIC) Study,” Thromb Haemost 70:380-385 (1993). Increased plasma concentration of vWF has been shown to be predictive of re-infarction and mortality in survivors of myocardial infarction, of cardiac events in healthy people and in patients with angina pectoris. The European Concerted Action on Thrombosis study showed that vWF predictability was not affected by the adjustment with other classical coronary risk factors such as body mass index, lipid disorders or smoking. As vWF levels are dependent on the acute phase reaction like fibrinogen, and vWF correlates positively with fibrinogen or C-reactive protein levels, it has to be evaluated if vWF is a risk factor irrespective of fibrinogen level. In type 2 diabetic patients vWF levels are higher in microalbuminuric patients. vWF is reportedly poorly or not at all related to insulin resistance.
Hyperactive platelets may form microaggregates leading to capillary microembolization. In patients with diabetes the resulting relative tissue hypoxia may in the long-term precede clinically detectable microangiopathy. It has been speculated that microembolization of the vasa vasorum of the large vessels by hyperactive platelets may also be the initial event in the development of atherosclerosis. Secretion of mitogenic, oxidative or vasoconstrictive substances by platelets activated in response to endothelial injury amplifies and accelerates the progression of atherosclerosis. Acute thrombotic events in the arterial circulation are also triggered by platelets.
The fibrinolytic system is natural defense against thrombosis. A balance exists between plasminogen activators and inhibitors, and impairment of this balance can be caused either by diminished release of tissue plasminogen activator (t-PA) or increased levels of plasminogen activator inhibitor 1 (PAI-1). PAI-1 is a serine protease inhibitor and evidence suggests that it is the major regulator of the fibrinolytic system. It binds and rapidly inhibits both single- and two-chain t-PA and urokinase. t-PA and PAI-1 rapidly form an inactive irreversible complex. Abnormalities of the fibrinolytic system have been described in both type 1 and type 2 diabetes. Impaired fibrinolysis, as described in diabetes type 2, is commonly accompanied by an increased plasma levels of PAI-1 and by increased concentration oft-PA antigen, which reflects predominantly t-PA/PAI-1 complexes. In type 1 diabetes results are mixed, and diminished, normal and enhanced fibrinolysis have all been reported. In subjects with type 2 diabetes a variety of risk factors are independently associated with impaired fibrinolysis: obesity, hypertension, dyslipidaemia, glucose intolerance, hyperinsulinaemia and insulin resistance. These factors often tend to converge and numerous studies have attempted to dissect out the independent contribution of the above risk factors in determining fibrinolytic activity in diabetes, but this task has been hampered by the complex relationship between them. In non-diabetic subjects, insulin resistance is paralleled by increased insulin and both correlate with triglyceride levels. Thus any one or more of these variables may explain interrelationship with PAI-1. By contrast in type 2 diabetes, insulin resistance, insulin concentration and triglyceride levels are less tightly interdependent in explaining increased PAI-1. Impaired fibrinolysis not only predisposes to thrombotic events but also plays a role in the formation and progression of atherosclerotic lesions. Increased synthesis of PAI-1 has been demonstrated in atherosclerotic lesions. This may lead to fibrin deposition during lesion rupture, contributing to the progression of the lesion. PAI-1 within the lesion inhibits plasmin formation, which plays an important role in cleaving extracellular matrix proteins, directly or via activation of metalloproteinases. This may lead to stabilization and further growth of atherosclerotic lesion. Changes in the fibrinolytic system also play an important role in microangiopathy. Urokinase and plasmin are activators of latent metalloproteinases, such as collagenases, that are responsible for proteolysis of extracellular matrix proteins. Increased PAI-1 may lead to basement membrane thickening observed in microangiopathy.
A large body of evidence also indicates strong independent direct correlation between high fibrinogen plasma levels and an increased risk of CAD. Fibrinogen levels are often increased in diabetes, and this elevation is associated with poor glycemic control. Kannel W B, et al., “Diabetes, fibrinogen, and risk of cardiovascular disease: the Framingham Experience,” Am Heart J 120:672-676 (1990). The intensity of endogenous fibrinolysis depends on a dynamic equilibrium involving plasminogen activators, primarily tissue-type plasminogen activator, and inhibitors. The principal physiologic inhibitor of tissue-type plasminogen activator is plasminogen activator inhibitor-1 (PAI-1). Attenuated fibrinolysis caused by an increase of PM-1 activity has been associated with increased risk for myocardial infarction in patients with established CAD. Kohler H P, Grant P J, “Plasminogen-activator inhibitor type 1 and coronary artery disease,” N Engl J Med 342:1792-1801 (2000). Reduced plasma fibrinolytic activity caused by increased PAI-1 levels is a characteristic feature of insulin resistance and hyperinsulinemia. Elevated concentrations of PAI-1 have been recognized consistently in the plasma of hyperinsulinemic type 2 diabetics but occur also in normoglycemic insulin-resistant subjects. Juhan-Vague I, Alessi M C, “PAI-1, obesity, insulin resistance and risk of cardiovascular events,” Thromb Haemost 78:656-660 (1997). The production of PAI-1 by adipose tissue has been demonstrated and could be an important contributor to the elevated plasma PAI-1 levels observed in insulin-resistant patients. Alessi M C, et al., “Production of plasminogen activator inhibitor 1 by human adipose tissue: possible link between visceral fat accumulation and vascular disease,” Diabetes 46:860-867 (1997). Hyperglycemia can also increase PAI-1 levels because it stimulates transcription of the PAI-1 gene through an effect on its promoter region. Chen Y Q, et al., “Sp1 sites mediate activation of the plasminogen activator inhibitor-1 promoter by glucose in vascular smooth muscle cells,” J Biol Chem 273:8225-8231 (1998). Although it is possible that some of the hemostatic abnormalities in diabetes are partly markers of underlying vascular disease rather than the primary abnormalities, the clotting and fibrinolytic profile of diabetic patients is said to bear a striking similarity to that of patients at high risk for future cardiovascular events. The prothrombotic state in diabetes is said to help explain the observation that intracoronary thrombus formation is more frequently found by angioscopic examination in diabetic patients with unstable angina, and its clinical correlate, the higher risk of adverse outcome, namely death, nonfatal infarction, or recurrent unstable angina. Silva J A, et al., “Unstable angina. A comparison of angioscopic findings between diabetic and nondiabetic patients,” Circulation 92:1731-1736 (1995); Aronson D, et al., “Mechanisms determining course and outcome of diabetic patients who have had acute myocardial infarction,” Ann Intern Med 126:296-306 (1997); Malmberg K, et al., “Impact of diabetes on long-term prognosis in patients with unstable angina and non-Q-wave myocardial infarction: results of the OASIS (Organization to Assess Strategies for Ischemic Syndromes) Registry,” Circulation 102:1014-1019 (2000); Calvin J E, et al., “Risk stratification in unstable angina. Prospective validation of the Braunwald classification,” JAMA 273:136-141 (1995). Thus, hyperglycemia induces a large number of alterations in vascular tissue that potentially promote accelerated atherosclerosis. Acosta J, et al., “Molecular basis for a link between complement and the vascular complications of diabetes,” Proc Natl Acad Sci USA 97:5450-5455 (2000).
Protein kinase C is also involved and the metabolic consequences of hyperglycemia are said to be seen in cells in which glucose transport is largely independent of insulin. The resulting intracellular hyperglycemia has been implicated in the pathogenesis of diabetic complications through the activation of the PKC system. Ishii H, et al., “Amelioration of vascular dysfunctions in diabetic rats by an oral PKC beta inhibitor,” Science 272:728-731 (1996); Koya D, King G L, “Protein kinase C activation and the development of diabetic complications,” Diabetes 47:859-866 (1998). High ambient glucose concentrations activate PKC by increasing the formation of diacylglycerol (DAG), the major endogenous cellular cofactor for PKC activation, from glycolytic intermediates such as dihydroxy-acetone phosphate and glyceraldehyde-3-phosphate. The elevation of DAG and subsequent activation of PKC in the vasculature can be maintained chronically. Xia P, et al., “Characterization of the mechanism for the chronic activation of diacylglycerol-protein kinase C pathway in diabetes and hypergalactosemia,” Diabetes 43:1122-1129 (1994).
PKC is a family of at least 12 isoforms of serine and threonine kinases. Although several PKC isoforms are reportedly expressed in vascular tissue, in the rat model of diabetes there is a preferential activation of PKC b2 in the aorta, heart, and retina, and PKC b1 in the glomeruli. Inoguchi T, et al., “Preferential elevation of protein kinase C isoform beta II and diacylglycerol levels in the aorta and heart of diabetic rats: differential reversibility to glycemic control by islet cell transplantation,” Proc Natl Acad Sci USA 89:11059-11063 (1992); Koya D, et al., “Characterization of protein kinase C beta isoform activation on the gene expression of transforming growth factor-beta, extracellular matrix components, and prostanoids in the glomeruli of diabetic rats,” J Clin Invest 100:115-126 (1997). The PKC system is ubiquitously distributed in cells and is involved in the transcription of several growth factors and in signal transduction in response to growth factors. In vascular smooth muscle cells, PKC activation has been reported to modulate growth rate, DNA synthesis, and growth factor receptor turnover. PKC activation increases the expression of transforming growth factor-b (TGF-b), which is one of the most important growth factors, regulating extracellular matrix production by activating gene expression of proteoglycans and collagen and decreasing the synthesis of proteolytic enzymes that degrade matrix proteins. Increased expression of TGF-b is thought to lead to thickening of capillary basement membrane, one of the early structural abnormalities observed in almost all tissues in diabetes. PKC b selective inhibitor (LY333531) attenuates glomerular expression of TGF-b and extracellular matrix proteins such as fibronectin and type IV collagen. Koya, supra; Koya D, et al., “Amelioration of accelerated diabetic mesangial expansion by treatment with a PKC beta inhibitor in diabetic db/db mice, a rodent model for type 2 diabetes,” FASEB J 14:439-447 (2000). Hyperglycemia-induced PKC activation also results in increased platelet-derived growth factor-b receptor expression on smooth muscle cells and other vascular wall cells (e.g., endothelial cells, monocyte-macrophages). Inaba T, et al., “Enhanced expression of platelet-derived growth factor-beta receptor by high glucose. Involvement of platelet-derived growth factor in diabetic angiopathy,” Diabetes 45:507-512 (1996).
Oxidative stress is widely invoked as a pathogenic mechanism for atherosclerosis. Among the sequelae of hyperglycemia, oxidative stress has been suggested as a potential mechanism for accelerated atherosclerosis. Baynes J W, Thorpe S R, “Role of oxidative stress in diabetic complications: a new perspective on an old paradigm,” Diabetes 48:1-9 (1999). Importantly, there appears to be a strong pathogenic link between hyperglycemia-induced oxidant stress and other hyperglycemia-dependent mechanisms of vascular damage, namely AGEs formation and PKC activation), and hyperglycemia can increase oxidative stress through several pathways. A major mechanism appears to be the hyperglycemia-induced intracellular reactive oxygen species, produced by the proton electromechanical gradient generated by the mitochondrial electron transport chain and resulting in increased production of superoxide. Nishikawa T, et al., “Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage,” Nature 404:787-790 (2000). Two other mechanisms have been proposed that may explain how hyperglycemia causes increased reactive oxygen species formation. One mechanism involves the transition metal-catalyzed autoxidation of free glucose, as described in cell-free systems. Through this mechanism, glucose itself initiates an autoxidative reaction and free radical production yielding superoxide anion (O2−) and hydrogen peroxide (H2O2). Wolff S P, “Diabetes mellitus and free radicals. Free radicals, transition metals and oxidative stress in the aetiology of diabetes mellitus and complications,” Br Med Bull 49:642-652 (1993). The other mechanism involves the transition metal-catalyzed autoxidation of protein-bound Amadori products, which yields superoxide and hydroxyl radicals and highly reactive dicarbonyl compounds. Baynes J W, Thorpe S R, “Role of oxidative stress in diabetic complications: a new perspective on an old paradigm,” Diabetes 48:1-9 (1999).
There is also evidence that hyperglycemia may compromise natural antioxidant defenses. Under normal circumstances, free radicals are rapidly eliminated by antioxidants such as reduced glutathione, vitamin C, and vitamin E. Reduced glutathione content, as well as reduced vitamin E, have been reported in diabetic patients. Yoshida K, et al., “Weakened cellular scavenging activity against oxidative stress in diabetes mellitus: regulation of glutathione synthesis and efflux,” Diabetologia 38:201-210 (1995); Karpen C W, et al., “Production of 12-hydroxyeicosatetraenoic acid and vitamin E status in platelets from type I human diabetic subjects,” Diabetes 34:526-531 (1985).
The interaction between AGE epitopes and the cell surface AGE receptor up-regulate oxidative stress response genes and release oxygen radicals. Thus, hyperglycemia simultaneously enhances both AGEs formation and oxidative stress, and the mutual facilitatory interactions between glycation and oxidation chemistry can contribute synergistically to the formation of AGEs, oxidative stress, and diabetic complications. Indeed, there are reportedly strong correlations between levels of glycoxidation products in skin collagen and the severity of diabetic retinal, renal, and vascular disease. Beisswenger P J, et al., “Increased collagen-linked pentosidine levels and advanced glycosylation end products in early diabetic nephropathy,” J Clin Invest 92:212-217 (1993). Oxidative stress may also be involved in the activation of DAG-PKC in vascular tissue. Nishikawa T, et al., “Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage,” Nature 404:787-790 (2000). Oxidants produced in the setting of hyperglycemia can activate PKC. Konishi H, et al., “Activation of protein kinase C by tyrosine phosphorylation in response to H2O2,” Proc Natl Acad Sci USA 94:11233-11237 (1997).
The risk for congestive heart failure (CHF) and idiopathic cardiomyopathy is also said to be strongly increased in diabetes. Kannel W B, et al., “Role of diabetes in congestive heart failure: the Framingham study,” Am J Cardiol 34:29-34 (1974); Shindler D M, et al., “Diabetes mellitus, a predictor of morbidity and mortality in the Studies of Left Ventricular Dysfunction (SOLVD) Trials and Registry,” Am J Cardiol 77:1017-1020 (1996); Ho K K, et al., “The epidemiology of heart failure: the Framingham Study,” J Am Coll Cardiol 22:6A-13A (1993). Although data on the effect of diabetes on the prognosis of patients with CHF are limited, several studies implicate diabetes as an independent predictor of poor prognosis in this setting. In the Studies of Left Ventricular Dysfunction study, diabetes was an independent predictor of morbidity and mortality in patients with symptomatic heart failure, asymptomatic patients with an ejection fraction less than or equal to 35%, and in the registry population. Shindler, supra. One reason for the poor prognosis in patients with both diabetes and ischemic heart disease seems to be an enhanced myocardial dysfunction leading to accelerated heart failure. Grundy S M, et al., “Diabetes and cardiovascular disease: a statement for healthcare professionals from the American Heart Association,” Circulation 100:1134-1146 (1999).
The cardiomyopathic process associated with diabetes mellitus manifests initially as diminished left ventricular compliance in the presence of normal left ventricular systolic function. Zarich S W, et al., “Diastolic abnormalities in young asymptomatic diabetic patients assessed by pulsed Doppler echocardiography,” J Am Coll Cardiol 12:114-120 (1988); Paillole C, et al., “Prevalence and significance of left ventricular filling abnormalities determined by Doppler echocardiography in young type I (insulin-dependent) diabetic patients,” Am J Cardiol 64:1010-1016 (1989); Mildenberger R R, et al., “Clinically unrecognized ventricular dysfunction in young diabetic patients,” J Am Coll Cardiol 4:234-238 (1984). Diastolic abnormalities occur in 27% to 69% of asymptomatic diabetic patients. A lower ejection fraction in response to dynamic exercise in the presence of a normal resting ejection fraction has been demonstrated in several studies, indicating that contractile reserve is decreased in many asymptomatic patients with diabetes. Mildenberger, supra; Shapiro L M, et al., “Left ventricular function in diabetes mellitus. II: Relation between clinical features and left ventricular function,” Br Heart J 45:129-132 (1981); Mustonen J N, et al., “Left ventricular systolic function in middle-aged patients with diabetes mellitus,” Am J Cardiol 73:1202-1208 (1994). Systolic dysfunction may appear, usually in patients with long-standing disease who suffer from advanced microvascular complications. Racy D C, “Which left ventricular function is impaired earlier in the evolution of diabetic cardiomyopathy? An echocardiographic study of young type 1 diabetic patients,” Diabetes Care 17:633-639 (1994). However, even subclinical cardiomyopathy with reduced myocardial reserve may become clinically important in the presence of myocardial ischemia or with coexistent uncontrolled hypertension. Stone P H, et al., “The effect of diabetes mellitus on prognosis and serial left ventricular function after acute myocardial infarction: contribution of both coronary disease and diastolic left ventricular dysfunction to the adverse prognosis. The MILTS Study Group,” J Am Coll Cordial 14:49-57 (1989).
It is also understood that the coexistence of hypertension and diabetes exerts a particularly deleterious effect on the heart. The coexistence of hypertension has been considered a major factor in the expression of diastolic dysfunction in diabetic patients. Grossman E, Messerli F H, “Diabetic and hypertensive heart disease,” Ann Intern Med 125:304-310 (1996). In hypertensive subjects, diabetes is an important precursor of CHF, with a greater relative risk in women than in men. Levy D, et al., “The progression from hypertension to congestive heart failure,” JAMA 275:1557-1562 (1996). The mechanisms responsible for the increased risk for the development of CHF are not fully understood, but may be related in part to an exaggerated increase in left ventricular mass. Grossman E, et al., “Left ventricular mass in diabetes-hypertension,” Arch Intern Med 152:1001-1004 (1992).
Obesity, which is characterized by insulin resistance and hyperinsulinemia, is also strongly correlated with increased left ventricular mass independent of age and blood pressure. Lauer M S, et al., “The impact of obesity on left ventricular mass and geometry. The Framingham Heart Study,” JAMA 266:231-236 (1991). Furthermore, left ventricular mass in normotensive obese subjects is related more to the severity of insulin resistance than to the obesity itself as expressed by the body mass index. Sasson Z, et al., “Insulin resistance is an important determinant of left ventricular mass in the obese,” Circulation 88:1431-1436 (1993).
In hypertensive patients with normal glucose tolerance, who commonly exhibit insulin resistance and hyperinsulinemia, left ventricular mass has been shown to correlate with the degree of insulin resistance. Ohya Y, et al., “Hyperinsulinemia and left ventricular geometry in a work-site population in Japan,” Hypertension 27:729-734 (1996); Verdecchia P, et al., “Circulating insulin and insulin growth factor-1 are independent determinants of left ventricular mass and geometry in essential hypertension,” Circulation 100:1802-1807 (1999). A similar association is also observed in nonhypertensive insulin-resistant subjects. Marcus R, et al., “Sex-specific determinants of increased left ventricular mass in the Tecumseh Blood Pressure Study,” Circulation 90:928-936 (1994).
Thus, hypertension, insulin resistance, hyperinsulinemia, and type 2 diabetes are all reported to be commonly associated and result in a high risk for cardiovascular complications. Reaven G M, Laws A, “Insulin resistance, compensatory hyperinsulinaemia, and coronary heart disease,” Diabetologia 37:948-952 (1994); Agewall S, et al., “Carotid artery wall intima-media thickness is associated with insulin-mediated glucose disposal in men at high and low coronary risk,” Stroke 26:956-960 (1995). Left ventricular mass is a strong predictor of cardiac and cerebrovascular morbidity independent of blood pressure or other risk factors, as well as a powerful risk factor for the development of symptomatic CHF, and it is believed that the association between insulin resistance and left ventricular hypertrophy may contribute to the increase risk of symptomatic CAD in insulin-resistant subjects.
Several reports have also focussed on metabolic abnormalities including abnormal intracellular Ca2+ handling, defects in myocardial glucose use, and activation of PKC as possible explanations for the pathogenesis of diabetic cardiomyopathy. Additionally, there may also be a role for AGEs, discussed above, in the pathogenesis of diabetic cardiomyopathy. Diabetic patients have increased arterial stiffness compared with nondiabetic individuals and manifest diminished left ventricular compliance at a young age. Several investigators have reported that diabetes has several features of accelerated aging at the tissue level and at the level of collagen itself. Aging and diabetes mellitus are associated with cross-linking and nonenzymatic glycosylation of collagen. This led to the concept that glycosylation could help to explain the progressive cross-linking of collagen during normal aging and at an accelerated rate in diabetes, leading to changes in vascular tissue mechanical properties. Thus, disturbances of vascular and cardiac mechanical properties in diabetes may be caused by a common mechanism. Among the structural alterations associated with AGEs formation is collagen-to-collagen cross-linking, which alters the structure and function of this protein, leading to tissue rigidity. Increased arterial stiffness in patients with diabetes is said to be strongly correlated with increased aorta and myocardial collagen advanced glycation. Airaksinen K E, et al., “Diminished arterial elasticity in diabetes: association with fluorescent advanced glycosylation end products in collagen,” Cardiovasc Res 27:942-945 (1993). Further evidence supporting the AGE hypothesis is the observation that agents that specifically inhibit AGE formation reportedly are useful to prevent the pathologic stiffening process of diabetes and aging. Norton G R, et al., “Aminoguanidine prevents the decreased myocardial compliance produced by streptozotocin-induced diabetes mellitus in rats,” Circulation 93:1905-1912 (1996); Huijberts M S, et al., “Aminoguanidine treatment increases elasticity and decreases fluid filtration of large arteries from diabetic rats,” J Clin Invest 92:1407-1411 (1993). For example, treatment of diabetic rats with aminoguanidine, an inhibitor of AGE formation, reportedly increased carotid artery compliance, decreases aortic impedance, and prevented the decreased myocardial compliance. Id.
It has been attempted with greater or lesser efficacy to pharmacologically influence the process of nonenzymatic glycation and AGE products formation using, in general, two approaches. The first is inhibition of the rearrangement from early to advanced glycation endproducts by means of hydrasine:aminoguanidine hydrochloride or analogue. The second is the breaking of already existing AGE products with substituted thiazolium salts. Pharmacologic activity of aminoguanidine may render impossible or retard some of microvascular complications in animal model. Although the mechanism of aminoguanidine action has not been completely understood, it may inhibit some stages in a series of chemical reactions leading to glycation end-product formation. In spite of the first encouraging results, clinical trials of aminoguanidine in patients with type 2 diabetes mellitus have been suspended due to adverse effects. See, for example, Brownlee M., “Negative consequences of glycation,” Metabolism 49(suppl 1): 9-13 (2000); Singh R, Barden A, Mori T, Beilin L., “Advanced glycation end-products: a review,” Diabetologia 44:129-146 (2001); Vlassara H, Bucala R, Striker L., “Pathogenic effects of AGEs: Biochemical, biologic, and clinical implications for diabetes and aging,” Lab Invest 70:138-151 (1994); Lyons T, Jenkins A J., “Glycation, oxidation and lipoxidation in the development of the complications of diabetes mellitus: a ‘carbonyl stress’ hypothesis,” Diabetes Rev 5:365-391 (1997).
As indicated herein, it is understood that diabetes mellitus is a major source of morbidity in developed countries. Among its co-morbid conditions, atherosclerosis is one of the most important. Since the availability of insulin, up to three-quarters of all deaths among diabetics can be directly attributed to CAD. In patients with type 1 diabetes, up to one third will die of CAD by the age of 50 years. A number of known risk factors for CAD, such as hypertension, central obesity and dyslipidemia, are more common in diabetics than in the general population. Thus diabetes represents a major contributing factor to the CAD burden in the developed world, and most of the excess attributed risk of CAD in diabetics cannot be readily quantified with the use of traditional risk factors analysis. As indicated, the relation between hyperglycemia and CAD is the subject of debate because serum glucose does not consistently predict the existence of CAD. However, recent prospective data have clearly established a link between a marker for chronic average glucose levels (HbA1c) and cardiovascular morbidity and mortality. There are established sequelae of hyperglycemia, such as cytotoxicity, increased extracellular matrix production and vascular dysfunction and all have been implicated in the pathogenesis of diabetes-induced vascular disease, and the formation of AGEs correlate directly with the vascular and renal complications of diabetes mellitus. As noted, patients with diabetes mellitus are particularly susceptible to morbidity and mortality resulting from cardiovascular diseases, especially atherosclerosis, the progression of which is characterized by infiltration of lipids into the vessel wall and the formation of fibrous tissue called the atheromatous plaque. Clinical symptoms of atherosclerosis do not usually occur until over half of the lumen becomes obstructed (occluded) by the plaque, typically in the fifth and sixth decades of life. Consequently, studies on the role of plasma lipids in health and in the genesis of CHD have dominated research on CHD over the past several decades. Current positive evidence documents the premise that the following are important risk factors: family history, a high plasma concentration of low-density lipoprotein (LDL) and a low concentration high density lipoprotein (HDL) cholesterol (separately as well as jointly), high plasma concentration of apoS (the major protein fraction of the LDL particle), high plasma lipoprotein (a) (Lp(a)) concentration, high plasma fibrinogen concentration, hypertension, diabetes, obesity, increased plasma concentration of homocysteine (all these themselves have genetic determinants), high dietary fat intake, lack of exercise, stress, and smoking.
The pathogenesis of the atherosclerosis in diabetes mellitus is not entirely clear and conventional risk factors such as smoking, obesity, blood pressure and serum lipids fail to explain fully this excess risk. As noted, important features in the pathogenesis of atherosclerosis appear to include vascular endothelial injury, platelet adhesion and activation, fibrin deposition, cellular proliferation, and low-density lipoprotein cholesterol accumulation. Fibrin deposition is an invariable feature in atherosclerotic lesions. Therefore, disturbances of haemostasis leading to accelerated fibrin formation (hypercoagulability) and delayed fibrin removal (impaired fibrinolysis) may contribute to the development of atherosclerosis. Hyperactive platelets, hypercoagulability and impaired fibrinolysis, as indicated above, also promote thrombosis formation at the site of ruptured atherosclerotic lesion and lead to final occlusion event in the progression of atherosclerosis. Although platelet counts are generally normal in patients with diabetes mellitus, multiple studies offer evidence of enhanced activation or increased platelet activity, and an increase in plasma levels of vWF, which is important for the adhesion of platelets to subendothelial structures, has been reported in diabetic patients.
In diabetes mellitus disturbances of haemostasis leading to hypercoagulability have been observed in numerous studies. Besides altered screening tests, alterations of several coagulation factors and inhibitors have been occasionally described. A problem encountered when studying the association between hypercoagulability and atherosclerosis is the number of laboratory tests proposed to detect hypercoagulability and the wide variability of such tests in a given subject. Results of cohort studies have shown that among different coagulation factors analyzed, increased concentration of fibrinogen, factor VII and vWF have predictive value for coronary atherosclerosis and can be considered as risk factors for cardiovascular events. Increase in these factors could participate in the pathogenesis of atherosclerosis, predominantly of coronary arteries. A relationship has been established between plasma concentration of fibrinogen, the quantity of fibrinogen and fibrin present in the vessel wall and the severity of atherosclerosis. These associations are more pronounced in diabetic patients.
Factor VII is a vitamin K dependent protein synthesized in the liver. It is the key enzyme in the initiation of blood coagulation. The Northwick Park Heart Study and the PROCAM study have shown that there is a positive correlation between increased factor VII and cardiovascular mortality. Plasma concentration of factor VII is closely related to several environmental factors, mainly triglycerides and cholesterol levels. These associations are highly dependent on dietary intake. An increase in factor VII has been described in diabetes mellitus and is more pronounced in those with microalbuminuria. Only limited data are available concerning the contributory role of insulin resistance to elevated factor VII. The relationship between factor VII and insulin and proinsulin have been described as very weak or present only in women. Factor VII which is influenced by the efficiency of the metabolism of triglyceride-rich lipoproteins could in this way be modified in insulin resistance.
Hypercoagulability can also be judged from increased levels of markers of coagulation system activation, which reflect enhanced thrombin generation. Prothrombin fragment 1+2 released when thrombin is formed from prothrombin is increased in diabetes. Once activated, thrombin is rapidly inactivated by antithrombin, forming thrombin-antithrombin complexes, which subsequently circulate and are removed by the liver. Multiple studies have documented elevated thrombin-antithrombin complexes in diabetes. Fibrinopeptide A is released when fibrinogen is converted to fibrin by thrombin. Thus, fibrinopeptide A levels are increased during coagulation. Measurement of fibrinopeptide A in diabetes has yielded a variety of results, from elevated to normal.
hyperinsulinemia has also been associated with cardiovascular disease in non-diabetic subjects. In those with type 2 diabetes the extent of hyperinsulinemia parallels plasma PAI-1 activity, and insulin has been implicated as a major physiological regulator of PAI-1. Despite population correlations of insulin and PAI-1, and the effect of insulin on PAI-1 production in vitro, a direct effect of insulin on PAI-1 levels in vivo in humans has not been shown, either with intravenous infusion of insulin or by an oral glucose load with the aim of producing portal hyperinsulinemia. Thus, in humans there is little evidence that interventions resulting in increased concentration of insulin in vivo increase PAM. On the other hand reducing insulin levels and insulin resistance by exercise, weight loss and the drug metformin has been shown to reduce PAI-1. In patients with type 2 diabetes approximately 30% of fasting immunoreactive insulin concentration consists of proinsulin-like molecules. The elevated levels of PAI-1 in these subjects may, therefore, be a consequence of precursor insulin rather than insulin itself.
Hyperglycemia is an additional risk factor for impaired fibrinolysis. Glucose can directly increase PAI-1 production in human endothelial cells. In patients with type 2 diabetes a significant correlation between glucose concentration and PAI-1 and has been observed. It has been proposed that insulin resistance or hyperinsulinemia could influence the synthesis of PAI-1 via effects on lipid metabolism. In patients with diabetes, dyslipidaemia, in particular high triglyceride and low high-density lipoprotein level, is common. Studies in vitro have reportedly demonstrated the effect of various lipoproteins on PAI-1 synthesis. VLDLs from hypertriglycer-idemic patients increase endothelial cell production of PAI-1 to a greater degree than that from normo-triglyceridaemic subjects. Oxidized LSLs also stimulate endothelial cell PAI-1 synthesis as does lipoprotein(a). Lipoprotein(a), LDSs, and HDLs also suppress t-PA secretion from human endothelial cells in dose dependent manner.
In sum, there is significant laboratory evidence of chronic platelet activation, enhanced coagulation and impaired fibrinolysis in patients with diabetes mellitus. These disturbances of haemostasis favor development of atherosclerosis and thrombosis in particularly of coronary arteries.
Metals are present naturally in body and many are essential for cells (e.g., Cu, Fe, Mn, Ni, Zn). However, all metals are toxic at higher concentrations. One reason metals may become toxic is because they may cause oxidative stress, particularly redox active transition metals, which can take up or give off an electron (e.g., Fe2+/3+, Cu+/2+) can give rise to free radicals that cause damage (Jones et al., “Evidence for the generation of hydroxyl radicals from a chromium(V) intermediate isolated from the reaction of chromate with glutathione,” Biochim. Biophys. Acta 286: 652-655 (1991); Li, Y. and Trush, M. A. 1993. DNA damage resulting from the oxidation of hydroquinone by copper: role for a Cu(II)/Cu(I) redox cycle and reactive oxygen generation,” Carcinogenes 7: 1303-1311 (1993). Another reason why metals may be toxic is because they can replace other essential metals in or enzymes, disrupting the function of these molecules. Some metal ions (e.g., Hg+ and Cu+) are very reactive to thiol groups and can interfere with protein structure and function.
As noted herein, humans subject to type 2 diabetes or abnormalities of glucose mechanism are particularly at risk to the precursors of heart failure, heart failure itself and a miscellany of other diseases of the arterial tree. It has been reported that in Western countries, more than 50% of patients with type 2 diabetes die from the effects of cardiovascular disease. See, Stamler et al., Diabetes Care 16:434-44 (1993). It has also been reported that even lesser degrees of glucose intolerance defined by a glucose tolerance test (impaired glucose tolerance, or “IGT”) still carry an increased risk of sudden death. See, Balkau et al., Lancet 354:1968-9 (1999). For a long time, it was assumed that this reflected an increased incidence of coronary atherosclerosis and myocardial infarction in diabetic subjects. However, evidence is mounting that diabetes can cause a specific heart failure or cardiomyopathy in the absence of atherosclerotic coronary artery disease.
Cardiac function is commonly assessed by measuring the ejection fraction. A normal left ventricle ejects at least 50% of its end-diastolic volume each beat. A patient with systolic heart failure commonly has a left ventricular ejection fraction less than 30% with a compensatory increase in end-diastolic volume. Hemodynamic studies conducted on diabetic subjects without overt congestive heart failure have observed normal left ventricular systolic function (LV ejection fraction) but abnormal diastolic function suggesting impaired left ventricular relaxation or filling. See, Regan et al., J. Clin. Invest. 60:885-99 (1977). In a recent study, 60% of men with type 2 diabetes without clinically detectable heart disease were reported to have abnounalities of diastolic filling as assessed by echocardiography. See, Poirier et al., Diabetes Care 24:5-10 (2001). Diagnosis may be made, for example, by noninvasive measurements. In the absence of mitral stenosis, mitral diastolic blood flow measured by Doppler echocardiography is a direct measure of left ventricular filling. The most commonly used measurement is the A/E ratio. Normal early diastolic filling is rapid and is characterized by an E-wave velocity of around 1 m/sec. Late diastolic filling due to atrial contraction is only a minor component, and the A-wave velocity is perhaps around 0.5 m/sec. This gives a normal A/E ratio of approximately 0.5. With diastolic dysfunction, early diastolic filling is impaired, atrial contraction increases to compensate, and the A/E ratio increases to more than 2.0.
Treatment of diabetic cardiomyopathy is difficult and the options are limited. Tight control of blood glucose levels might prevent or reverse myocardial failure, although this may be true only in the early stages of ventricular failure. Angiotensin converting enzyme inhibitors such as captopril improve survival in heart failure particularly in patients with severe systolic heart failure and the lowest ejection fractions. There are, however, various therapies for diabetic cardiomyopathy that are not recommended. For example, inotropic drugs are designed to improve the contraction of the failing heart. However, a heart with pure diastolic dysfunction is already contracting normally and it is believed that inotropic drugs will increase the risk of arrhythmias. Additionally, there appears to be no logical reason to use vasodilator drugs that reduce after-load and improve the emptying of the ventricle because ejection fraction and end-diastolic volume are already normal. After-load reduction may even worsen cardiac function by creating a degree of outflow obstruction.
Diuretics are the mainstay of therapy for heart failure by controlling salt and water retention and reducing filling pressures. However, they are contraindicated in diastolic dysfunction where compromised cardiac pump function is dependent on high filling pressures to maintain cardiac output. Venodilator drugs such as the nitrates, which are very effective in the management of systolic heart failure by reducing pre-load and filling pressures, are understood to be poorly tolerated by patients with diastolic heart failure. Ejection fraction and end-systolic volume are often normal and any reduction in pre-load leads to a marked fall in cardiac output. Finally, there is concern about the use of β-blockers in heart failure because of their potential to worsen pump function. There is also concern regarding the administration of β-blockers to patients with diabetes who are treated with sulphonylurea drugs and insulin due to a heightened risk of severe hypoglycaemia.
Thus, it will be understood that the mechanisms underlying various disorders of the heart, the macrovasculature, the microvasculature, and the long-term complications of diabetes, including associated heart diseases and conditions and long-term complications, are complex and have long been studied without the discovery of clear, safe and effective therapeutic interventions. There is a need for such therapies, which are described herein. | {
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Cloud Service Providers (CSPs) provide a scalable multi-tenant cloud infrastructure. To implement the multi-tenant cloud infrastructure CSPs have need to deliver layer 2 and layer 3 network services or functions, e.g., firewalls, load balancers, network accelerators, etc. Network services may be daisy-chained, thereby forming a service chain. Service chains define a set of layer 2 and layer 3 service functions and their order, e.g., service1->to->service2, to be applied to selective packets as they are forwarded through a network. The order in which services are applied is predetermined through an orchestration function and that order is mapped into each network node that is involved in the forwarding of packets through a given service chain. The mapping of forwarding state-to-service chain structure is referred to as a service path. The service path for a given service chain may be unidirectional or bidirectional dependent on whether one or more of the service functions in the chain hold state information that needs to be maintained in the forward and reverse packet forwarding paths. | {
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People may sometimes be at a location where they want food, but are not able to go to a restaurant or store. Accordingly, they may want to have food delivered to them. To meet this demand, a courier may obtain food prepared by a restaurant and deliver the food to a customer at a delivery location. For example, a service may enable customers to order food items, and may arrange for couriers to deliver the food items to the customers. However, conventional food deliveries can take a relatively long time between the time at which the customer places the order and the time at which the food is delivered to the customer. | {
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This invention relates generally to spectroscopic systems. More particularly, in one embodiment, the invention relates to a spectroscopic system for characterizing test specimens using a plurality of spectral data types.
Spectral analysis of biological specimens has been used for disease diagnosis. In general, spectra are recorded as values of amplitude, typically measured as a response to an excitation, as a function of wavelength (or the inverse of wavelength, namely frequency). In the field of spectral analysis, different kinds of information are conveyed by different spectral types. For example, fluorescence spectra are recorded using a source of excitation illumination that is absorbed by a specimen and that causes the specimen to emit a fluorescence spectrum that depends in part on the transfer of energy within and among atoms and/or molecules in the specimen. An illumination source for use in observing and recording fluorescence spectra generally operates at a selected monochromatic wavelength, or a narrow range of wavelengths. Different sources of illumination that operate at different wavelengths can excite different constituents of a specimen. In addition, different sources of illumination that operate at different wavelengths can excite the same constituent with different efficiencies. Thus, a fluorescence spectrum can depend on both the excitation wavelength that is used to illuminate a specimen and on the composition of the specimen itself. Other effects also play a role in determining a fluorescence spectrum, for example, instrumental effects, effects relating to polarization of the illumination, or thermal effects.
Some progress has been made in using various optical spectral methods for analysis of test specimens, including biological specimens. However, the wide variety of physical and chemical influences present in a test specimen that play roles in determining an observed spectrum make difficult both the choice of a suitable illumination source, and the interpretation of the resulting spectrum. This is in part true because there are so many influences on the kind and amount of information that an optical spectrum conveys that it is hard to find clear cause and effect relationships among the multitude of competing influences.
The invention provides methods of determining the disease state of a biological specimen based upon a reflectance spectrum residual derived by subtracting from a reflectance spectrum obtained from a test specimen an average reflectance spectrum obtained from a plurality if healthy specimens. In a preferred embodiment, members of the plurality of healthy specimens are determined to be healthy based upon the fluorescence spectra emitted by those samples. Typically, the specimen to be tested exhibits a fluorescence spectrum that is not characteristic of healthy tissue.
The reflectance spectrum residual provides a criterion for diagnostic classification of a specimen that is judged to be indeterminate in classification by its fluorescence spectrum alone. Accordingly, methods of the invention resolve diagnostic ambiguities created when a specimen produces a fluorescence spectrum that is not characteristic of a healthy tissue. Similarly, methods of the invention are also useful to resolve diagnostic ambiguities created when the fluorescence spectrum of a test specimen is not characteristic of any known disease state.
In one aspect, the invention provides a method of determining a condition of a test specimen. The method comprises recording both fluorescence and reflectance spectra from specific specimen. The method then comprises identifying a plurality of specimens having a fluorescence spectrum characteristic of a known condition; obtaining an average reflectance spectrum based upon the plurality of first test specimens; obtaining a reflectance spectrum from a test specimen that produces a fluorescence spectrum that is not characteristic of the known condition; and obtaining a reflectance spectrum residual by subtracting the average reflectance spectrum from the reflectance spectrum obtained from the test specimen. Determination of the condition of the test specimen is based upon the reflectance spectrum residual. In a preferred embodiment, the condition of the test specimen is based upon an amplitude of one or more features of the reflectance spectrum residual. For purposes of the invention a xe2x80x9cconditionxe2x80x9d is a state of disease, including a healthy state or simply the physiological makeup of the specimen and/or the patient from whom it was obtained.
In one embodiment, the plurality of specimens producing the average reflectance spectrum comprises tissue specimens and the test specimen is a tissue specimen of the same type. In one embodiment, the tissue specimens are human cervical tissue specimens, the condition of which is healthy, and the condition of the test specimen is determined by methods of the invention. In one embodiment, cervical tissue producing the average reflectance spectrum are selected from normal squamous tissue, metaplasia, mile cervical intraepithelial neoplasia (CIN I), and moderate to severe cervical intraepithelial neoplasia (CIN II/III). In another embodiment, methods of the invention further comprise obtaining additional optical information from the test specimen, and evaluating the additional optical information in comparison to the fluorescence spectrum and the reflectance spectrum from the test specimen to determine the condition of the test specimen. In one embodiment, the additional optical information is video information. In another embodiment, the additional optical information is an optical image.
In one aspect, the invention relates to a spectroscopic system for determining a condition of a test specimen. The system comprises a data collection module that collects a fluorescence spectrum characteristic of a known condition from each of a plurality of first specimens, observes a reflectance spectrum from each member of the plurality, and observes a reflectance spectrum from a test specimen that is observed to produce a second fluorescence spectrum that is not characteristic of the known condition. The system further comprises a computation module that computes an average reflectance spectrum based upon each member of the plurality of first specimens, and that computes a reflectance spectrum residual by subtracting the average reflectance spectrum from the reflectance spectrum obtained from a test specimen, and an analysis module that determines the condition of the test specimen based at least in part upon the reflectance spectrum residual.
The foregoing and other objects, aspects, features, and advantages of the invention will become more apparent from the following description and from the claims. | {
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1. Field of the Invention
The present invention relates to an analytical method for analyzing mass spectrometric data, a mass spectrometric data analyzing apparatus, amass spectrometric data analyzing program, and a solution offering system.
2. Description of Related Art
There has been an increasing need for a mass spectrometer which has a tandem mass spectrometric function to dissociate a substance (or a parent ion) to improve the identification precision of the substance from mass spectrometric data obtained by the mass spectrometer, and to perform further mass spectrometry of the dissociated ions. The method for identifying the parent ion and for deriving the supposed structure of the parent ion with the mass spectrometric data (i.e., MS data) of the parent ion and the mass spectrometric data (i.e., MS2 data) of the dissociated ions is mainly classified into the following methods:
(1) A database retrieving method of the mass spectrometric data (i.e., the MS data) of the parent ion;
(2) A database retrieving method of the mass spectrometric data (i.e., the MS data and the MS2 data) of the parent ion and the dissociated ions; and
(3) A method for suppositions based on the mass spectrometric data (i.e., the MS data and the MS2 data) of the parent ion and the dissociated ions but not depending on the database.
On One example of the related art (2) is disclosed in JP-A-8-124519. In this disclosure, for the individual peaks of the mass spectrum or mass spectrometric data, the candidates for the ion species corresponding to the peak mass are extracted with reference to the peak database, and the candidates for the eliminated radicals corresponding to the elimination mass are extracted with reference to the elimination radical database. Moreover, the candidates for the parent ion are determined with reference to the structure constructing database which is stored with rules for constructing the parent ion from the dissociated ions and the eliminated radicals.
In an amino acid configuration analysis supporting software “SeqMS” developed by Ohsaka University, on the other hand, the related art (3) is exemplified by identifying about ten amino acid configurations of peptide without resorting to the database retrieval. This software derives the amino acid configuration candidates by the statistical procedures which are based on the graph theory using the weighting values of the dissociation probability determined empirically (or experimentally) from the mass spectrometric data of the peptide ions and their dissociated ions.
When the database retrievals of the related arts (1) and (2) are used as the method for identifying the parent ion and for deriving the supposed structure of the parent ion by the mass spectrometric data (i.e., the MS data) of the parent ion and the mass spectrometric data (i.e., the MS2 data) of the dissociated ions, however, the parent ion is difficult to identify, and the supposed structure is difficult to derive, because no data is present in the database for a substance having an unknown structure.
When the statistical processing based on the graph theory and the information processing of a numerical arrangement are performed as the method without resorting to the database retrieval, as disclosed in the related art (3), on the other hand, it is the current practice that the identification precision of the parent ion is seriously lowered to one half or less.
Therefore, a main object of the present invention is to cope with an unknown structure substance thereby to identify the structure of a parent ion highly precisely and to derive a supposed structure. | {
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1. Field of the Invention
The field of invention relates to prelubrication apparatus, and more particularly pertains to a new and improved auxiliary oil pump apparatus wherein the same is directed to the preliminary lubrication of an internal combustion engine prior to operation thereof.
2. Description of the Prior Art
Prelubrication of various automobile engines and internal combustion engines in general has been recognized in the prior art as a remedy for a problem to minimize accelerated abrasion between various reciprocating and relatively moving components within the internal combustion engine. Such apparatus is exemplified in U.S. Pat. Nos. 4,112,910; 4,524,734; 4,875,551; 4,940,114; and 4,936,272.
Accordingly, it may be appreciated that there continues to be a need for a new and improved auxiliary oil pump apparatus as set forth by the instant invention which addresses both the problems of ease of use as well as effectiveness in construction and in this respect, the present invention substantially fulfills this need. | {
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This invention pertains to polishing systems and methods for polishing substrates.
The trend in the semiconductor industry continues to concentrate on reducing the size of semiconductor devices while improving the planarity of their surfaces. More specifically, it is desirable to achieve a surface of even topography by decreasing the number and allowable size of surface imperfections. A smooth topography is sought-after because it is difficult to lithographically image and pattern layers applied to rough surfaces. A conventional way of planarizing the surfaces of these devices is to polish them with a polishing system.
During polishing, it is often useful to polish one wafer surface material faster than another. For example, in shallow-trench isolation (STI), it is important to polish away an overlayer of silicon dioxide, until a silicon nitride layer is exposed, and then to remove as little of the exposed silicon nitride layer as possible. This can be accomplished by a polishing system that polishes away silicon dioxide at a faster rate than silicon nitride. The difference in the rate of polishing between two materials, such as silicon dioxide and silicon nitride, is called selectivity. Increased silicon dioxide-silicon nitride selectivity is a highly desirable property in STI polishing systems.
An accepted method of polishing (e.g., planarizing) semiconductor devices involves polishing the surface of the semiconductor with a polishing composition and/or a polishing pad, such as is accomplished by chemical-mechanical polishing (CMP). In a typical CMP process, a wafer is pressed against a polishing pad in the presence of a slurry under controlled chemical, pressure, velocity, and temperature conditions. The slurry generally contains small, abrasive particles that abrade the surface of the wafer in a mixture with chemicals that etch and/or oxidize the newly formed surface of the wafer. The polishing pad generally is a planar pad made from a continuous phase matrix material such as polyurethane. Thus, when the polishing pad and/or the wafer moves with respect to the other, material is removed from the surface of the wafer mechanically by the abrasive particles and chemically by the etchants and/or oxidants in the slurry.
While the aqueous chemicals desirably react chemically with the substrate, they also are reactive with the abrasive particles. This reaction can xe2x80x9csoftenxe2x80x9d the abrasive particle surfaces, rendering the abrasive less abrasive. Moreover, the reaction of the chemical component with the abrasive particle surface lowers the concentration of that component available for reaction with the substrate surface during polishing. As a result, the polishing performance of premixed CMP slurries may not be optimal for the polishing of solid surfaces, including IC wafer surfaces, rigid disk surfaces, glass surfaces, magnetic media, etc. Furthermore, because CMP slurries must be stable for the extended periods over which they arc typically stored before use, the chemical additives available for use in slurries is limited by their reactivity with other components in the slurry. This consideration also limits the concentration of additives that can be incorporated into slurries.
Thus, there remains a need for improved polishing systems and methods. The invention provides such a polishing system and method These and other advantages of the invention, as well as additional inventive features, will be apparent from the description of the invention provided herein.
The invention provides polishing systems that comprise a liquid carrier, an alkali metal ion, a compound comprising an amine group and at least one polar moiety, wherein the polar moiety contains at least one oxygen atom (hereinafter referred to as an xe2x80x9camine-containing, compoundxe2x80x9d), and a polishing pad and/or an abrasive. The abrasive can be dispersed in the liquid carrier of the polishing system or bound to the polishing pad. In a first embodiment, the alkali metal ion and the amine-containing compound desirably are present in a concentration such that the total ion concentration of the polishing system is above the critical coagulation concentration. In a second embodiment, the polishing system comprises about 0.05 wt. % to about 0.15 wt. % KOH and about 0.4 M to about 0.8 M of the amine-containing compound. The invention further provides polishing a portion of a substrate with a polishing system of the invention, preferably beginning about 6 hours or less after the polishing system is prepared.
The invention provides polishing systems and methods for polishing a substrate. Generally, the polishing systems comprise, consist essentially of, or consist of (a) a liquid carrier, (b) an alkali metal ion, (c) a compound comprising an amine group and at least one polar moiety, wherein the polar moiety contains at least one oxygen atom, and (d) a polishing pad and/or an abrasive. In a first embodiment, the polishing system has a total ion concentration, which is above the critical coagulation concentration. In a second embodiment, the polishing system comprises about 0.05 wt. % to about 0. 5 wt. % KOH and about 0.4 M to about 0.8 M of the compound comprising an amine group and at least one polar moiety, wherein the polar moiety contains at least one oxygen atom. The polishing methods generally comprise contacting a surface of a substrate with a polishing system and polishing at least a portion of the substrate. In a first embodiment, the polishing system used in the polishing method is one of the aforementioned polishing systems. In a second embodiment, the polishing system used in the polishing method comprises (a) a liquid carrier, (b) an alkali metal ion, (c) a compound comprising an amine group and at least one polar moiety, wherein the polar moiety contains at least one oxygen atom, and (d) a polishing pad and/or an abrasive, and a portion of the substrate is polished with the polishing system before the polishing system components reach a chemical equilibrium after the system is prepared.
Typically, each polishing system is used about 6 hours or less after the polishing system is prepared, which generally will be before the polishing system reaches a chemical equilibrium. Preferably, the polishing system is used about 4 hours or less (e.g., about 2 hours or less, about 1 hour or less, about 30 minutes or less, about 10 minutes or less, about 5 minutes or less, or even about 1 minute or less) after the polishing system is prepared. Indeed, the polishing system can be used seconds (e.g., about 30 seconds, or less or about 10 seconds or less) after the polishing system is prepared, such as when the polishing system components are mixed very near or at the point-of-use of the polishing system (e.g., on the polishing pad and/or substrate being polished).
The term xe2x80x9ccomponentxe2x80x9d as used herein includes individual ingredients (e.g., acids, bases, oxidizers, water, etc.) as well as any combination of ingredients (e.g., aqueous compositions, abrasive slurries, mixtures and solutions of oxidizers, acids, bases, complexing agents, etc.) that are stored separately and combined to form a polishing system.
The polishing systems and methods of the invention can be used to polish any suitable substrate. Suitable substrates are typically wafers used in the semiconductor industry that are in need of polishing or planarizing. They comprise, for example, a metal, metal oxide, metal composite, metal alloy, or mixtures thereof. The substrate can comprise metals such as copper, aluminum, titanium, tungsten, gold, and combinations (e.g., alloys or mixtures) thereof. The substrate also can comprise metal oxides such as, alumina, silica, titania, ceria, zirconia, germania, magnesia, and co-formed products thereof, and mixtures thereof. In addition, the substrate can comprise metal composites and/or alloys such as metal nitrides (e.g., silicon nitride, tantalum nitride, titanium nitride, and tungsten nitride), metal carbides (e.g., silicon carbide and tungsten carbide), nickel-phosphorus, alumino-borosilicate, borosilicate glass, phosphosilicate glass (PSG), borophosphosilicate glass (BPSG), silicon-germanium alloys, and silicon-germanium-carbon alloys. The substrate also can comprise semiconductor base materials such as single-crystal silicon, poly-crystalline silicon, amorphous silicon, silicon-on-insulator, and gallium arsenide. The polishing systems and methods of the invention are not limited to semiconductor polishing, they also can be applied to glass substrates, including technical glass, optical glass, and ceramics, of various types known in the art.
The polishing systems and methods of the invention can be used to polish any part of a substrate (e.g., a semiconductor device) at any stage in the production of the substrate. For example, a particularly effective use of the polishing systems and methods of the invention is in polishing a semiconductor device in conjunction with shallow trench isolation (STI) processing or in conjunction with the formation of an interlayer dielectric (ILD) as is known in art.
The polishing systems described herein comprise an abrasive, a polishing pad, or both. Preferably, the polishing systems comprise both an abrasive and a polishing pad. The abrasive can be fixed on the polishing pad and/or can be in particulate form and suspended in the liquid carrier. The polishing pad can be any suitable polishing pad. The liquid carrier and substances dissolved or suspended (e.g., dispersed) therein, such as the alkali metal ion, the compound comprising an amine group and at least one polar moiety, wherein the polar moiety contains at least one oxygen atom, and the abrasive (when present and suspended in the liquid carrier), form the polishing composition, upon which all concentrations (e.g., weight percentage and molarity values) are based as recited therein. Thus, the concentrations recited herein are not based upon substances not dissolved or suspended in the liquid carrier (such as the polishing pad and any abrasive embedded therein).
Any suitable abrasive can be used in conjunction with the inventive polishing systems. Suitable abrasives are capable of polishing a substrate surface without introducing deleterious scratches or other imperfections in the substrate surface. The abrasive preferably is a metal oxide. Suitable metal oxide abrasives include, for example, alumina, silica, titania, ceria, zirconia, and magnesia, as well as co-formed products thereof, mixtures thereof, and chemical admixtures thereof. Silica is the preferred abrasive, with fumed silica being more preferred.
The abrasive can have any suitable abrasive particle characteristics depending on the desired polishing effects. In particular, the abrasive can have any suitable surface area. A suitable abrasive surface area, for example, is a surface area ranging from about 5 m2/g to about 430 m2/g (e.g., about 5-200 m2/g), as calculated from the method of S. Brunauer, P. H. Emmet, and I. Teller, J. Am. Chem. Soc., 60, 309 (1938). Desirably, the surface area of the abrasive used in conjunction with the invention is about 90 m2/g or more.
The abrasive can be combined with (e.g., suspended in) any suitable liquid carrier to form a dispersion or suspension (i.e., a xe2x80x9cslurryxe2x80x9d). Suitable liquid carriers generally include polar solvents, preferably water or an aqueous solvent. Where the abrasive is included in a dispersion, the dispersion can have any concentration of abrasive that is suitable for polishing. Generally, about 0.1 wt. % silica or more is contemplated. Desirably the polishing system will have 5-30 wt. % silica. Polishing systems containing 10-25 wt. % silica are preferred.
Alternatively, the abrasive in the polishing systems can be fixed (e.g., embedded) in or on a polishing pad. The aforementioned considerations as to the type of abrasive particle suitable for dispersions are applicable to embedded abrasives. Any suitable amount of abrasive can be embedded in the pad. A suitable amount is any amount sufficient to provide for polishing of a substrate surface at a suitable rate without introducing deleterious scratches or other imperfections in the substrate surface.
The alkali metal ion present in the polishing systems can be any suitable alkali metal ion. Suitable alkali metal ions include any of the univalent basic metals of group I of the periodic table. For example, sodium, potassium, rubidium, and cesium ions can be used. Potassium and cesium ions are preferred, with potassium ions being more preferred. Any suitable source of alkali metal ion can be used. For example, alkali metal salts or alkali metal hydroxides (e.g., KCI or KOH) are suitable sources of alkali metal ions.
The alkali metal ion can be present in the polishing systems in any suitable concentration, desirably such that the total ion concentration of the polishing system is above the critical coagulation concentration. Preferably, the alkali metal ion is present in the polishing system in a concentration of about 0.15 M or more (e.g., about 0.2 M or more). More preferably, the alkali metal ion is present in the polishing system in a concentration of 0.25 M or more, about 0.3 M or more, about 0.35 M or more, about 0.4 M or more, or even about 0.45 M or more. Generally, the alkali metal ion is present in the polishing system in an amount that does not exceed 1.5 M, preferably an amount that does not exceed 0.75 M (e.g., about 0. 15-0.75 M, or more preferably, about 0.2 M-0.5 M).
The amine-containing compound, which, as previously described, is a compound comprising an amine group and at least one polar moiety, wherein the polar moiety contains at least one oxygen atom (e.g., amino acids, amino alcohols, and the like) can be any suitable such compound in the polishing systems of the invention. Suitable amine-containing compounds include dimethylpropanolamine (also know as 2-dimethylamino-2-methyl-1-propanol or DMAMP), 2-amino-2-methyl-1-propanol (AMP), 2-(2-aminoethylamino)ethanol, 2-(isopropylamino)ethanol, 2-(methylamino)ethanol, 2-(diethylamino)ethanol, 2-(2-(dimethylamino)ethoxy)ethanol, 1,1xe2x80x2-[[3-(dimethylamino)propyl]imino]-bis-2-propanol, 2-(butylamino)ethanol, 2-(tert-butylamino)ethanol, 2-(diisopropylamino)ethanol, N-(3-aminopropyl)morpholine, and mixtures thereof.
The amine-containing compound can be present in the polishing systems in any suitable concentration, desirably such that the total ion concentration of the polishing system is above the critical coagulation concentration. Preferably, the amine-containing compound is present in the polishing system in a concentration of about 0.2 M or more (e.g., about 0.5 M or more). More preferably, the amine-containing compound is present in the polishing system in a concentration of about 0.7 M or more, about 0.8 M or more, about 0.9 M or more, or even about 1 M or more. It is also suitable for the amine-containing compound to be present in the polishing system in a concentration of about 1.1 M or more (e.g., about 1.5 M or more). Generally, the amine-containing compound is present in the polishing system in a concentration that does not exceed 3 M, preferably in an amount that does not exceed 1.4 M (e.g., about 0.2-1.4 M, or more preferably, about 0.7-1.1 M).
In a first embodiment, the polishing system contains both an alkali metal ion and a compound comprising an amine group and at least one polar moiety, wherein the polar moiety contains at least one oxygen atom, wherein the total ion concentration of the polishing system is above the critical coagulation concentration. The combination of the alkali metal ion and the amine-containing compound has a synergistic effect on the polishing rate achieved by the polishing system when the total ion concentration of the system is above the critical coagulation concentration.
The critical coagulation concentration (CCC) is defined herein as the lowest total ion concentration of the polishing system required to induce the coagulation of a stable colloidal suspension (e.g., to form a gel). In the context of the invention, coagulation can be described as the process by which the dispersed phase of a colloid (e.g., a slurry) is made to aggregate and thereby separate from the continuous phase, eventually forming a gel. This occurs when the ions present in the polishing system gather closely around the colloidal particles, effectively neutralizing the overall charge of the individual particles. Once this occurs, the particles can move closer together and eventually aggregate. Thus, the CCC is a function of the colloidal particle size as well as a function of the valences of the ions present in the polishing system. The stronger the counterion, the more tightly packed the colloidal particles will become, and thus the more likely the particles will agglomerate.
Since the CCC is related to the total ion concentration present in the polishing system, it varies both with the specific alkali metal ion and the specific amine-containing compound used in the polishing system. For example, a concentration of about 0.15 M or more of the alkali metal ion and a concentration of about 0.2 M or more of the amine-containing compound generally are sufficient to raise the total ion concentration of the polishing system above the CCC.
The CCC can be determined by any suitable method, many of which are known in the art and can be readily employed. One such method, for example, involves the Schulze-Hardy rule, which states that the CCC of counterions is found to be inversely proportional to the sixth power of its valence. Other suitable methods for calculating the CCC, including the Schulze-Hardy rule, are set forth, for example, in Hsu and Kuo, J. Colloid Interface Sci., 185, 530-537 (1997).
Although the polishing system of the first embodiment desirably utilizes a total ion concentration well above the CCC, no agglomeration or sedimentation effects will be observed in the polishing system as used in the polishing method of the invention because the mixing of the components takes place at or near the time of use (i.e., polishing). In effect, this invention allows for higher concentrations of all components to be present in the polishing system without adverse gelling consequences. As a result, superior polishing rates can be achieved as compared to similar conventional CMP slurries.
In a second embodiment, the alkali metal ion is KOH that is present in the final polishing system (after mixing) in a concentration of about 0.05 wt. % to about 0.15 wt. % (e.g., about 0.08 wt. % to about 0.12 wt. %) and the amine-containing compound is present in the final polishing system (after mixing) in a concentration of about 0.4 M to about 0.8 M (e.g., about 0.5 M to about 0.7 M).
The polishing systems optionally further comprise ammonium salts (e.g., tetramethylammonium hydroxide (TMAH) and quaternary ammonium compounds). The ammonium salt can be any suitable cationic amine-containing compound, such as, for example, hydrogenated amines and quaternary ammonium compounds, that adsorbs to the silicon nitride layer present on the substrate being polished and reduces, substantially reduces, or even inhibits (i.e., blocks) the removal of silicon nitride during polishing. A preferred polishing system comprises a 1:1 equal weight ratio mixture of dimethylpropanolamine and tetramethylammonium hydroxide.
The polishing systems can have any pH that provides suitable polishing rates. Generally, the pH of the polishing system is about 7 or more (e.g., about 8 or more). Preferably, the pH of the present polishing system is about 9 or more (e.g., about 9-14). More preferably, the pH of the polishing system will be in the range of about 10-13 or even about 10-12. Because the inventive method disclosed herein provides for use of the polishing system at about 6 hours after mixing or less and preferably at the point-of-use, a higher pH can be used than would otherwise be possible for polishing systems that are allowed to reach chemical equilibrium, which systems must be stable upon storage for extended periods such as days, weeks, or months before use. The present polishing system is largely free of this constraint, requiring only that it be stable enough to provide suitable polishing in about 6 hours or less after it is prepared.
At its simplest, the polishing system consists essentially of a liquid carrier, an alkali metal ion, a compound containing an amine group and at least one polar moiety, wherein the polar moiety contains at least one oxygen atom, and a polishing pad and/or an abrasive. In this polishing system, the total ion concentration desirably is above the critical coagulation concentration. As mentioned previously, the liquid carrier is preferably a polar solvent, particularly water.
A variety of other additives can be used in conjunction with the polishing systems. For example, film-forming agents, complexing agents, surfactants, rheological control agents, polymeric stabilizers or dispersing agents, and/or halide ions can be present in the polishing system.
Any suitable film-forming agent (i.e., corrosion-inhibitor) can be used in conjunction with the polishing systems. For example, in STI polishing methods, suitable film-forming, agents generally include surface-active agents (i.e., surfactants) that preferentially adsorb to and prevent polishing of silicon nitride. Therefore, suitable film-forming agents include, for example, alkylamines, alkanolamines, hydroxylamines, phosphate esters, sodium laurylsulfate, fatty acids, polyacrylates, polymethacrylates, polyvinylphosphonates, polymalate, polystyrenesulfonate, and polyvinylsulfonate. Other film-forming agents include, for example, benzotriazole, triazole, benzimidazole, and mixtures thereof.
Any suitable complexing agent (i.e., chelating agent or selectivity enhancer) can be used in conjunction with the polishing systems. Suitable complexing agents include, for example, carbonyl compounds (e.g., acetylacetonates and the like), simple carboxylates (e.g., acetates, aryl carboxylates, and the like), carboxylates containing one or more hydroxyl groups (e.g., glycolates, lactates, gluconates, gallic acid and salts thereof, and the like), di-, tri-, and poly-carboxylates (e.g., oxalates, phthalates, citrates, succinates, tartrates, malates, edetates (e.g., disodium EDTA), mixtures thereof, and the like), and carboxylates containing one or more sulfonic and/or phosphonic groups. Suitable chelating or complexing agents also can include, for example, di-, tri-, or poly-alcohols (e.g., ethylene glycol, pyrocatechol, pyrogallol, tannic acid, and the like) and phosphate-containing compounds (e.g., phosphonium salts and phosphonic acids).
Any suitable surfactant and/or rheological control agent can be used in conjunction with the polishing systems, including viscosity enhancing agents and coagulants. Suitable rheological control agents include polymeric rheological control agents, such as, for example, urethane polymers (e.g., urethane polymers with a molecular weight greater than about 100,000 Daltons), acrylates comprising one or more acrylic subunits (e.g., vinyl acrylates and styrene acrylates), and polymers, copolymers, and oligomers thereof, and salts thereof Preferably, the rheological control agent is a low molecular weight carboxylate base or a high molecular weight polyacrylamide agent. Suitable surfactants include, for example, cationic surfactants, anionic surfactants, anionic polyelectrolytes, nonionic surfactants, amphoteric surfactants, fluorinated surfactants, mixtures thereof, and the like.
The polishing systems can contain any suitable polymeric stabilizer or other surface-active dispersing agent. Suitable stabilizers include, for example, phosphoric acid, organic acids, tin oxides, organic phosphonates, mixtures thereof, and the like.
The compounds recited herein have been classified for illustrative purposes, and there is no intent to limit the uses of these compounds to their noted classifications. As those of skill in the art will recognize, certain compounds may perform differently in different contexts and/or perform more than one function. For example, some compounds can function both as a chelating agent and an oxidizing agent (e.g., certain ferric nitrates and the like).
Any of the components used in conjunction with the invention can be provided in the form of a mixture or solution in an appropriate carrier liquid or solvent (e.g., water or an appropriate organic solvent). Furthermore, the compounds, alone or in any combination, can be used as components of the polishing system. Two or more components then desirably are individually stored and subsequently mixed to form the polishing system. In this regard, it is suitable for the polishing system to be prepared (e.g., for all the components to be mixed together) no more than 6 hours prior to delivery to the polishing pad or to the surface of the substrate. It is also suitable for the polishing system to be prepared on the surface of the polishing pad or on the surface of the substrate, through delivery of the components of the polishing system from two or more distinct sources, whereby the components of the polishing system meet at the surface of the polishing pad or at the surface of the substrate (e.g., at the point-of-use). In either case, the flow rate at which the components of the polishing system are delivered to the polishing pad or to the surface of the substrate (i.e., the delivered amount of the particular components of the polishing system) can be altered prior to the polishing process and/or during the polishing process, such that the polishing characteristics, such as rate, selectivity, and/or viscosity of the polishing system is altered.
When two or more of the components are combined prior to reaching the point-of-use, the components can be combined in the flow line and delivered to the point-of-use without the use of a mixing device. Alternatively, one or more of the flow lines can lead into a mixing device to facilitate the combination of two or more of the components. Any suitable mixing device can be used. For example, the mixing device can be a nozzle or jet (e.g., a high pressure nozzle or jet) or an in-line mixer through which two or more of the components flow. Alternatively, the mixing device can be a container-type mixing device comprising one or more inlets by which two or more components of the polishing slurry are introduced to the mixer, and at least one outlet through which the mixed components exit the mixer to be delivered to the point-of-use, either directly or via other elements of the apparatus (e.g., via one or more flow lines). Furthermore, the mixing device can comprise more than one chamber, each chamber having at least one inlet and at least one outlet, wherein two or more components are combined in each chamber. If a container-type mixing device is used, the mixing device preferably comprises a mixing mechanism to further facilitate the combination of the components. Mixing mechanisms are generally known in the art and include stirrers, blenders, agitators, paddled baffles, gas sparger systems, vibrators, etc.
A component can have any pH appropriate in view of the storage and contemplated end-use, as will be appreciated by those of skill in the art. Moreover, the pH of a component used in conjunction with the invention can be adjusted in any suitable manner, e.g., by adding a pH adjuster, regulator, or buffer. Suitable pH adjusters, regulators, or buffers include acids, such as, for example, inorganic acids (e.g., hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid) and organic acids (e.g., acetic acid, citric acid, malonic acid, succinic acid, tartaric acid, and oxalic acid). Suitable pH adjusters, regulators, or buffers also include bases, such as, for example, inorganic hydroxide bases (e.g., sodium hydroxide, potassium hydroxide, ammonium hydroxide, cesium hydroxide, and the like) and carbonate bases (e.g., sodium carbonate and the like).
A substrate can be polished (e.g., planarized) by contacting the surface of the substrate with the polishing systems using any suitable technique. For example, in one typical CMP process, a wafer is pressed against a polishing pad using the inventive polishing system under controlled chemical, pressure, velocity, and temperature conditions and the pad and the wafer are moved with respect to each other. Material is then removed from the surface of the wafer.
A substrate can be polished with the polishing systems with any suitable polishing pad (e.g., polishing surface). Suitable polishing pads include, for example, woven and non-woven polishing pads. Moreover, suitable polishing pads can comprise any suitable polymer of varying density, hardness, thickness, compressibility, ability to rebound upon compression, and compression modulus. Suitable polymers include, for example, polyvinylchloride, polyvinylfluoride, nylon, fluorocarbon, polycarbonate, polyester, polyacrylate, polyether, polyethylene, polyamide, polyurethane, polystyrene, polypropylene, and coformed products thereof, and mixtures thereof. As discussed above, the abrasive of the polishing system can be fixed (e.g., embedded) in whole or in part, in or on the polishing pad. Such fixation on the polishing pad can be accomplished, for example, by blending the abrasive into the aforementioned polymers during the formation of the polishing pad or by adhering the abrasive to the pad after the pad is formed using such adherents as are known.
The polishing systems are particularly well suited for polishing a substrate that has undergone shallow trench isolation (STI) processing. STI processing typically involves providing a silicon substrate on which is deposited a layer of silicon dioxide and a layer of silicon nitride. Trenches are etched following photolithography and are filled with silicon dioxide. The excess silicon dioxide is planarized until the silicon nitride is fully exposed, such that the silicon oxide remaining in the trenches is approximately level with the silicon nitride level on the mesa regions or with the pad oxide level. Desirably, the polishing is carried out in such typical STI processing with the polishing systems and/or methods of the invention, preferably such that the silicon dioxide is removed and planarization stops at the silicon nitride layer.
Preferred formulations of the polishing systems can provide selective polishing of silicon oxide surfaces relative to silicon nitride surfaces. The selectivity can be controlled, to some extent, by altering the relative concentrations of the components of the polishing system. Without wishing to be bound by any particular theory, it is believed that cationic species (i.e., amines, such as hydrogenated amines, and quaternary ammonium compounds) adsorb to the silicon nitride layer and reduce, substantially reduce, or even inhibit (i.e., block) the removal of silicon nitride during polishing. The alkali metal ion of the polishing system neutralizes the cationic amine, thereby reducing its ability to adsorb to, and inhibit the removal of, the silicon nitride layer. Accordingly, silicon nitride removal by the polishing system can be controlled by altering the relative concentrations of the alkali metal ion and the amine-containing compound in the polishing system, as well as by altering the pH of the polishing system.
When desirable, the polishing systems and methods of the invention can be used to polish a substrate with a polishing selectivity of silicon oxide to silicon nitride (i.e., oxide:nitride) of about 2:1 or more (e.g., about 5:1 or more), or even an oxide:nitride selectivity of about 10:1 or more (e.g., about 15:1 or more). Certain formulations can exhibit even higher oxide:nitride selectivities, such as about 25:1 or more, or even about 35:1 or more (e.g., about 45:1 or more), and when very high selectivity is required even about 55:1 or more, about 65:1 or more, or even about 75:1 or more (e.g., about 90:1 or more).
The polishing methods desirably utilize at least one dispenser, which simultaneously or sequentially dispenses one or more components of a polishing system from the flow lines onto the polishing surface (e.g., the substrate surface or the polishing pad). A single dispenser can be used, from which a single component or any combination of components of the polishing system can be dispensed. Alternatively, the polishing methods can utilize more than one dispenser from which the components of the polishing system are independently dispensed (e.g., one dispenser for each component). Generally, however, the polishing methods utilize more than one dispenser from each of which different combinations or ratios of components can be dispensed. For example, two or more dispensers can be utilized, each delivering different components simultaneously or sequentially to the same polishing surface.
Following polishing of a composite substrate, the used polishing system can be combined with any compound(s) suitable for enhancing the disposability of the polishing system. Suitable compounds include, for example, acids which will decrease the pH of the used polishing system, calcium-containing salts which will act as complexing agents to fluoride ions, and other compounds known to ordinary artisans. These compounds can be added to the polishing system in any suitable manner. It is suitable, for example, for the compound to be added to the waste stream by which the polishing system exits the polishing surface. | {
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Horizontal plate filters are commonly used for various industrial application for filtering different types of liquids, such as coolants for machines. A typical filter for this use is disclosed in U.S. Pat. No. 4,065,390.
Filters of the horizontal plate type have been considered for use in filtering liquids which comprise foods, pharmaceutical preparations and other substances containing bacteria; however, conventional horizontal plate filters are designed and constructed in a manner such that it is extremely difficult or practically impossible to adequately clean the parts of the filter plates of the filter to meet sanitation requirements and to prevent contamination of filtrate passing through the plates. Specifically, filter plates of this type of filter generally have fixed manifolds interiorly of the plates. These manifolds have inner surfaces which cannot be properly reached by a cleaning solution, such as a high pressure jet of hot water or steam. Moreover, such manifolds do not have the quality of finish that is required for food or pharmaceutical grade service. Also, crevices are formed interiorly of the manifolds when the manifolds are welded to the adjacent walls, and these crevices collect filtered matter and are virtually impossible to clean properly, thus promoting bacterial and fungal growth in the manifolds. The crevices will also concentrate mildly corrosive substances and promote the phenomenon commonly called crevice corrison which leads to rapid weld failure and the inclusion of corrosion products in the filtrate.
Because of the foregoing drawbacks of conventional filters of the horizontal plate type, a need has arisen for an improved filter plate for such a filter so that the filter can be used for food and pharmaceutical grade service. | {
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Basic automatic and security lighting systems are well known in prior art. Generally, these devices turn on a light source automatically when the presence of one or more persons is detected within its range. The light source continues to illuminate for a predetermined period of time after the detection ceases. A light sensitive component is usually incorporated to inhibit the activation of the light source when the ambient light level is high. There are two broad categories, namely indoor and outdoor automatic lights. The latter have two inherent limitations. Firstly, they require installation. They have to be installed at a considerable height and wired permanently to the building's electrical system, usually by technical personnel. Secondly, they cannot be designed with many user programmable functions (modes) as it would be inconvenient to control them because of the height. For example, an outdoor motion detector as disclosed in U.S. Pat. No. 4,943,712 by Richard L. Wilder, has an override mode which could be activated by disrupting the power switch in a predetermined sequence within a short period of time. This can be confusing to non-technical users and impractical when there are more than two modes to control. Indoor automatic and security lights such as disclosed in U.S. Pat. No. 5,015,994 by Kenneth Hoberman and Kim Kirwan solve the installation problem as they can be plugged into a standard wall power outlet by a prolonged plug built into the self-contained lighting devices. However, their application is limited because existing wall outlets may not be situated in a favourable location for detection, illumination and/or ambient light sensing. This constraint may render it impossible to use such devices under certain circumstances. In addition, the self-contained construction of such indoor devices limits the type, size and wattage of the bulbs used.
While all preceding systems of the art have brought about a certain degree of convenience and protection providing automatic lighting and security, there remains the need for a versatile, easily installed, user friendly and full feature device to provide programmable illumination and security at the same time. | {
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The present invention relates to improvements in robots.
Numerous branches of activity currently employ robots for performing certain functions, either because the function to be performed is repetitive and it may very easily be entrusted to an automatic device, or because the function must be performed in a medium hostile or inaccessible to man (manipulations of dangerous products, radioactive products, taking of samples from a planet). Each robot is most often intended to solve a particular problem which corresponds to a specific and unique case, and in the present state of technology, a solution is found for all the particular problems.
Robots are generally constituted by a chain of a plurality of members articulated to one another, each point of articulation comprising drive means for controlling the relative movement of two members and monitoring means, for example a coder. A central computer receives the data from the coders and controls the drive means to cause the robot to make the desired gestures.
This arrangement has the drawback of making the mobile units heavy. This is a minor disadvantage for high-power robots intended for displacing heavy loads, the weight of the drive means remaining negligible with respect to the load displaced. On the other hand, it is a serious drawback for small robots, intended for manipulating pieces weighing a few grams within small places. The weight and dimensions of the drive means and the coders are then disproportionate with respect to those of the loads displaced and often to the place available. | {
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This invention relates to the removal of sulfur oxides from flue gases. More particularly, the invention is directed at a novel ammonia double alkali process for the extraction of sulfur oxides from furnace waste gases. This process of absorption and regeneration is usually cyclic. It comprises an ammonia-based extraction of sulfur oxides from a gas; calcium regeneration of the used scrubbing liquor with separation and disposal of the sulfur by-product, a portion of these solids being recycled to the regeneration stage; and recycle of the now regenerated liquor for further sulfur oxide extraction.
Sulfur dioxide (SO.sub.2) and sulfur trioxide (SO.sub.3) are air pollutants. Sulfur dioxide and to a lesser extent sulfur trioxide are present in stack gases resulting from the combustion of coal, oils and other fuels which contain sulfur, from pyrometallurgical operation involving sulfide ores, and from power generation, and various other chemical and petroleum operations.
Accordingly, many processes have been developed to remove sulfur oxides from atmospheric discharges of waste gases. Those processes finding effective use in commercial applications must remove sulfur oxides from waste gases with high process and equipment reliability, result in minimum added cost in equipment, material or energy, and produce a by-product which is easily and safely disposable. It should however be recognized that even ideal scrubbing processes and equipment represent a major added cost to industrial operations.
Presently, the most favored commercial processes for waste gas cleaning are aqueous systems containing lime or limestone. One class of these wet scrubbing processes is based on the reaction of lime or limestone with sulfur oxides to produce various sulfur salts of calcium, the insoluble calcium salts being removed from the system. U.S. Pat. Nos. 3,883,639, 3,980,756, and 4,024,220 illustrate these systems. The single scrubber circulating loop of this first class of conventional lime or limestone processes is seriously disadvantaged by scale formation. This scale causes numerous operating problems, uneconomical operating costs, and low process reliability. Moreover, sulfur oxide removal efficiencies of conventional single alkali scrubbing processes are often too low to meet the more strict waste gas standards now required of industry.
To avoid these disadvantages inherent in former single alkali processes, commercial operations are beginning to investigate and utilize double alkali processes wherein the former single stage process has been split into a number of intermediate steps designed to improve the reliability of operation, utilization of material, sulfur oxide removal efficiency, and handling properties of the solid waste. For example, whereas in conventional single alkali processes the absorption of sulfur oxide from flue gas and production of waste product occur primarily in a single reactive step, in double alkali processes sulfur absorption and waste production are separated through the use of an intermediate soluble alkali absorption stage. Oxide absorption and waste product production then occur in separate system components. Such separation accomplishes two important objectives. First, it permits flue gas scrubbing with a soluble alkali, thus the rate of the sulfur oxide absorption is limited by the rate of transfer from the flu gas to the scrubbing liquor. In former systems, the rate of lime/limestone dissolution was also an important factor limiting the rate of the scrubbing reaction. Therefore, double-alkali systems have the potential for higher oxide removal efficiencies than the former single alkali systems. Additionally, the use in double alkali systems of other than calcium containing scrubbing liquors minimizes calcium concentrations in the scrubber and piping so as better to prevent scaling and plugging in these critical areas. Finally, relegation of the lime/limestone reaction to a location more specifically designed for this chemical exchange increases the potential for high lime/limestone utilization in double-alkali processes.
There are a number of double-alkali processes described in the art. For example, sodium or other alkali metal-based processes are disclosed in N. Kaplan, "Introduction To Double-Alkali Flue Gas Desulfurization Technology", EPA Flue Gas Desulfurization Symposium, New Orleans, La., Mar. 8-11, 1976 and U.S. Pat. Nos. 3,775,532, 3,883,639, 3,944,649, 3,961,021, 3,965,242, 3,987,149, 3,989,796, and 3,989,797.
Ammonia-based sulfur scrubbing processes are also described in the art, for example in U.S. Pat. Nos. 1,740,342, 2,082,006, (Re. 21,631), 2,405,747, 3,579,296, 3,695,829, 3,843,789, 3,880,983 and 3,944,649. These processes employ heat, acidification and crystallization, alkaline earth metal oxides, or alkaline earth metal hydroxides to regenerate the used scrubbing liquors.
These conventional soluble alkali processes, although displaying more efficient sulfur oxide removal from flue gases, are still disadvantaged by inferior sulfate removal during the precipitation and regeneration stage, sulfate being produced in scrubbing systems by oxidation of sulfur dioxide and sulfites. Failure to remove sulfate contaminants during regeneration, a difficult task as calcium sulfate is more soluble than calcium sulfite in aqueous solutions over wide pH ranges, reduces the sulfur oxide absorption capability of the regenerated liquor by tying up ammonia values making them unavailable for further sulfur scrubbing. Moreover, sulfate concentration build-up can adversely affect alkali utilization during regeneration, contribute to gypsum scaling in the scrubber and other process equipment, and eventually lead to shut down of the chemical absorption-regeneration process. Therefore, avoidance of sulfate build-up is critical to any long term operation of these scrubbing systems. E.g., U.S. Pat. No. 3,579,296, column 3, lines 5-19.
Numerous attempts have been made in the art to avoid such destructive increases in liquor sulfate concentration. Most are techniques directed to encourage more effective removal of sulfate during regeneration usually as solid calcium sulfate or gypsum, gypsum being more soluble in aqueous solutions than calcium sulfite, the other major waste product. One such process is described in U.S. Pat. No. 2,082,006. There, the acidity of the lime/limestone regeneration solution is increased to prevent the precipitation of calcium sulfite and encourage calcium sulfate precipitation.
Another technique, described in U.S. Pat. No. 2,405,747, suggests removing a bleed stream from the regenerated liquor and reacting it with lime or limestone under conditions designed to precipitate gypsum from the partially regenerated liquor and thus prevent sulfate build-up in the liquor. Other bleed stream extractive techniques are disclosed in U.S. Pat. Nos. 2,086,379, 2,128,027, 3,695,829, 3,961,021, 3,965,242.
A third technique, described in U.S. Pat. Nos. 3,579,296, 3,873,532, 3,972,980, 3,980,756, provides a settling means following regeneration with a recycle of a portion of the settled solids to the regeneration stage to promote desupersaturation of the recausticized liquor relative to calcium sulfate and precipitation of gypsum. The recausticized liquor from this process must have the high calcium content consistent with gypsum precipitation. Therefore, it cannot be reused in the sulfur oxide extractive process without further treatment since high calcium concentrations in the scrubbing liquor contribute to scaling and reduce lime/limestone utilization efficiency. Accordingly, the regenerated liquor is usually treated with soda ash to reduce the calcium ion concentration to levels more acceptable to subsequent sulfur oxide scrubbing.
Another method disclosed, for example in U.S. Pat. No. 3,775,532, employs a two step regeneration process. First, the spent scrubbing solution containing both absorbed sulfite and sulfate ions is treated with limestone to precipitate and remove calcium sulfite. Then, the partially regenerated liquor is treated with lime to remove the sulfate as gypsum. Again calcium concentrations in the regenerated liquor are excessive and disadvantage later scrubbing and regeneration. Other multistage regenerations are disclosed in U.S. Pat. Nos. 3,944,649 and 3,987,149. In this regard it is noteworthy that the Environmental Protection Agency in EPA Report 600/7-77-050b has concluded that there is no viable approach which eanbles the use of limestone alone for regeneration of liquors having significant amounts of sulfate, even though there are considerable economic incentives for the substitution of limestone for lime in double alkali processes.
Therefore, while some of these techniques have been successful in limiting the concentration of sulfate in the regenerated liquor, all have required additional material, equipment, stages or bleed stream treatments to encourage the necessary gypsum precipitation. Moreover, failure subsequently to reduce those calcium levels necessary for gypsum precipitation from the process liquors contributes to scaling in the scrubber and disadvantages other process stages. Therefore other equipment, stages and treatment are necessary to remove that excess calcium ion inherent in regeneration schemes operated in the gypsum precipitation mode. | {
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The present invention relates to a power-assisted steering apparatus for turning the steerable wheels of a vehicle.
A known power-assisted steering apparatus includes a pinion gear, a valve sleeve, and a torsion bar. The pinion gear includes a recessed end for receiving an end of the torsion bar. The end of the torsion bar includes a spline for fixing the end of the torsion bar relative to the pinion gear. A pin connects the valve sleeve to the pinion gear. Care must be taken when assembling the torsion bar, the valve sleeve, and the pinion gear.
The present invention is a power-assisted steering apparatus for turning steerable wheels of a vehicle. The apparatus comprises a rack bar that is connectable with the steerable wheels of the vehicle. Linear movement of the rack bar turns the steerable wheels. The apparatus also includes a hydraulic motor for, when actuated, moving the rack bar linearly and a one-piece monolithic component. The one-piece monolithic component has a pinion gear portion for meshingly engaging the rack bar, a valve sleeve portion for cooperating with a valve core for actuating the hydraulic motor, and a torsion bar portion for connection with the valve core and twisting in response to rotation of the valve core relative to the valve sleeve portion to actuate the hydraulic motor. | {
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As mobile devices have become ubiquitous, even globally, an individual who has access to a mobile device becomes very comfortable with the navigation of the device's functionality and applications. Presently, any individual with a mobile device expects to consume, share and experience content on the mobile device. | {
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1. Field of Invention
The invention relates to the field of coded multimedia and its storage and delivery to users, and more particularly to such coding when either the channel and decoding resources may be limited and time varying, or user applications require advanced interaction with coded multimedia objects.
2. Description of Related Art
Digital multimedia offers advantages including manipulation, multigeneration processing, error robustness and others, but incurs constraints due to the storage capacity or transmission bandwidth required, and thus frequently requires compression or coding for practical applications. Further, in the wake of rapid increases in demand for digital multimedia over the Internet and other networks, the need for efficient storage, networked access, search and retrieval, a number of coding schemes, storage formats, retrieval techniques and transmission protocols have evolved. For instance, for image and graphics files, GIF, TIF and other formats have been used. Similarly, audio files have been coded and stored in RealAudio, WAV, MIDI and other formats. Animations and video files have often been stored using GIF89a, Cinepak, Indeo and others.
To play back the plethora of existing formats, decoders and interpreters are often needed and may offer various degrees of speed and quality performance depending on whether these decoders and interpreters are implemented in hardware or in software, and particularly in the case of software, on the capabilities of the host computer. If such content is embedded in web pages accessed via a computer (e.g. a PC), the web browser needs to be set up correctly for all the anticipated content and recognize each type of content and support a mechanism of content handlers (software plugins or hardware) to deal with such content.
The need for interoperability, guaranteed quality and performance and economies of scale in chip design, as well as the cost involved in content generation for a multiplicity of formats has lead to advances in standardization in the areas of multimedia coding, packetization and robust delivery. In particular, ISO MPEG (International Standards Organization Motion Picture Experts Group) has standardized bitstream syntax and decoding semantics for coded multimedia in the form of two standards referred to as MPEG-1 and MPEG-2. MPEG-1 was primarily intended for use on digital storage media (DSM) such as compact disks (CDs), whereas MPEG-2 was primarily intended for use in a broadcast environment (transport stream), although it also supports an MPEG-1 like mechanism for use on DSM (program stream). MPEG-2 also included additional features such as DSM Command and Control for basic user interaction as may be needed for standardized playback of MPEG-2, either standalone or networked.
With the advent of inexpensive boards/PCMCIA cards and with availability of Central Processing Units (CPUs), the MPEG-1 standard is becoming commonly available for playback of movies and games on PCs. The MPEG-2 standard on the other hand, since it addresses relatively higher quality applications, is becoming common for entertainment applications via digital satellite TV, digital cable and Digital Versatile Disk (DVD). Besides the applications and platforms noted, MPEG-1 and MPEG-2 are expected to be utilized in various other configurations, in streams communicated over network and streams stored over hard disks/CDs, as well as in the combination of networked and local access.
The success of MPEG-1 and MPEG-2, the bandwidth limitation of Internet and mobile channels, the flexibility of web-based data access using browsers, and the increasing need for interactive personal communication has opened up new paradigms for multimedia usage and control. In response, ISO-MPEG started work on a new standard, MPEG-4. The MPEG-4 standard has addressed coding of audio-visual information in the form of individual objects and a system for composition and synchronized playback of these objects. While the MPEG-4 development of such a fixed parametric system continues, in the meantime, new paradigms in communication, software and networking such as that offered by the Java language have offered new opportunities for flexibility, adaptivity and user interaction.
For instance, the advent of the Java language offers networking and platform independence critical to downloading and executing of applets (java classes) on a client PC from a web server which hosts the web pages visited by the user. Depending on the design of the applet, either a single access to the data stored on the server may be needed and all the necessary data may be stored on the client PC, or several partial accesses (to reduce storage space and time needed for startup) may be needed. The latter scenario is referred to as streamed playback.
As noted, when coded multimedia is used for Internet and local networked applications on a computer like a PC, a number of situations may arise. First, the bandwidth for networked access of multimedia may be either limited or time-varying, necessitating transmission of the most significant information only and followed by other information as more bandwidth becomes available.
Second, regardless of the bandwidth available, the client side PC on which decoding may have to take place may be limited in CPU and/or memory resources, and furthermore, these resources may be time-varying. Third, a multimedia user (consumer) may require highly interactive nonlinear browsing and playback; this is not unusual, since a lot of textual content on web pages is capable of being browsed using hyperlinked features and the same paradigm is expected for presentations employing coded audio-visual objects. The parametric MPEG-4 system may only be able to deal with the aforementioned situations in a very limited way, such as by dropping objects or temporal occurrences of objects it is incapable of decoding or presenting, resulting in choppy audio-visual presentations. Further, MPEG-4 may not offer any sophisticated control by the user of those kinds of situations. To get around such limitations of the parametric system, one potential option for MPEG-4 development is in a programmatic system.
The use of application programming interfaces (APIs) has been long recognized in the software industry as a means to achieve standardized operations and functions over a number of different types of computer platforms. Typically, although operations can be standardized via definition of the API, the performance of these operations may still differ on various platforms as specific vendors with interest in a specific platform may provide implementations optimized for that platform. In the field of graphics, Virtual Reality Modeling Language (VRML) allows a means of specifying spatial and temporal relationships between objects and description of a scene by use of a scene graph approach. MPEG-4 has used a binary representation (BIFS) of the constructs central to VRML and extended VRML in many ways to handle real-time audio/video data and facial/body animation. To enhance features of VRML and to allow programmatic control, DimensionX has released a set of APIs known as Liquid Reality. Recently, Sun Microsystems has announced an early version of Java3D, an API specification which among other things supports representation of synthetic audiovisual objects as scene graph. Sun Microsystems has also released Java Media Framework Player API, a framework for multimedia playback. However, none of the currently available API packages offer a comprehensive and robust feature set tailed to the demands of MPEG-4 coding and other advanced multimedia content. | {
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This invention relates to tilt and height control for chairs or the like, and is particularly directed to providing an adjustment mechanism for varying the tilt of a back support and the height of the back support and a seat in a chair.
U.S. Pat. No. 4,328,943 issued on May 11, 1982, directed to a tilt control mechanism for a chair achieving height variation by suitable activation of a gas cylinder mechanism. The control assembly disclosed in that patent is particularly suited for tilt control in a chair in which the seat and back support together tilt as a unit. The present invention, on the other hand, is directed to tilt and height adjustment in a chair in which only the back support tilts.
The present invention provides such control in a compact mechanism utilizing a gas cylinder actuator having a cam surface thereon and which is pivotally mounted so that the cam surface activates the gas cylinder upon appropriate pivotal movement of the actuator. A blocker plate is also utilized which pivotally moves between one position in which tilting of the back support is prevented and another position in which tilting is permitted. The actuator and blocker plate are coupled together so that pivotal movement of one is accompanied by pivotal movement of the other. This is preferably achieved by use of an activating lever having two terminal portions, one of which is responsible for the pivoting of the gas cylinder actuator and the other of which causes pivoting of the blocker plate.
The compactness of the overall assembly of the present invention is achieved in large part by closely mounting with respect to each other the gas cylinder actuator and the blocker plate, both of which are mounted for pivotal movement about axes substantially perpendicular to each other. Additionally, the prevention of tilting in the chair is achieved by the blocking of a pin carried by the moving tilt mechanism, in this case the pin preferably extending through the spring that biases the back support of the chair in an upright position.
The invention will be more completely understood by reference to the following detailed description of a presently preferred embodiment thereof . | {
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The present invention relates to an improved lead acid battery element containing metal impurity inhibiting polymeric additives, which are added to the positive active material, negative active material and/or battery separator to inhibit the detrimental effects of certain metals on the efficiency of a lead acid battery, particularly the negative plate battery element and to macroporous additives that enhance active material utilization efficiency and improvement in the utilization of sulfuric acid electrolyte necessary for the discharge reaction of a lead acid battery.
Metal impurities can be introduced into a lead acid battery through the use of any of the materials used in the manufacture of the battery. For example, metal impurities can be introduced in the lead and leady oxides used in the manufacture of the active material, the materials of construction including the lead grids, alloying agents, electrolyte and water. Nearly all metallic impurities, if they are nobler than lead, have a smaller hydrogen overvoltage than pure lead. Therefore, they increase hydrogen evolution even if they are deposited in minute concentrations on the surface of the negative plates. These metals cause a continued gas evolution even after charging is completed. Hydrogen is evolved on the deposited metal with low hydrogen overvoltage, which can be short-circuited with lead. The effect of metal on the gassing particularly postcharge gassing decreases in the following sequence: Pt, Au, Te, Ni, Co, Fe, Cu, Sb, Ag, Bi and Sn. The presence of 0.3 ppm of platinum in the acid can cause a doubling of the self-discharge rate. Tin can produce this effect at 0.1%. Freshly deposited antimony is especially active. Besides the discharge of the negative plates with concomitant hydrogen evolution, these materials also move the end of charge voltage of the negative plates toward more positive values. The hydrogen evolution increases with rising acid density. Because the hydrogen overvoltage decreases with temperature, the self-discharge increases.
In addition, antimony is often added to grid lead in order to make the lead more fluid and more easily cast into the shapes necessary for storage battery grids. Further, it also hardens the resulting casting so that it can be further processed in the plant without damage. In certain battery applications, it may be necessary for the battery to withstand extreme resistance to corrosion of positive plate grids. In that event, higher antimony contents typically within the range of 4.5 to 6 percent are incorporated into the grid to form a lead antimony alloy. Antimony in these concentrations are generally only used in positive grids particularly grids intended for corrosion resistant batteries. Corrosion resistance typically means the ability to withstand the destructive effects of excessive charge or overcharge.
Antimony in the grid metal produces a definite effect on the charge voltage characteristics of the fully charged wet battery. The higher the antimony percentage in the grid metal, the lower the charge voltage and conversely, as the antimony is decreased so the charge voltage increases until pure lead is attained, which produces the highest voltage on charge. Since the use of antimony has gradually been lowered from a maximum of about 12.0% to a maximum of about 6.0% antimony, the charge voltage of average batteries has increased.
Contaminant metals, hereinafter referred to as metal impurities including antimony from the positive grids, during service life, slowly goes into solution in the sulfuric acid electrolyte and from there it is believed to electroplate onto the surface of the negative plates. Once there, it acts as an additional electrode with the grid and the lead active material of the negative plates. This combination creates local action, promoting self-discharge and contributes to poor wet battery shelf life. In addition, the battery""s charge voltage slowly decreases during life and, in the voltage regulated electrical circuit of a car, the difference between the two becomes greater. The car voltage regulator is set at a voltage just slightly higher than the normal charge voltage of the battery. Thus, the generator is able to restore electrical energy to the battery, as needed, to keep it charged. With metal deposition and the lowering of the battery charge voltage, the generator output into the battery increases as an overcharge, which hastens the deterioration of the battery in service, until failure occurs. Therefore, it is very desirable to inhibit the detrimental effects of antimony on the negative plate.
A new battery element which inhibits the detrimental effect of soluble metal impurity on the negative plate has been discovered. In brief, the battery elements include the addition of an organic polymer having functional groups with a preferential affinity for the metal impurity in the cation or anion state, to the positive active material, the negative active material or the separator which separates the positive and negative plates within a lead acid battery and which typically is a reservoir for sulfuric acid electrolyte.
A new battery element, which improves utilization efficiency of the active material in a lead acid battery has been discovered. In brief, the battery elements include the addition of macroporous containing particle additives to the active material in the positive or negative plates of a lead acid battery to improve overall utilization efficiency and the utilization of sulfuric acid electrolyte during discharge of the battery.
In one broad aspect, the present battery elements comprise the addition of an organic polymer containing functional groups with a preferential affinity for metal impurity in the cation or anion state to the positive active material, the negative active material and/or the separator which separates the positive plates from the negative plates in a lead acid battery. In a preferred embodiment, the organic polymers are porous, i.e. the porosity of the polymer allows the soluble metal impurity in the electrolyte to contact both the outer surface of the polymers and the internal surfaces created by the porosity of the organic polymers. The functional groups having a preferential affinity for metal impurity include both functional groups on the outer surface and internal surfaces in contact with soluble metal impurity in the electrolyte. The metal impurity inhibiting additives are typically incorporated into the negative active material, the positive active material and/or the separator in an amount sufficient to inhibit the detrimental effects of metal impurity on the negative plate.
In another broad aspect, the present battery elements comprise the addition of macroporous additives to the active material present in the positive and/or negative plates in a lead acid battery. In a further preferred embodiment, the macroporous particles have a reduced affinity for bonding with the active material in the positive and negative plates, i.e. a substantially reduced bonding of lead ion with the polymeric functional groups.
As set forth above, metal impurities can be introduced into the battery during the battery manufacturing process, particularly in the starting materials used for battery manufacture. Many of the metal impurities can exist in the anion or cation form i.e. a negative or positive charge respectively in sulfate solutions such as that represented by sulfuric acid electrolyte. Depending on the molarity of the sulfuric acid electrolyte and the metal impurity, such cation/anion forms can change as the molarity changes. Depending on such sulfuric acid molarity, it is believed that platinum, gold, thallium, nickel, cobalt, iron, copper, antimony, silver, bismuth and tin can exist as anions even though such existence as anions may be weak or unstable. Further, such anion forms may predominant at the sulfuric acid electrolyte concentrations, which exist after battery charging. One of the particularly detrimental metal impurities is platinum.
As set forth above, such metal impurities can be introduced into the lead acid battery during manufacturing. In a number of battery designs, grid materials not having antimony as an alloying agent are used for battery manufacture. However, even in these types of batteries using nonantimony containing grids, antimony can be introduced as an impurity in the starting materials for battery manufacture including the starting lead and leady oxide type materials.
As set forth above, antimony, which is present in the positive grid as an alloying agent, can be oxidized and/or corroded to form a soluble antimony ion, which diffuses and/or migrates to the negative plate. Antimony at the negative plate can produce a number of detrimental problems such as self discharge and gassing particularly hydrogen formation. Antimony ion from the positive grid can exist in both the anion and cation form, i.e. a negative or positive charge respectively. It is believed that the form of the anion or cation is dependent on the oxidation state of the antimony, i.e. +3 or +5, the molarity of the sulfuric acid and the battery voltage. For example, it is believed that antimony can exist as SbO2+ cation and SbO3xe2x88x92 anion in the antimony +5 state and as SbOSO4xe2x88x92, Sb(SO4)2xe2x88x92 SbO2 in the antimony +3 state. These +3 anion forms are believed to exist when the molarity of the sulfuric acid is greater than one but may not exist at the fully recharged battery voltage. In addition, it is believed that antimony may exist as Sb+3 or SbO+ in the antimony +3 state again depending on molarity and battery voltage. As set forth above, the sulfuric acid electrolyte participates in the discharge reactions taking place in the lead acid battery. Thus, the wt % sulfuric acid can decrease from 30-40 wt % sulfuric acid to from 10-14 wt % sulfuric acid depending on the type of battery design and the initial sulfuric acid concentration in the electrolyte. The amount of sulfuric acid remaining will be dependent on the percent of discharge of the battery with less sulfuric acid remaining when batteries are discharged to 80% or more.
The organic polymers having functional groups with a preferential affinity for metal impurities in the anion or cation state inhibit the detrimental effects of soluble metal impurity on the negative plate. While the exact mechanism of inhibition is not known, it is believed that the metal impurity anion or cation is bound by the functional group such as by the anion replacing the anion present on the functional group in an anionic polymer or by a cation replacing the cation when the organic polymer contains cation functional groups. Although anion and/or cation replacement is believed to be one mechanism for inhibiting the adverse effects of metal impurity ions, metal impurities can also form complexes and/or be solvated to inhibit the detrimental effect of metal impurities on the negative plate and such mechanisms are included in then the term inhibiting. One of the major discoveries of the battery elements of this invention is the inhibition of metal impurities over the varying sulfuric acid molarities and battery potentials (voltages) that occur during the charge discharge reactions in a lead acid battery. Further it has been discovered that the metal impurity which has been inhibited by the organic polymer additive is not substantially and detrimentally desorbed and/or released from the polymer under the sulfuric acid molarity and battery voltage conditions and changes in a lead acid battery, that is the metal impurity inhibition continues during a plurality of charge/discharge reactions within the battery.
As set forth above, the organic polymers containing functional groups can introduce cations and/or anions into the battery element which cations or anions can be displaced by the metal impurity anion and/or cation. Further, the affinity of the organic polymer having such metal impurity inhibiting functional groups have a stronger binding and/or complex formation and/or solvation of metal impurity ions when compared to any intermediate soluble lead ions such as lead +2 which may be formed during the conversion of solid lead, solid lead peroxide to insoluble lead sulfate. As is known by those having skill within the lead acid battery art, cations and/or anions which are displaced by metal impurity cations or anions should not introduce any substantial detrimental effects on battery performance.
As set forth above, one of the classes of organic polymers has functionality, which have affinity for metal impurity in the cation form. The metal impurity cation displaces the cation associated with the functional group. Typically, the cation displaced can be hydrogen ion or, for example, sodium ion. The organic polymers having such cation functionality can be further classified as strongly acidic cation polymers or weakly acidic cation polymers. Particularly preferred strongly acidic cation polymers are those containing sulfonic acid groups or their sodium salt i.e. sulfonic groups preferably in the hydrogen form. Typical examples of polymers containing the sulfonic acid and/or sulfonate functionality are those derived from polystyrene crosslinked divinylbenzene, phenol-formaldehyde polymers and other like aromatic containing polymers.
As set forth above the organic polymer can have different functional groups such as functional groups containing strongly acidic functionality such as sulphonic and phosphonic functionality on the same organic polymer. As set forth above, strongly acidic cation polymers are preferred for inhibiting the effects of metal impurities. A particularly preferred functionality on the polymer is phosphonic acid and/or phosphonate here in after refered to as phosphonic functionality. Typical examples of such functionality are:
where R is typically hydrogen or sodium ion, preferably hydrogen.
In general the phosphonic functionality can be incorporated into the polymer matrix by chemical reaction including grafting of such functionality, on for example the aromatic portion of polystyrene and/or phenol-formaldehyde polymers. In addition, the functionality can be incorporated by the copolymerization unsaturated vinylmono or gem of phosphonic acid or ester monomers with other monomers patricularly styrene, with still other monomers such as acrylate or acrylovitrile together with a cross-linking agent such as divinylbenzene. A typical monomer used for such copolymerization is vinylidene diphosphonic acid or the ester thereof to produce gem phosphonic functionality. Further examples of such polymers are polymers having a plurality of amino alkylene, phosphonic acid or phosphonate associated with the organic polymer.
As set forth above bis-derivatives are also useful including imino-bis(methylenephosphonic acid). The particularly preferred functionality is amino methylelephosphonic acid groups on polystyrene cross-linked with divinylbenzene.
As set forth above, phosphonic functionality can be incorporated into the polymer by reaction with an existing polymermatrix or by copolymerization of for example a vinyl phosphonic monomer. A prefered polymer is one containing polymerized styrene monomer either as a home polymer or an inter polymer with other polymerized monomeric units. Such polymers containg polymerized styrene are generally referred to as polystyrene polymers.
As set forth above the organic polymer can have different functional groups such as functional groups containing strongly acidic functionality such as sulphonic and phosphonic functionality on the same organic polymer.
The weakly acidic cation polymers in general have carboxylic functionality and/or the sodium salt associated with the organic polymer. Typical examples of such polymers are those derived from unsaturated carboxylic acids such as acrylic, methacrylic or maleic crosslinked with another monomer such as divinylbenzene or ethylene dimethacrylate. The preferred organic polymers containing cation functionality are the strongly acidic cation polymers having sulfonic acid functionality.
As set forth above, the organic polymer can have functionality having a preferential affinity for soluble metal impurity anions, i.e. the anion associated with the functionality is displaced by the soluble metal impurity anion in the electrolyte. The organic polymers having anion functionality can have both strongly basic and weakly basic anion functionality. Typical examples of strongly basic anion containing functionality are those having an ammonium functionality associated with the organic polymer. As set forth above, the anion associated with the functionality, typically sulfate or chloride, is displaced by the metal anion within the electrolyte. Typical ammonium groups associated with the polymer include trimethyl ammonium ion and dimethylethanol ammonium ion. Other groups include isothiouronium and derivatives thereof. Typical examples of organic polymers are polystyrene cross-linked with divinylbenzene. The ammonium ion with an appropriate anion can be attached directly to, for example, the aromatic ring of the polystyrene or through, for example, a methylene bridge. Typical examples of weakly basic polymers having anion functionality are polymers, which contain tertiary aliphatic or aromatic aliphatic amine functionalities on the polymer such as polystyrene or a polyunsaturated carboxylic acids. Such polymers are typically cross-linked with a cross-linking agent such as the cross-linking agents referred to above. Further, the polymer basic anion functionality can be obtained through aliphatic polyamine condensation reactions to produce the organic polymer. Typically, the weak base anion resins contain primary, secondary and/or tertiary amine groups generally as a mixture. Typical examples of such amine groups are trimethyl amine and dimethylethanolamine. The preferred organic polymers having anion type functionality are the strongly basic anion containing functionality particularly for their strong binding and low release or desorption of metal impurity properties preferably having ammonium functionality, particularly for incorporation into the negative plates. Since the electrolyte in the lead acid battery is sulfuric acid, it is preferred to use sulfate as the anion to be displaced by metal anion.
As set forth above the organic polymers can contain primary secondary or tertiary amine groups including aliphtaic polyamene functionality. Further as set forth above, such organic polymers can contain aliphatic amine functionality. Further, as set forth above such polymers can contain amine functionality with acid functionality. Particularly preferred functionalities associated with the organic polymer which contain both amine and acidic functionality are those containing secondary and tertiary amine functionality and strong acid functionality, such as for example, the examples set forth above.
A particularly preferred class of aliphatic aromatic amine functionality are those having amino pyridine groups associated with the organic polymer. Examples of such groups can be represented by the formula.
where in R is preferably an aliphatic substituent, an aliphatic polyamino substituent or a 2-picolene containing substituent Rxe2x80x2 is preferably alkylene, preferably methyleneand Rxe2x80x3 is a non-substantially interfering substituent, preferably hydrogen. Particularly preferred additives are organic polymers having functionality from 2-picolylamine, N-methly-2-picolylamine, N-2hydroxyethyl)-2-picolylamine, N-(2-methylaminoethyl)-2-picolylamine and bis-(2-picolyl)amine.
The aromatic aliphatic amine functionalities particularly the 2-picolylamine, such as bis-(2-picolyl)amine, are particularly useful in inhibiting the detrimental effects of copper and nickel.
As set forth above the organic polymers can contain primary secondary or tertiary amine groups including aliphtaic polyamene functionality. Further as set forth above, such organic polymers can contain aliphatic amine functionality. Further, as set forth above such polymers can contain amine functionality with acid functionality. Particularly preferred functionalities associated with the organic polymer which contain both amine and acidic functionality are those containing secondary and tertiary amine functionality and strong acid functionality, such as for example, the examples set forth above.
The organic polymers having functional groups with affinity for metal impurity are typically within the particle size ranges, porosities, surface areas, additive concentration and such other physical properties set forth below with respect to porosity additives. The porosity of the preferred organic polymers can vary over a wide range such as within the ranges set forth below with respect to micro and macro porosity. The porosity of the preferred organic polymers is that which allows the metal impurity ion, cation and/or anion to permeate the organic polymer particle thereby affording good contact with the functional groups attached to the external and internal surfaces of the particles. The total displacement capacity of the organic polymer having such functional groups is typically greater than one milliequivalent of displaceable anion or cation per gram of polymer, preferably greater than three and still more preferably greater than five.
Any suitable positive active electrode material or combination of such materials useful in lead-acid batteries may be employed in the present invention. The positive active electrode material can be prepared by conventional processes. For example, a positive active electrode material precursor paste of lead sulfate and litharge (PbO) in water can be used, or conventional pastes, such as those produced from leady oxide, sulfuric acid and water, can be used. After the paste is applied to the grid material, it is dried and cured. The precursor paste may be converted to lead dioxide by applying a charging potential to the paste.
Any suitable negative active electrode material useful in lead-acid batteries may be employed in the present invention. One particularly useful formed negative active electrode material comprises lead, e.g., sponge lead. Conventional lead paste prepared from leady oxide, sulfuric acid, water and suitable expanders can be used.
Each of the cells of a lead acid battery further includes a non-electrically conductive separator acting to separate the positive and negative electrodes of the cell and to hold electrolyte. Any suitable material may be used as a separator provided that it has no substantial detrimental effect on the functioning of the cells or battery. Typical examples of separator material for batteries include glass fiber, sintered polyvinyl chloride and microporous polyethylene, which have very small pore sizes. Certain of these separators are formed as envelopes, with the pasted plates inside and the separator edges sealed permanently. Typically only the positive plates are encased in the separator. Separators uses for sealed lead-acid batteries operating on the oxygen recombination principle, i.e., oxygen recombinant batteries include one or more layers of silica-based glass, preferably separators formed of a highly absorptive porous mat of acidwettable binder free microfine glass fibers. Typically, a mix of fibers may be employed whose individual fibers have an average diameter in the range of a bout 0.2 to about 10 microns, more preferably about 0.4 to 5.0 microns, with possible minor amounts of larger gauge fibers to facilitate production of the mat. The porosity is preferably high, more preferably in the range of about 80% to about 98% and still more preferably about 85% to about 95%, if in the compressed state in the cell (slightly higher in the uncompressed state). The separator preferably has a relatively high surface area, more preferably in the range about 0.1 to about 20 m2/g, which facilitates the absorption and retention of relatively large amounts of acid electrolyte volumetrically while, if desired, still having a substantial unfilled pore volume permeable to oxygen for transport directly through the separator for consumption at the negative electrode. The particularly preferred separator materials have a surface area as measured by the BET method of in the range about 0.2 to about 3.0 m2/g., 30 especially about 1.0 to about 2.0 m2/g.
As set forth above metal impurities are particularly detrimental in sealed lead acid batteries operating on the oxygen recombination principal, i.e. recombinant batteries. A number of impurity metals can exert a deleterious effect on the performance of recombinant batteries by for example, effecting one of more of the performance requirements of the recombinant batteries such as by increasing oxygen, evolution at the positive electrode, increasing hydrogen evolution at the negative electrode, inhibiting oxygen recombination at the negative electrode and in increasing the amount of water lost by the battery. Typical examples of metals that are particularly deleterious in recombinant batteries are arsenic, antimony, cobalt, chromium, nickel and tellurium.
As set forth above, the metal impurity inhibiting additives can be incorporated directly into the positive active material or negative active material for reducing the detrimental effects of the soluble metal impurity on the negative plates. Further, the metal impurity inhibiting additives, as set forth above, can be coated on the separator such as the glass fiber mats used in lead acid batteries. Further, the metal impurity inhibiting additives can be incorporated into the porous polymeric separators, such as polyvinyl chloride and microporous polyethylene. Typical concentrations of the additives associated with the separator is less than about 10 wt % preferably less than about 5 wt % basis the weight of the separators. The preferred metal impurity inhibiting additives are the porous organic polymers, which allow for the inhibiting effect of the additives while not detrimentally adversely effecting the flow of electrolyte from and/or through the separator to the positive and negative plates.
In another broad aspect for manufacturing tin dioxide coated porous substrates, the process comprises contacting a porous substrate with a composition comprising a tin oxide precursor, such as tin chloride forming components, including stannic chloride, stannous chloride, tin complexes and mixtures thereof, preferably stannous chloride, at conditions, preferably substantially non-deleterious oxidizing conditions, more preferably in a substantially inert environment or atmosphere, effective to form a tin oxide precursor-containing coating, such as a stannous chloride-containing coating, on at least a portion of the substrate. The substrate is preferably also contacted with at least one dopant-forming component, such as at least one fluorine component, at conditions, preferably substantially non-deleterious oxidizing conditions, more preferably in a substantially inert atmosphere, effective to form a dopant-forming component-containing coating, on at least a portion of the substrate. The coated porous particles are particularly useful in a number of applications, particularly lead acid batteries, for example, monopolar and bipolar batteries, catalyst, resistance heating elements, electrostatic dissipation elements, electromagnetic interference shielding elements, electrostatic bleed elements, protective coatings, field dependent fluids and the like. In practice the particles which are preferred for use in such applications in general have an average length in the range of from about 20 microns to about 7 mm and an average thickness in the range of from about 20 microns to about 7 mm, the average length and thickness being different or the same depending on particle geometry and application. As set forth above, the substrate can be optimized for a particular application and the particular electrical and/or mechanical requirements associated with such end use application. For example, in applications in which the particles are combined with other materials, such as polymers and positive active material of a lead acid battery and depending on the requirements of the application, ranges of from about 3 microns to about 300 microns, or even less than about 5 microns, typically ranges of from about 3 microns to about 150 microns or from about 5 microns to about 75 microns are useful. The porous inorganic substrates, can be characterized by bulk density (gm/cc) which is the weight or mass per unit volume considered only for the particle itself, i.e., includes the internal pore volume, surface area (M2/gm), total pore volume (cc(hg)/gm), pore size distribution and percent apparent porosity. In general, it is preferred that the bulk density be from about 3% to about 85% more preferably from about 10% to about 70%, more preferably, from about 10% to about 60% of the true density of the substrate material. Bulk densities less-than about 5% are also useful. In addition, the porous substrate can have a wide range of surface area (M2/gm) of from about 0.01 to about 700 preferably having a moderate to high surface area, preferably, from about 10 M2/gm to about 600 M2/gm, more preferably, from about 50 M2/gm to about 500 M2/gm.
The pore volume is preferably from about 0.4 cc/gm to about 3.5 cc/gm, or even up to about 5 cc/gm, more preferably from about 0.7 cc/gm to about 4.5 cc/gm more preferably from about 0.7 cc/gm to about 3.25 cc/gm. The pore size distribution can vary over a wide range and can have various distributions including multi-modal, for example, bi-modadistribution of pores including macro pores and micro pores. There ideally exists a relationship between pore diameter, surface area and pore volume, thus fixing any two variables generally determines the third. In general, the mean (50%) pore diameter for macro pores, i.e., generally classified as having a pore diameter greater than about 750 angstroms can vary from about 0.075 microns to about 150 microns, more preferably, from about 0.075 microns to about 10 microns. Micro porosity, generally classified as a porosity having a mean pore diameter of less than about 750 angstroms can vary over a wide range. In general, the mean pore diameter for micro porosity can vary from about 20 angstroms to about 750 angstroms, more preferably, from about 70 angstroms to about 600 angstroms. The ratio of macro to micro porosity can vary over a wide range and depending on the application, can be varied to provide optimized performance as more fully set forth under the various applications. In general, the ratio of percent macro porosity to micro porosity expressed as that percent of the total porosity can vary from abaut 0% to about 95%, more preferably, from about 5% to about 80% macro porosity and from about 100% to about 5%, more preferably from about 95% to about 20% micro porosity.
As set forth above, the porous substrate can be inorganic for example, carbon and carbide, i.e., silicon carbide, sulfonated carbon and/or an inorganic oxide. Typical examples of inorganic oxides which are useful as substrates include for example, substrates containing one or more alumino silicate, silica, alumina, zirconia, magnesia, boria, phosphate, titania, ceria, thoria and the like, as well as multi-oxide type supports such as alumina phosphorous oxide, silica alumina, zeolite modified inorganic oxides, e.g., silica alumina, perovskites, spinels, aluminates, silicates, e.g., zirconium silicate, mixtures thereof and the like. A particularly unique porous substrate is diatomite, a sedimentary rock composed of skeletal remains of single cell aquatic plants called diatoms typically comprising a major amount of silica. Diatoms are unicellular plants of microscopic size. There are many varieties that live in both fresh water and salt water. The diatom extracts amorphous silica from the water building for itself what amounts to a strong shell with highly symmetrical perforations. Typically the cell walls exhibit lacework patterns of chambers and partitions, plates and apertures of great variety and complexity offering a wide selection of shapes. Since the total thickness of the cell wall is in the micron range, it results in an internal structure that is highly porous on a microscopic scale. Further, the actual solid portion of the substrate occupies only from about 10-30% of the apparent volume leaving a highly porous material for access to liquid. The mean pore size diameter can vary over a wide range and includes macroporosity of from about 0.075 microns to 10 microns with typical micron size ranges being from about 0.5 microns to about 5 microns. As set forth above, the diatomite is generally amorphous and can develop crystalline character during calcination treatment of the diatomite. For purposes of this invention, diatomite as produced or after subject to treatment such as calcination are included within the term diatomite.
As set forth above, porous substrate particles can be in many forms and shapes, especially shapes which are not flat surfaces, i.e., non line-of-site materials such as pellets, extrudates, beads, including spheres, flakes, aggregates, rings, saddles, stars and the like. The percent apparent porosity, i.e., the volume of open pores expressed as a percentage of the external volume can vary over a wide range and in general, can vary from about 20% to about 92%, more preferably, from about 40% to about 90%. In practice, the bead particles, including spheres, which are preferred for use in certain applications in general have a roundness associated with such particles generally greater than about 70% still more preferably, greater than about 85% an still more preferably, greater than about 95%. The bead products of this invention offer particular advantages in many of such applications disclosed herein, including enhanced dispersion and rheology.
Acid resistant inorganic substrates, especially fibers, flakes, and glass fibers, are particularly useful substrates, when the substrate is to be used as a component of a battery, such as a lead-acid electrical energy storage battery.
The porous substrate for use in lead-acid batteries, because of availability, cost and performance considerations, generally comprises acid resistant glass, and/or ceramics more preferably in the form of particles, for example, fibers, and/or flakes, and/or beads including spheres and/or extrudates as noted above. The solid substrates including organic polymers for use in lead-acid batteries are acid resistant. That is, the substrate exhibits some resistance to corrosion, erosion, oxidation and/or other forms of deterioration and/or degradation at the conditions present, e.g., at or near the positive plate, negative plate or positive or negative side of bipolar plates or separator, in a lead-acid battery. Thus, the substrate should itself have an inherent degree of acid resistance. If the substrate is acid resistant, the physical integrity and electrical effectiveness of the whole present battery element, is better maintained with time relative to a substrate having reduced acid resistance. If glass or ceramic is used as the substrate particle, it is preferred that the glass has an increased acid resistance relative to E-glass. Preferably, the acid resistant glass or ceramic substrate is at least as resistant as is C-or T-glass to the conditions present in a lead-acid battery. Preferably the glass contains more than about 60% by weight of silica and less than about 35% by weight of alumina, and alkali and alkaline earth metal oxides.
As set forth above, one of the preferred applications for use of the porous substrates is in lead acid batteries. Thus, the substrates can be added directly to the positive active material of a lead acid battery, i.e., the positive electrode to improve battery performance, particularly positive active material utilization efficiency. One particular, unique aspect of the porous substrates is that the substrate is able to provide an internal reservoir for holding sulfuric acid electrolyte required for carrying out the electrochemical reactions in the positive active material. More particularly, the porosity improves overall, high rate performance of the positive active material, i.e. improved utilization efficiency at varying rates of discharge time, including high rates and at short discharge times.
As set forth above, the physical properties of the porous substrates can vary widely. It is preferred that the substrate have sufficient macro porosity and percent apparent porosity to allow for the utilization of the electrolyte sulfuric acid contained in the pores during discharge of the positive active material and, in addition, that the bulk density be selected to reduce the overall weight of the positive active material while enhancing the overall performance of the battery. In general, the preferable percent apparent porosity can vary from about 40% to about 92%, more preferably, from about 70% to about 90%. The preferred ratio of percent macro porosity to percent micro porosity can vary over a wide range and in general is from about 20% to about 95% macro porosity, more preferably, from about 45% to about 90% macro porosity with the balance being micro porosity. The mean pore diameter, particularly mean macro pore diameter, can vary over a wide range with the utilization of electrolyte during the condition of the discharge of the battery being an important factor i.e., at high rate discharges, such as cold cranking, high macro porosity is preferred. Preferred mean macro pore diameter is from about 1 micron to about 150 microns, more preferably, from about 5 to about 100 microns or even from about 0.075 micron to about 10 micron and still more preferably from about 0.1 to about 5 microns.
As set forth above, a particularly preferred substrate is a porous particle, i.e. porous support, particularly beads, including spheres, extrudates, pellets, rings, saddles, stars, etc., preferably within the bulk density, macro porosity, micro porosity, apparent percent porosity and surface areas as set forth above. The coated particles can provide improved performance in various applications, particularly, in the positive active material of lead acid batteries. As set forth above, the porous substrate can provide a reservoir for electrolyte sulfuric acid, which participates in the electrochemical reaction during discharge of the positive active material. A particularly unique embodiment of the present invention is the use of the porous substrate itself as an additive in the positive active material to provide a reservoir of electrolyte sulfuric acid while providing a light weight additive for incorporation into the positive active material. Such particles are porous and within the ranges as set forth above particularly the preferred ranges. Such porous substrates can be further coated with additional components such as with other surface components, which may improve recharge, i.e. oxidation as well as other conductive components. As set forth above, the porous substrate with or without an additional component provides unexpected improvement in the performance of the positive active material, particularly, in the high rate discharge conditions such as cold cranking under lower than ambient temperature conditions.
Another particularly unique embodiment of the present invention is the use of the porous substrate itself as an additive in the negative active material to provide a reservoir of electrolyte sulfuric acid while providing a lightweight additive for incorporation into the negative active material. Such particles are porous and within the ranges as set forth above for the porous substrates particularly the preferred ranges. Such porous substrates can be further coated with additional components such as other surface components, which may improve recharge, discharge and/or overall life of the battery, such as conductive components which are stable at the conditions of the negative electrode such as carbon and conductive metals, which coated porous substrates are included within the scope of this invention and the term porous substrate. The porous substrate with or without an additional component provides unexpected improvement in the performance of the negative active material particularly under cold cranking conditions particularly multiple cold cranking under lower that ambient temperature conditions. As set forth above, the porous substrate can provide unexpected improvement in cold cranking typically 0 degrees F. or lower during a series of multiple cold cranking. In addition, the porous substrates in the negative active material can provide for improved active material surface area maintenance and active material morphology maintenance particularly at elevated temperatures such as from about 60-80 degrees C. or higher.
Typically, the porous substrates with or without additional components are incorporated into the positive and negative active material typically at a concentration of up to about 5-wt %, typically up to about 3-wt % basis the active material.
As set forth above, it is preferred that the porous substrate particles have sufficient macroporosity and percent apparent porosity for the utilization of the electrolyte sulfuric acid contained in the pores during discharge of the active material. Further, as set forth above, the preferred mean macropore diameter is from about 0.075 microns to about 10 microns and still more preferably from about 0.1 to about 5 microns. Particularly preferred solid porous particles that exhibit sufficient macroporosity to allow for improved utilization of sulfuric acid electrolyte are silica containing inorganic oxides preferably diatomites particularly those as set forth above and organic based materials particularly polyolefins still more preferably polypropylene.
As set forth above, the porous substrates are acid resistant and include a wide variety of materials, including inorganic and organic based materials. The porous substrates can be in a wide variety of shapes, including shapes that are reduced in size during the manufacture of the positive active material, such as in the blending and/or mixing of the porous substrate in positive active material manufacture. It is preferred that the resulting particles if reduced in size maintain porosity parameters within the ranges as set forth above. It is also preferred, that the particles have sufficient stiffness and or resistance to detrimental permanent deformation in order to maintain sufficient porosity for the sulfuric acid in the pores to participate in a number of repetitive discharge and charge cycles, such as greater than 50 cycles or even 100 cycles.
Further unique embodiment of the present invention is the use of a resilient organic porous substrate which resists detrimental permanent deformation maintains sufficient porosity for the sulfuric acid in the pores, has resiliency to be deformed under the conditions of discharge particularly mechanical forces in the active material of the lead acid battery and has resiliency to approach or attain its original geometry upon recharge of the battery. In a lead acid battery, the densities of the active material change i.e. lead at a density of 11.34 gram/cc, lead peroxide at a density of 9.4 grams/cc, (negative and positive plate respectively) change during discharge of the battery to lead sulfate having a density of 6.2 grams/cc i.e. lead sulfate. Upon recharge, the lead sulfate is converted back to lead and lead peroxide in the negative and positive plates respectively. The resilient organic porous substrates have the ability to be deformed during discharge and approach or attain their original geometry during recharge of the battery. The changes in density and the ability of the porous substrate to be deformed allows for increased availability and a greater amount of sulfuric acid from the pores of the substrate as a function of time to participate in a number of repetitive discharge and charge cycles leading to increased utilization efficiency. Typical examples of resilient organic porous substrates are elastomeric or rubber-like porous substrates wherein the pores allow the sulfuric acid to participate in discharge and charge cycles. Further examples of such organic resilient porous substrates are organic polymers including for example organic polymers selected from the group consisting of polyolefins, polyvinyl polymers, -phenol formaldehyde polymers, polyesters, polyvinylesters, cellulose and mixtures thereof. The polymers are selected to be acid resistant and compatible with the active material at the conditions of the electrode in which they are in contact. Various resilient organic porous substrates particularly porous particles can be produced using suspension polymerization of a dispersed phase consisting of monomers, cross-linking agents, initiators i.e. catalysts and a co-solvent that functions to aid pore formation. The particle size, pore volume, pore size distribution and macroporosity can be varied within the ranges as set forth above. Such resilient organic porous substrates including particles as set forth above have geometries and are typically used within the ranges as set forth above for the coated porous substrates, particularly the preferred ranges and, as set forth above, as to their use in positive active and negative active material. Depending on the particular active material in which such resilient porous substrates are incorporated, such porous substrates can be further coated with additional components such as with other surface components, which may improve overall properties such as discharge, recharge and life of the active materials.
As set forth above, the porous substrates including resilient porous substrates can be incorporated into the positive and negative active material. The various porous substrates provide a reservoir of electrolyte sulfuric acid in the active material. The reservoir of sulfuric acid in the porous substrates can be added to the porous substrate prior to the addition of the porous substrate to the positive and negative active material or incorporated into the porous substrate from the sulfuric acid electrolyte present in the lead acid battery. Further, other liquids such as water can be substituted for sulfuric acid if a liquid is added to the porous substrate prior to the addition of the porous substrate to the active material. As is recognized by those of skill in the art, only liquids which do not have an adverse detrimental effect on the performance of the battery should be added to the porous substrate prior to addition to the active material.
In a still further embodiment and as is set forth above, the porous substrate particles can be coated with another material. One such material is a component which gives hydrophobic character to the porous substrate, i.e. the porous substrate with the component is not water wet to the same degree as without the component. Such change to hydrophobic character can enhance the flow of electrolyte within the active material by limiting the bonding of the active material to the pores present in the porous particles and to particle surfaces. A particularly preferred component is a silica based size having hydrophobic alkyl groups such as methyl, ethyl or isooctyl which provide for hydrophobic character on the surface of the porous particles. Many of the organic porous particles within the scope of this invention have inherent hydrophobic properties such as the polyolefins whereas others have a combination of hydrophilic and hydrophobic properties. As set forth above, it is preferred that the porous particles have sufficient hydrophobic character to reduce the permanent bonding of the active material to the surfaces of the porous particles particularly the pores of the particles. The reduced bonding of the active material to the porous particles allows for improved diffusion of the sulfuric acid electrolyte to the interior of the active material associated with the positive and/or negative plate.
As set forth above, the additives are typically incorporated into the positive and negative active material at a concentration of up to about 5-wt %. The porous particle additives and the antimony inhibiting additives are incorporated during battery manufacture preferably during the production of the paste prior to application on the grid material. The additives can be incorporated into, for example, the lead, leady oxide powders to which the sulfuric acid and water are added. Alternatively, the additives can be mixed into the precursor paste prior to applying on the grid material. It is preferred that the additives be incorporated such as to provide a uniform distribution of the additive particles throughout the entire paste, active material.
Further, the porous substrate as set forth above can be an acid resistant organic material, including organic polymeric materials as set forth above. Preferred polymers are polyolefin polymers, polyvinyl polymers, phenolformaldehyde polymers, polyesters, polyvinylesters and mixtures thereof. Preferred polymers are polyolefins, preferably polypropylene, phenolformaldehyde polymers and polyvinylester, particularly modacrylic polymers. | {
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Sliders are often mounted to the bottom surface of a load to act as a buffer between the load and the surface on which the load rests. Typically, sliders take the form of convex discs mounted to the bottom surface of the load by means of adhesive, nails, or the like. The slider disperses the weight of the load over an enlarged area and allows the load to be slid over the supporting surface. Further, the slider prevents the scratching or marring of the supporting surface when the load is moved and prevents the forming of a depression in the supporting surface when the load remains in one place for an extended period of time.
While functional for their intended purpose, prior sliders have certain limitations. More specifically, repeated movement of the load along a supporting surface may cause the connection means that attaches the slider to the load to fail such that the slider may become detached from the bottom of the load. This, in turn, may result in the load engaging the floor and becoming damaged. Alternatively, prior sliders may not function properly on high friction surfaces such as a concrete factory floor. Consequently, prior sliders are not often used to move heavy loads across concrete factory floors. Further, if these floor sliders are used on a high friction floor, the load may become detached from the sliders and engage the floor. Once again, this may result in the load becoming damaged. Therefore, it is a highly desirable to provide a slider that may be simply and easily secured to the bottom surface of a heavy load and that facilitates sliding of such load along a high friction surface such as a concrete factory floor.
Therefore, it is a primary object and feature of the present invention to provide a slider that may be securely maintained beneath a bottom surface of a load.
It is a further object and feature of the present invention to provide a slider that is inexpensive to manufacture and simple to utilize.
It is a still further object and feature of the present invention to provide a slider that facilitates the sliding of a load over a wide variety of supporting surfaces.
In accordance with the present invention, a slider is provided for facilitating the sliding of a load on a supporting surface. The slider includes a base having an upper surface for supporting the load and a lower surface. A plurality of slider elements extends from the lower surface of the base. Each slider element has a generally arcuate outer surface that is engageable with the supporting surface.
The slider also includes a support having an upper surface and a lower surface interconnected to the upper surface of the base. A pad has an upper surface for engagement with the load and a lower surface interconnected to the upper surface of the support. The upper surface of the pad has a high co-efficient of friction. A rigid wire is positioned between the upper surface of the support and the lower surface of the pad. The wire partially overlaps the slider elements.
It is contemplated for each slider element to terminate at a generally flat apex. It is also contemplated for the slider to include a lubricating pad depending from the lower surface of the base. The lubricating pad is engageable with the supporting surface for lubricating the supporting surface. A first slider element of the plurality of slider elements may have a predetermined radius and a second slider element of the plurality of slider elements may also have a predetermined radius. The predetermined radius of the first slider is greater than the predetermined radius of the second slider.
The slider may also include a generally flat mat having an opening therethough. The base is receivable in the opening of the mat. The mat has an upper surface, a lower surface and on outer edge. A ramp may be operatively connected to the outer edge of the mat. The ramp has an upper edge lying in a generally common plane with the upper surface of the mat and a lower edge adjacent the supporting surface.
In accordance with a further aspect of the present invention, a slider is provided for facilitating the sliding of a load on a supporting surface. The slider includes a support platform having an upper surface for receiving the load thereon and a lower surface. A plurality of slider elements extends from the lower surface of the support platform. Each slider element has an outer surface engageable with the supporting surface. A lubricating pad depends from the lower surface of the supporting platform and is engageable with the supporting surface for lubricating the supporting surface.
The support platform includes an upper layer having an upper surface defining the upper surface of the support platform and a lower surface; an intermediate layer having an upper surface bonded to the lower surface of the upper layer and a lower surface; and a lower layer having an upper surface bonded to the lower surface of the intermediate layer and a lower surface defining the lower surface of the support platform. The upper layer is formed from a resilient pad such that the upper surface of the upper layer has a high co-efficient of friction. A rigid wire is positioned between the upper layer of the support platform and the intermediate layer of the support platform. The wire partially overlaps the slider elements.
It is contemplated for each slider element to terminate at a generally flat apex. It is also contemplated for a first slider element of the plurality of slider elements to have a predetermined radius and for a second slider element of the plurality of slider elements to also have a predetermined radius. The predetermined radius of the first slider is greater than the predetermined radius of the second slider.
The slider may also include a generally flat mat having an opening therethough. The support platform is receivable in the opening of the mat. The mat has an upper surface, a lower surface and on outer edge. A ramp may be operatively connected to the outer edge of the mat. The ramp has an upper edge lying in a generally common plane with the upper surface of the mat and a lower edge adjacent the supporting surface.
In accordance with a still further aspect of the present invention, a method is provided for sliding a load over a supporting surface. The method includes the steps of providing a slider having a first side for receiving the load thereon and a second side engageable with the supporting surface, and depositing a lubricant adjacent the slider as the load is slid on the slider over the supporting surface.
The slider includes a support platform having an upper surface for receiving the load thereon and a lower surface, and a plurality of slider elements extending from the lower surface of the support platform. Each slider element has an outer surface engageable with the supporting surface. The support platform includes a resilient pad having an upper surface that defines the upper surface of the support platform and a lower surface, and a base having an upper surface affixed to the lower surface of the pad and a lower surface that defines the lower surface of the support platform.
The method may include the additional steps of reinforcing the support platform and depositing the slider within an opening in a mat. The mat has upper and lower surfaces. Advertising indicia may be placed on the upper surface of the mat. The step of reinforcing the support platform includes the additional step of positioning a wire between the resilient pad and the base. | {
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The present invention relates to a head lamp for an automobile, and more particularly to a sealed beam lamp having a halogen bulb.
Generally, in a sealed beam lamp enclosing a halogen bulb, the bulb has a high beam filament and a low beam filament arranged therein. These filaments are arranged to be parallel in a rotary axis of a reflector when disposed to the sealed beam lamp. These filament have a desired length respectively. Therefore, if they were arranged so that a light source is brought to a desired position relative to the focal point on the rotary axis, the position of the light source is out of due to the length of the filaments and characteristics of light distribution vary. The characteristics of light distribution in the above mentioned lamp, particularly in a sealed beam lamp, are defects that a distant projection of light becomes bad because the extremely downward light beam increases and a limitation to forward sight occurs when the filaments are arranged to not emit an upward dazzle light beam. | {
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1. Technical Field
The present invention relates to a nitrogen-containing tricyclic compound useful as a medicine, a medicine containing the same and processes for producing the same. More particularly, it relates to a novel nitrogen-containing tricyclic compound useful as a medicine for diseases against which the effect of inhibiting the binding of IgE receptor xcex3 to a tyrosine kinase of 72 kDa is efficacious.
2. Prior Art
The bronchial asthma and the atopic diseases in human beings appear in consequence of highly intriacate vital reactions. It is suspected that most of these conditions are caused because various chemical mediators liberated from mast cells and basophils, as triggered by antigen-antibody reactions, induce vital disturbances as by contracting such smooth muscles as bronchial muscles and vessels of the pulmonary circulation or enhancing permeability of blood vessels.
As the chemical mediators liberated from mast cells and basophils, histamine, leukotrienes, prostaglandins, TNF, etc. have been known. It is well known that histamine, among other substances mentioned above, is the most significant chemical mediator for the allergic rhinitis and the urticaria in human beings. The leucotrienes comprise leucotrienes B4, C4, and D4 and the relation thereof with the asthmatic convulsion has been attracting attention.
Heretofore, the development of medicines for the prevention, alleviation, or elimination of the crisis of symptoms of allergic diseases has been aimed at repressing the creation and liberation of such chemical mediators or antagonizing the effects thereof.
Sodium cromoglycate (Intal(trademark)) having been marketed since 1969 is a typical example of these drugs.
However, the conventional antiallergic agents typified by Intal(trademark) show difference in the chemical mediator liberation inhibitory concentration between in vitro and in vivo. Moreover, sensitivities to these drugs widely vary from patient to patient and their action mechanisms still remain unknown in many points.
Mast cells and basophils closely relating to allergic diseases have a highly affinitive receptor, Fcxcex5 RI, for the IgE antibody on the cell membrane thereof. IgE antibody""s binding to this receptor forms a cross-linkage with the corresponding polyvalent antigen, the intracellular signal transmission mechanism is activated. Then histamine is liberated or leukotrienes and prostaglandins are formed and liberated, thus inducing the onset of the so-called allergic symptoms. It is furthermore considered that the cytokines such as TNF and interleukins thus produced interact with other cells and thus make the diseases chronic.
Under these circumstances, the present inventors have paid their attention to the activation of a non-receptor type tyrosine kinase located at the early stage in the activation of the intracellular signal transmission mechanism upon liberation of chemical mediators from mast cells or basophils. It is known that this tyrosine kinase is activated when it binds to the phosphorylated tyrosine activation motif (TAM) region in the IgE receptor xcex3 chain. By inhibiting this binding to thereby inhibit the activation of the tyrosine kinase of 72 kDa, the activation of the intracellular signal transmission mechanism depending on the IgE antibody in mast cells or basophils can be inhibited. As a result, also the liberation of the above chemical mediators can be inhibited. The present inventors have found out that desired objects can be achieved by using nitrogen-containing tricyclic compounds represented by the following formula (I), thus completing the present invention.
An object of the present invention is to provide a novel acridone derivative and a pharmacologically acceptable salt thereof which is efficacious in preventing or treating asthma, allergic rhinitis, atopic dermatitis, urticaria, hay fever, gastrointestinal allergy, food allergy, etc. Another object of the present invention is to provide a medicine containing as the active ingredient the compound, a hydrate thereof or a pharmacologically acceptable salt thereof.
Accordingly, the present invention relates to a nitrogen-containing tricyclic compound represented by the following formula (I), a hydrate thereof or a pharmacologically acceptable salt thereof:
{wherein R1, R2, R3, R4, R5, R6, R7 and R8 are the same or different from each other and each represents hydrogen, hydroxy, cyano, nitro, optionally substituted carbamoyl, halogeno, optionally halogenated lower alkyl, optionally substituted cycloalkyl, optionally halogenated lower alkoxy, acyl, optionally protected carboxy, optionally substituted aryl, optionally substituted heteroaryl, cycloalkylalkyl, hydroxylated alkyl, alkoxyalkyl, optionally protected carboxyalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, cyanoalkyl, acylalkyl, optionally substituted carbamoylalkyl, optionally halogenated alkenyl, hydroxyalkenyl, alkoxyalkenyl, optionally protected carboxyalkenyl, optionally substituted arylalkenyl, optionally substituted heteroarylalkenyl, cyanoalkenyl, acylalkenyl, optionally substituted carbamoylalkenyl, optionally halogenated alkynyl, hydroxyalkynyl, alkoxyalkynyl, optionally protected carboxyalkynyl, optionally substituted arylalkynyl, optionally substituted heteroarylalkynyl, cyanoalkynyl, acylalkynyl, optionally substituted carbamoylalkynyl, hydroxyalkoxy, alkoxyalkoxy, optionally protected carboxyalkoxy, optionally substituted arylalkoxy, optionally substituted heteroarylalkoxy, xe2x80x94Axe2x80x94NR9R10 [wherein A represents optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene or a single bond; and R9 and R10 are the same or different from each other and each represents hydrogen, optionally halogenated lower alkyl, optionally substituted aryl or acyl, or R9 and R10 may form together with the nitrogen atom to which they are bonded a ring optionally having additional nitrogen, oxygen or sulfur], or
[wherein B represents optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene or a single bond; R11 represents optionally halogenated lower alkyl or amino optionally substituted by lower alkyl; and x represents an integer of from 0 to 2];
provided that two of R1, R2, R3, R4, R5, R6, R7 and R8 adjacent to each other may form together with the carbon atom to which they are bonded a ring optionally containing oxygen, sulfur or nitrogen and optionally substituted;
Z represents
[wherein y represents an integer of from 0 to 2],
[wherein R12, R13, R14, R15, R16 and R17 are the same or different from each other and each represents hydrogen, optionally substituted carbamoyl, optionally halogenated lower alkyl, optionally substituted cycloalkyl, acyl, optionally halogenated lower alkylsulfonyl, optionally substituted arylsulfonyl, optionally protected carboxy, optionally substituted aryl, optionally substituted heteroaryl, cycloalkylalkyl, hydroxylated alkyl, alkoxyalkyl, optionally protected carboxyalkyl, optionally substituted arylalkyl, optionallysubstitutedheteroarylalkyl, cyanoalkyl, acylalkyl, optionally substituted carbamoylalkyl, optionally halogenated alkenyl, hydroxyalkenyl, alkoxyalkenyl, optionally protected carboxyalkenyl, optionally substituted arylalkenyl, optionally substituted heteroarylalkenyl, cyanoalkenyl, acylalkenyl, optionally substituted carbamoylalkenyl, optionally halogenated alkynyl, hydroxyalkynyl, alkoxyalkynyl, optionally protected carboxyalkynyl, optionally substituted arylalkynyl, optionally substituted heteroarylalkynyl, cyanoalkynyl, acylalkynyl, optionally substituted carbamoylalkynyl, xe2x80x94Wxe2x80x94NR18R19 (wherein W represents optionally branched alkylene, optionally branched alkenylene, optionally branched alkynylene or a single bond; R18 and R19 are the same or different from each other and each represents hydrogen, optionally halogenated lower alkyl or acyl, or R18 and R19 may form together with the nitrogen atom to which they are bonded a ring optionally containing additional nitrogen, oxygen or sulfur)];
D represents optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene or
(wherein m and 1 are each an integer of from 0 to 6; the ring A means an optionally substituted hydrocarbon ring or an optionally substituted heterocycle); and
Q represents optionally substituted carbamoyl, acyl, acylalkyl, optionally protected carboxy, optionally substituted heteroaryl, or xe2x80x94NR20R21 [wherein R20 and R21 are the same or different from each other and each represents hydrogen, optionally halogenated lower alkyl, optionally halogenated lower alkoxy, hydroxylated alkyl, alkoxyalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted aryloxy, optionally substituted arylalkoxy, optionally substituted heteroaryloxy, optionally substituted heteroarylalkoxy, optionally protected carboxyalkyl, acyl, optionally substituted acylalkyl, optionally substituted acylamino, optionally substituted acylaminoalkyl, cyanoalkyl, optionally substituted carbamoylalkyl, optionally substituted aminoalkyl, cyanoalkyl, acylalkyl, cycloalkyl, cycloalkylalkyl or amidino optionally substituted by lower alkyl, or R20 and R21 may form together with the nitrogen atom to which they are bonded an optionally substituted 3- to 8-membered ring which may have, as its ring-member other than carbon, at least one member selected from the group consisting of nitrogen, sulfur, oxygen and xe2x80x94NR22 (wherein R22 represents hydrogen, optionally halogenated lower alkyl, acyl, optionally substituted acylalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl or xe2x80x94S(O)sxe2x80x94(Y)uxe2x80x94R23 (wherein R23 represents hydrogen, optionally halogenated lower alkyl or optionally substituted aryl; Y represents methylene; s is an integer of from 0 to 2; and u is 0 or 1))];
provided that the following cases are excluded:
(1) the one where R5 and R6 are both hydrogen atoms;
(2) the one where Z is
[wherein y is an integer of from 0 to 2]; R5 is fluoro; and R6 is fluoro or trifluoromethyl; and
(3) the one where Z is
[wherein y is an integer of from 0 to 2]; R5 is carboxy; and R6 is chloro}.
The term xe2x80x9chalogen atomxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7 and R8 in the formula (I) means fluorine, chlorine, bromine, iodine, etc.
The term xe2x80x9clower alkylxe2x80x9d in xe2x80x9coptionally halogenated lower alkylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22 and R23 means linear or branched C1-6 alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1,2-dimethylpropyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 2-ethylpropyl, n-hexyl, 1,2-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, 1-ethyl-2-methylpropyl and 1-methyl-2-ethylpropyl groups.
In such a case, the term xe2x80x9coptionally halogenatedxe2x80x9d means that the above alkyl may be substituted by 1 to 3 halogen atoms such as fluorine, chlorine, bromine or iodine. Namely, the xe2x80x9coptionally halogenated lower alkylxe2x80x9d as used in the formula (I) includes trifluoromethyl, dibromoethyl and the like.
The term xe2x80x9clower alkenylxe2x80x9d in xe2x80x9coptionally halogenated lower alkenylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17 R20 and R21 means linear or branched C1-6 alkenyl, for example, vinyl, 1-propenyl, 2-propenyl, isopropenyl, 2-methyl-1-propenyl, 3-methyl-1-propenyl, 2-methyl-2-propenyl, 3-methyl-2-propenyl, 1-butenyl, 2-butenyl and 3-butenyl groups. The lower alkenyl as used herein further includes the above-mentioned alkenyl substituted by 1 to 3 halogen atoms.
The term xe2x80x9clower alkynylxe2x80x9d in xe2x80x9coptionally halogenated lower alkynylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, R16, R17, R20 and R21 means linear or branched C1-6 alkynyl, for example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 3-methyl-1-propynyl and 2-methyl-3-propynyl groups. The lower alkynyl as used herein further includes the above-mentioned alkynyl substituted by 1 to 3 halogen atoms.
The term xe2x80x9ccycloalkylxe2x80x9d in xe2x80x9coptionally substituted cycloalkylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, R16, R17, R20 and R21 means C3-8 ones such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl groups.
The term xe2x80x9ccycloalkylalkylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7 and R8 means those wherein the above lower alkyl is attached to any carbon atom of the above cycloalkyl.
The term xe2x80x9clower alkoxyxe2x80x9d in xe2x80x9coptionally halogenated lower alkoxyxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R20 and R21 means linear or branched C1-6 alkoxy, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, 1,2-dimethylpropyloxy, 1,1-dimethylpropyloxy, 2,2-dimethylpropyloxy, 2-ethylpropyloxy, n-hexyloxy, 1,2-dimethylbutyloxy, 2,3-dimethylbutyloxy, 1,3-dimethylbutyloxy, 1-ethyl-2-methylpropyloxy and 1-methyl-2-ethylpropyloxy groups.
In such a case, the term xe2x80x9coptionally halogenatedxe2x80x9d means that the above alkoxy may be substituted by 1 to 3 halogen atoms such as fluorine, chlorine, bromine or iodine. Namely, the xe2x80x9coptionally halogenated lower alkoxyxe2x80x9d as used herein includes trifluoromethoxy, dibromoethoxy and the like.
The term xe2x80x9cacylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22 and Q means those derived from saturated aliphatic monocarboxylic acids such as acetyl, propionyl, butyryl, valeryl, isovaleryl and pivaloyl groups, those derived from unsaturated aliphatic carboxylic acids such as acryloyl, propioloyl, methacryloyl, crotonoyl and isocrotonoyl groups, those derived from carbocyclic carboxylic acids such as benzoyl, naphthoyl, toluoyl, hydroatropoyl, atropoyl and cinnamoyl groups, those derived from heterocyclic carboxylic acids such as furoyl, thenoyl, nicotinoyl and isonicotinoyl groups, those derived from hydroxy carboxylic acids or alkoxy carboxylic acids such as glycoloyl, lactoyl, glyceroyl, tropoyl, benzyloyl, salicyloyl, anisoyl, vaniloyl, piperonyloyl and galloyl groups and those derived from various amino acids.
The term xe2x80x9cacylalkylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, R16, R17, R20, R21, R22 and Q means those wherein the above acyl is attached to any carbon atom of the above lower alkyl. Examples thereof include acetylmethyl, propionylmethyl, benzoylethyl, naphthoylpropyl, cinnamoylpropyl, salicyloylbutyl, nicotinoylpentyl and glyceroylhexyl groups, though, needless to say, the present invention is not restricted thereto.
The term xe2x80x9cacylalkenylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, R16 and R17 means those wherein the acyl is attached to any carbon atom of the above alkenyl. Examples thereof include benzoyl-1-ethylenyl and 3-nicotinoyl-2-propylenyl, though, needless to say, the present invention is not restricted thereto.
The term xe2x80x9cacylalkynylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, R16 and R17 means those wherein the acyl is attached to any carbon atom of the above lower alkynyl.
The term xe2x80x9chydroxylated alkylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R12, R13, R14, R15, R16, R17, R20 and R21 means those wherein 1 to 3 hydroxyl groups are attached to any carbon atom of the above lower alkyl, for example, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 2,3-dihydroxypropyl and 3,4-dihydroxybutyl groups.
The term xe2x80x9chydroxyalkenylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, R16 and R17 means those wherein hydroxy is attached to any carbon atom of the above lower alkenyl.
The term xe2x80x9chydroxyalkynylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, R16 and R17 means those wherein hydroxy is attached to any carbon atom of the above lower alkynyl.
The term xe2x80x9calkoxyalkylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, R16, R17, R20 and R21 means those wherein the above lower alkoxy is attached to any carbon atom of the above lower alkyl, for example, methoxymethyl, ethoxymethyl, ethoxyethyl and 2-ethoxypropyl groups, though the present invention is not restricted thereto.
The term xe2x80x9calkoxyalkenylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, R16 and R17 means those wherein the above lower alkoxy is attached to any carbon atom of the above lower alkenyl, for example, methoxyethylenyl and ethoxypropylenyl groups, though the present invention is not restricted thereto.
The term xe2x80x9calkoxyalkynylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, R16 and R17 means those wherein the above lower alkoxy is attached to any carbon atom of the above lower alkynyl.
The term xe2x80x9ccyanoalkylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R12, R13, R14, R15, R16, R17, R20, R21, R22 and R23 means those wherein cyano is attached to any carbon atom of the above lower alkyl, for example, cyanomethyl, 1-cyanoethyl, 2-cyanoethyl, 1-cyanopropyl and 2-cyanopropyl groups.
The term xe2x80x9ccyanoalkenylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R12, R13, R14, R15, R16 and R17 means those wherein cyano is attached to any carbon atom of the above lower alkenyl.
The term xe2x80x9ccyanoalkynylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R12, R13, R14, R15, R16 and R17 means those wherein cyano is attached to any carbon atom of the above lower alkynyl.
The term xe2x80x9chydroxyalkoxyxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7 and R8 means those wherein hydroxy is attached to any carbon atom of the above lower alkoxy, for example, hydroxymethoxy, 1-hydroxyethoxy, 2-hydroxyethoxy, 1-hydroxypropoxy, 2-hydoxypropoxy and 3-hydroxypropoxy groups.
The term xe2x80x9calkoxyalkoxyxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7 and R8 means those wherein the above lower alkoxy is attached to any carbon atom of the above lower alkoxy, for example, methoxymethoxy, 1-methoxyethoxy, 2-methoxyethoxy, ethoxymethoxy, 1-ethoxyethoxy, 2-ethoxyethoxy, 1-methoxypropoxy and 2-methoxypropoxy groups.
The term xe2x80x9carylxe2x80x9d in xe2x80x9coptionally substituted arylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, R16, R17, R20, R21, R22 and R23 means, for example, phenyl, 1-naphthyl, 2-naphthyl and anthracenyl groups.
The term xe2x80x9carylxe2x80x9d in xe2x80x9coptionally substituted arylalkylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R12, R13, R14, R15, R16, R17, R20, R21 and R22 has the same meaning as the one defined above. In such a case, the term xe2x80x9calkylxe2x80x9d has the same meaning as that of xe2x80x9clower alkylxe2x80x9d defined above.
The term xe2x80x9coptionally substituted heteroarylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R12, R13, R14, R15, R16, R17, R20, R21, R22 and Q means those derived from single or fused rings containing 1 to 4 heteroatoms of at least one type selected from the group consisting of sulfur, oxygen and nitrogen atoms. Examples thereof include pyrrolyl, thienyl, furyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiadiazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzothienyl, benzofuranyl, isobenzofuranyl, benzimidazolyl, indazolyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, quinolyl, isoquinolyl, cinnolin, phthalazyl, quinoxalyl, naphthyridyl, quinazolyl and imidazopyridyl groups.
The term xe2x80x9coptionally substituted heteroarylalkylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R12, R13, R14, R15, R16, R17, R20, R21 and R22 means those wherein the above heteroaryl is attached to any carbon atom of the above lower alkyl.
The term xe2x80x9coptionally substituted heteroarylalkenylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R12, R13, R14, R15, R16 and R17 means those wherein the above heteroaryl is attached to any carbon atom of the above lower alkenyl.
The term xe2x80x9coptionally substituted heteroarylalkynylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R12, R13, R14, R15, R16 and R17 means those wherein the above heteroaryl is attached to any carbon atom of the above lower alkynyl.
The term xe2x80x9coptionally substituted carbamoylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R12, R13, R14, R15, R16, R17 and Q means carbamoyl optionally having 1 or 2 substituents on the nitrogen atom.
The terms xe2x80x9coptionally substituted carbamoylalkyl, carbamoylalkenyl and carbamoyalalkynylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R12, R13, R14, R15, R16, R17, R20 and R21 mean those wherein optionally substituted carbamoyl is attached to any carbon atom of the above lower alkyl, alkenyl and alkynyl.
Examples of the substituents in the optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted arylalkenyl, optionally substituted heteroarylalkenyl, optionally substituted arylalkynyl, optionally substituted heteroarylalkynyl, optionally substituted arylalkoxy, optionally substituted heteroarylalkoxy, optionally substituted carbamoyl, optionally substituted carbamoylalkyl, optionally substituted carbamoylalkenyl and optionally substituted carbamoylalkynyl include hydroxy; lower alkyl such as methyl, ethyl, n-propyl and isopropyl; lower alkoxy such as methoxy, ethoxy, n-propoxy and isopropoxy; halogen atom such as fluorine, chlorine, bromine and iodine; cyano; acyl such as acetyl, propionyl and benzoyl; amino; nitro: optionally protected carboxyl; carbamoyl; acylamino; sulfamoyl; alkylsulfonylamino; arylsulfonylamino; heteroaryl; carboxyalkyl; carboxyalkoxy; heteroarylalkyl; heteroarylalkoxy; methylenedioxy; and ethylenedioxy. The substituents are selected therefrom.
Examples of the protective groups in the xe2x80x9coptionally protected carboxyxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, R14, R15, R16, R17, R20, R21 and Q include lower alkyl such as methyl, ethyl and tert-butyl; lower alkyl substituted by optionally substituted phenyl such as p-methoxybenzyl, p-nitrobenyl, 3,4-dimethoxybenzyl, diphenylmethyl, trityl and phenethyl; halogenated lower alkyl such as 2,2,2-trichloroethyl and 2-iodoethyl; lower alkanoyloxy-substitutedloweralkyl suchaspivaloyloxymethyl, acetoxymethyl, propionyloxymethyl, butyryloxymethyl, varelyloxymethyl, 1-acetoxyethyl, 2-acetoxyethyl, 1-pivaloyloxyethyl and 2-pivaloyloxyethyl; higher alkanoyloxy-substitutedloweralkyl suchaspalmitoyloxyethyl, heptadecanoyloxymethyl and 1-palmitoyloxyethyl; lower alkoxycarbonyloxy-substituted lower alkyl such as methoxycarbonyloxymethyl, 1-butoxycarbonyloxyethyl and 1-(isopropoxycarbonyloxy)ethyl; carboxy-substituted lower alkyl such as carboxymethyl and 2-carboxyethyl; benzoyloxy-substituted lower alkyl optionally substituted by heteroaryl such as 3-phthalidyl, 4-glycyloxybenzoyloxymethyl, etc.; (substituted dioxolene)-substituted lower alkyl such as (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl; cycloalkyl-substituted lower alkanoyloxy-substituted lower alkyl such as 1-cyclohexylacetyloxyethyl; and cycloalkyloxycarbonyloxy-substituted lower alkyl such as 1-cyclohexyloxycarbonyloxyethyl. Moreover, various acid amides are also usable therefor. In summary, the carboxy-protective group may be an arbitrary one, so long as it is decomposed by some means to give a carboxylic acid in vivo.
The term xe2x80x9coptionally protected carboxylalkylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R12, R13, R14, R15, R16, R17, R20 and R21 means those wherein carboxy optionally having the above protective group(s) is attached to any carbon atom of the above lower alkyl.
The term xe2x80x9coptionally protected carboxylalkoxyxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R12, R13, R14, R15, R16, R17, R20 and R21 means those wherein optionally protected carboxy is attached to any carbon atom of the above lower alkoxy. In such a case, the protective group has the same meaning as the one defined above.
The term xe2x80x9coptionally protected carboxyalkenylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R12, R13, R14, R15, R16 and R17 means those wherein optionally protected carboxy is attached to any carbon atom of the above lower alkenyl. In such a case, the protective group has the same meaning as the one defined above.
The term xe2x80x9coptionally protected carboxyalkynylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R12, R13, R14, R15, R16 and R17 means those wherein optionally protected carboxy is attached to any carbon atom of the above lower alkynyl. In such a case, the protective group has the same meaning as the one defined above.
Examples of the ring in xe2x80x9cR20 and R21 may form together with the nitrogen atom to which they are bonded a ringxe2x80x9d of the formula xe2x80x94NR20R21 as used in the definition of Q include aziridine, azetidine, pyrrolidine, piperidine, perhydroazepine, perhydroazocine, piperazine, homopiperazine, morpholine, thiomorpholine, thiomorpholine dioxide, indoline, isoindoline, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, 2,3-dihdyrobenzoxazine, 2,3-dihydrobenzothiazine, pyrrole, imidazole, pyrazole, triazole, tetrazole, indole, isoindole, indazole and benzotriazole.
(a) The term xe2x80x9calkylenexe2x80x9d as used in the definition of A, B and W means methylene, ethylene, trimethylene, tetramethylene, pentamethylene or hexamethylene.
(b) The term xe2x80x9calkenylenexe2x80x9d as used in the definition of A, B and W means ethenylene, propenylene, butenylene, pentenylene, hexenylene, butanedienylene, pentanedienylene, hexanedienylene or hexanetrienylene.
(c) The term xe2x80x9calkynylenexe2x80x9d as used in the definition of A, B and W means ethynylene, propynylene, butynylene, pentynylene, hexynylene, butanediynylene, pentanediynylene, hexanediynylene or hexanetriynylene.
(d) The term xe2x80x9chydrocarbon ringxe2x80x9d as used in the definition of the ring A means cyclopropane, cyclobutane, cyclopentane, cyclohexane, benzene, naphthalene, etc.
(e) The term xe2x80x9cheterocyclexe2x80x9d as used in the definition of the ring A means pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, homopiperazine, pyrrole, pyrazole, imidazole, triazole, tetrazole, oxazole, thiazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine, indole, imidazopyridine, quinoline, naphthyridine, phthalazine, etc.
In the case of the compounds of the present invention having asymmetric carbon atoms, it is needless to say that the optical isomers thereof are also included in the scope of the present invention. Furthermore, hydrates thereof are included in the scope of the present invention.
Examples of the pharmacologically acceptable salts as used in the present invention include inorganic acid salts such as hydrochlorides, hydrobromides, sulfates and phosphates; organic acid salts such as acetates, maleates, tartrates, methanesulfonates, benzenesulfonates and toluenesulfonates; and salts of amino acids such as aspartic and glutamic acids.
To facilitate the understanding of the present invention, and not by way of limitation, typical examples of the compounds of the present invention will be given. Each compound is expressed in a free state:
1) 1,2-dimethyl-10-[3-[(2-hydroxy-3-methylphenyl)methylamino]propyl]phenothiazine-5-dioxide
2) 1,2-dimethyl-10-[3-[(3-chloro-2-hydroxyphenyl)methylamino]propyl]phenothiazine-5-dioxide
3) 1,2-dimethyl-10-[3-[(5-methoxy-2-furanyl)methylamino]propyl]phenothiazine-5-dioxide
4) 1,2-dimethyl-10-[3-[(3-methoxy-2-thienyl)methylamino]propyl]phenothiazine-5-dioxide
5) 1,2-dimethyl-10-[3-(4-hydroxy-4-phenylpiperidinyl)propyl]phenothiazine-5-dioxide
6) 1,2-dimethyl-10-[3-(4-benzylpiperazinyl)propyl]phenothiazine-5-dioxide
7) 1,2-dimethyl-10-[3-[N-[(2-hydroxyphenyl)methyl]methylamino]propyl]-phenothiazine-5-dioxide
8) 1,2-dimethyl-10-[3-[N-[(2-hydroxy-3-methylphenyl)methyl]methylamino]propyl]-phenothiazine-5-dioxide
9) (E,Z)-3,4-dimethyl-10-(3-benzylaminopropyl)-9-acridoneoxime-O-(2-carboxyethyl) ether
10) (E,Z)-3,4-dimethyl-10-(3-benzylaminopropyl)-9-acridoneoxime-O-(1-carboxyethyl) ether.
The compounds of the present invention can be produced by combining generally known methods. Now, main processes generally usable for producing the compounds of the present invention will be illustrated.
Production Process 1
Compounds of the formula (I) wherein Z is xe2x80x94S(O)yxe2x80x94 and Q is xe2x80x94NR20R21 can be produced by the following process.
i) A phenothiazine derivative represented by the formula (II) synthesized by a publicly known method [for example, those described in J. Org. Chem., 20, 1577 (1955); ibid., 35, 4254 (1970); J. Chem. Soc., (C) 2437 (1970); and Chem. Ind., 238 (1966).] is reacted in the presence of a base with a compound represented by the formula (III) having leaving groups at both ends to thereby give a phenothiazine derivative represented by the formula (IV). Preferable examples of the base usable herein include sodium hydride, n-butyllithium and t-butoxypotassium. Preferable examples of the leaving groups include halogeno and sulfonate. Any reaction solvent may be used therefor, so long as it remains inert during the reaction. Next, the leaving group Lxe2x80x2 in the compound (IV) is substituted by phthalimide. The resulting phthalimide compound represented by the formula (V) is then treated with hydrazine hydrate to give an amine compound represented by the general formula (VI). Next, this amine compound (VI) is condensed under dehydration with an aldehyde compound (VII: wherein R represents alkyl, alkenyl, alkynyl, aryl or heteroaryl). The Schiff base thus obtained is then treated with a reducing agent such as sodium borohydride to give an alkylamine compound represented by the formula (VIII). Any reaction solvent may be used therefor, so long as it remains inert during the reaction.
Alternatively, the phthalimide compound (V) serving as an intermediate may be synthesized in the following manner. Namely, the compound (II) is reacted with a compound having a leaving group L at one end and a protected hydroxyl group at another end to give a compound represented by the formula (IVxe2x80x2). Subsequently, the compound (IVxe2x80x2) isdeblocked in a conventional manner to give an alcohol (IVxe2x80x3), which is then reacted with phthalimide under the conditions of the Mitsunobu reaction to give a phthalimide compound.
ii) The compound (IV) is treated with a primary or secondary amine, or the compound (VI) is treated with a compound having a leaving group L (IX and/or Xxe2x80x2) to give a compound represented by the formula (X).
iii) A sulfoxide compound (XI) and a sulfonyl compound (XII) can be produced by oxidizing the sulfur atoms in the compounds (VIII) and (IX) or oxidizing the sulfur atom in the stage of the intermediate (IV) or (VI) in the process of the above i) or ii) followed by appropriate reactions.
Production Process 2
Compounds of the formula (I) wherein Z is xe2x80x94C(xe2x95x90NOR12)xe2x80x94 or xe2x80x94C(xe2x95x90NNR13R14) and Q is xe2x80x94NR20R21 can be produced by the following process.
An acridone compound (XIII) synthesized by a publicly known method (for example, the one described in JP-A 7-3161359) is reacted with a compound (III) to give a compound (XIV). Next, this compound (XIV) is reacted with potassium phthalimide to give a compound (XV). Then the compound (XV) is reacted with oxalyl chloride. The acridinium salt thus obtained is reacted with a hydroxylamine derivative (R12ONH2: wherein R12 is as defined above) or a hydrazine derivative (R13R14NNH2: wherein R13 and R14 are each as defined above) to give a compound represented by the formula (XVI) or (XVIxe2x80x2). Then the obtained compound is reacted with hydrazine hydrate to give a primary amine compound represented by the formula (XVII) or (XVIIxe2x80x2). Further, secondary or tertiary amines can be produced in accordance with the methods of i) of ii) in the above production process 1. Production Process 3
Compounds represented by the formula (I) wherein Z is xe2x80x94C(xe2x95x90CR16R17)xe2x80x94 and Q is xe2x80x94NR20R21 can be produced by the following process.
The compound represented by the formula (XIV) given in the production process 2 is reacted with a metal compound Mxe2x80x94CHR16R17 (wherein M means a metal and R16 and R17 are each as defined above such as alkyl lithium, etc.) to give an acridan compound represented by the formula (XVIII). Next, this product is treated in the same manner as the one described in the production process 1 ii) to give an amine compound represented by the formula (IX).
Production Process 4
Compounds represented by the formula (I) wherein Z is xe2x80x94C(xe2x95x90O)N(R15)xe2x80x94 or xe2x80x94N(R15C(xe2x95x90O)xe2x80x94 and Q is xe2x80x94NR20R21 can be produced by the following process.
The procedure of the step i) or ii) in the production process 1 was repeated while replacing the phenothiazine derivative represented by the formula (II) employed In the production process 1 by a dibenzodiazepine derivative (XX or XXxe2x80x2) produced by a publicly known method [Indian J. Chem., 23B, 85 (1984).] or Production Example 13 or 14. Thus a compound represented by the formula (XXI or XXIxe2x80x2) can be obtained.
Production Process 5
Compounds of the formula (I) wherein Q is heteroaryl can be produced by the following process.
The compound represented by the formula (XXII) obtained by the production processes 1, 2, 3 and 4 and having a leaving group Lxe2x80x2 is treated with magnesium to give a Grignard reagent. Next, this Grignard reagent is reacted with an optionally substituted heteroaryl halide derived from, e.g., pyridine or pyrimidine in the presence of 1,3-bis(diphenylphosphino)propane nickel dichloride [Ni (dppp) Cl2] to give a compound represented by the formula (XXIV).
Production Process 6
Compounds of the formula (I) wherein Q is optionally substituted carbamoyl, acyl or optionally protected carboxy can be produced by the following process.
The compound represented by the formula (XXII) obtained by the production processes 1, 2, 3 and 4 and having a leaving group Lxe2x80x2 is treated with a reagent for cyanation such as sodium cyanide in the presence of a base to give a nitrile compound (XXV), which is then hydrolyzed to give an unsubstituted carbamoyl compound (XXVI) or an ester or carboxylic acid represented by the formula (XXVII). A substituted carbamoyl compound (XXVIII) can be obtained by alkylating or aralkylating the unsubstituted carbamoyl compound (XXVI) or reacting the ester or a reactive derivative (acid halide, reactive ester, etc.) derived from the carboxylic acid in a conventional manner with a primary or a secondary amine. A protected carboxyl compound can be obtained by reacting the reactive derivative derived from the carboxylic acid with an alcohol derivative.
To illustrate the usefulness of the present invention, pharmacological experimental examples will be given. | {
"pile_set_name": "USPTO Backgrounds"
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1. Field of the Invention
This invention relates to a vehicle room lamp which is provided within a vehicle room (or compartment), and is switched between the ON-state (for illuminating the room) and the OFF-state by pressing a light-transmitting member such as a lens.
2. Related Art
An automobile is equipped with a vehicle room lamp (or interior lamp) so as to ensure that the passenger can comfortably get in and out of the automobile at night. For example in a passenger car, such a vehicle room lamp is usually mounted at a central portion of a ceiling of the passenger room (or compartment), and the whole of the passenger room is uniformly illuminated by light distributed by this lamp. The vehicle room lamp is so disposed that a switch can be operated both from a front seat side and a rear seat side. Generally, the switch can be located in any one of three positions, that is, an ON position, an OFF position and a DOOR ACTUATED position.
JP-A-2002-316579 Publication discloses a technical concept in which a push switch is turned on and off by a lens plate (which transmits light from a bulb therethrough in a spreading manner) such that the lens plate is used instead of a knob for operating the switch so as to turn on and off the bulb. With this construction, a box-like body can be formed into a compact size, and besides a vehicle room lamp with a novel design can be produced.
However, in such a conventional vehicle room lamp with the box-like body of a compact design as disclosed in Patent Literature 1 and others, a projection formed on a reverse surface of the lens plate is held against the push switch, and when the user presses the lens plate, the projection presses the push switch to switch the same so as to turn on and off the bulb. Therefore, light from the bulb is intercepted by this projection, and besides the thickness of the light-transmitting lens plate is increased because of the provision of the projection. Therefore, a shadow of the projection, etc., are formed on a design surface of the lens plate at the reverse side of the projection relative to the bulb, so that light and dark portions are formed on the illumination surface (i.e., the design surface) of the lens plate, and therefore it has been difficult for the illumination surface to become luminous uniformly over the entire area thereof.
It may be proposed to provide the switch and the projection at the outside of the lens plate. In this case, however, the box-like body, etc., of the vehicle room lamp increase in size, and this is not desirable because of a limited space available within the vehicle and for other reasons. | {
"pile_set_name": "USPTO Backgrounds"
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This invention relates to a fluid flow pressure-sensing device. | {
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The present application generally relates to information processing apparatuses and methods and computer programs. More particularly, the application relates to an information processing apparatus and method and a computer program in which, not only the use of content stored in information recording media, but also the use of data generated or obtained by users afterwards, such as downloaded data, can be controlled on the basis of management units.
Various software data (hereinafter referred to as “content”), such as audio data, e.g., music, image data, e.g., movies, game programs, and various application programs, can be stored on recording media, for example, Blu-ray Discs™ using blue laser light, digital versatile discs (DVDs), mini discs (MDs), compact discs (CDs), as digital data. In particular, Blu-ray discs using blue laser light are high-density recording discs and can record a large volume of video content as high-quality image data.
Digital content is stored in various information recording media, such as those described above, and is provided to users. A user uses the digital content by playing it back on the user's personal computer (PC) or a player, such as a disc player.
Generally, the distribution rights of many content data, such as music data and image data, are owned by creators or sellers of such content data. Basically, therefore, certain usage restrictions are imposed when distributing content, that is, the use of content is allowed only for authorized users, thereby preventing unauthorized copying.
According to digital recording apparatuses and recording media, images and sound can be repeatedly recorded and played back without a loss in quality. Thus, the distribution of illegally copied content via the Internet, the circulation of recording media, such as compact disc recordable (CD-R) discs, recording copied content thereon, so-called “pirated discs”, the use of copied content stored in hard disks of, for example, PCs, are widespread.
DVDs or large-capacity recording media, such as those using blue laser light which have recently been developed, can record a large volume of data, for example, up to several movies, on one medium, as digital information. Since video information can be recorded as digital information as described above, it is becoming important to perform copyright protection by preventing unauthorized copying. Nowadays, to prevent unauthorized copying of digital data, various techniques for preventing unauthorized copying are practically applied to digital recording apparatuses or recording media.
For example, in DVD players, a content scrambling system is employed. According to the content scrambling system, data, such as, video data or sound data, is encrypted and recorded on, for example, a digital versatile disc read only memory (DVD-ROM), and a key for decrypting the encrypted data is supplied to licensed DVD players. A license is given to DVD players that are designed in compliance with predetermined operation rules, for example, agreeing not to perform unauthorized copying. Accordingly, licensed DVD players can decrypt data recorded on a DVD-ROM by using the given key to play back images or sound from the DVD-ROM.
On the other hand, unlicensed DVD players are unable to play back data recorded on the DVD-ROM since they do not have the key for decrypting the encrypted data. In this manner, in the content scrambling system, DVD players that do not satisfy conditions demanded for receiving a license are unable to play back digital data from a DVD-ROM, thereby preventing unauthorized copying.
A management system for content stored in information recording media is constructed, as described above. Another type of system that allows users to easily download content, such as effect sound, moving pictures, and still images, that can serve as materials for video products is disclosed in Japanese Unexamined Patent Application Publication No. 2003-140662. Additionally, a technique for substituting data indicating part of a piece of music with another data is disclosed in Japanese Unexamined Patent Application Publication No. 2002-311967. It is difficult, however, to implement the secure data management or usage management for data generated by executing programs stored in information recording media by users or data or content obtained from external servers.
To perform the secure management for data generated by executing programs stored in information recording media by users or data obtained from external servers, it is necessary to handle individual data by, for example, setting a password for each data by a user input or by encrypting each data by using a cryptographic key obtained from an external source. In this data management structure, however, if the number of data generated or obtained by users afterwards is increased, the number of cryptographic keys or passwords is also increased. Additionally, the location of data becomes unclear and the correspondence between stored data and the cryptographic keys or passwords also becomes unclear. Sufficient measures have not yet been taken for the usage management for such subsequently generated/obtained data.
In particular, in an environment where various application programs can be run, such as in a PC, generally, directories managed by a general-purpose file system are set, and files generated by the corresponding programs can be accessed from various applications. Accordingly, it is preferable that, as well as normal files, subsequently generated/obtained data that should be managed by the content management system be also set in management directories of the general-purpose file system. In this case, however, if special settings are not made, the subsequently generated/obtained data is accessed from various application programs, which cause the unauthorized use or tampering of the data. | {
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The present invention relates to centrifugal fluid machines such as a pump or compressor and, more particularly, relates to a centrifugal fluid machine in which noise and pressure pulsation may be suitably abated.
A flow distribution which is not uniform in the peripheral direction occurs at the outlet of an impeller due to the thickness of a vane and secondary flow or boundary layer occurring between the vanes. Such nonuniform pulsating flow interferes with the leading edge of the vanes of a diffuser or a volute tongue, resulting in a periodical pressure pulsation and causing a noise. In some cases, such pressure pulsation vibrates the diffuser and furthermore vibrates a casing or an outer casing outside thereof through a fitting portion, whereby the vibration is propagated into the air surrounding the pump to cause a noise.
In a centrifugal pump as disclosed in Zulzer Technical Review Vol. 62 No.1 (1980) PP.24-26, the noise is reduced by varying radius of the trailing edge of vanes of the impeller or the peripheral position of the trailing edge of the vanes in the direction of axis of rotation. Further, in an electric fan as disclosed in Japanese Patent Laid-Open Publication No. 51-91006, a pressure increasing section and a noise abatement section (the noise abatement section being the portion where the peripheral position of a volute tongue is varied in the direction of axis of rotation) are formed on the volute wall of a volute casing and the peripheral distance of the noise abatement section is made substantially equal to the peripheral distance between the trailing edges of the vanes that are next to each other in the impeller, so that the flow from the impeller does not impact the volute tongue all at once. In this manner, a shift in phase in the direction of axis of rotation occurs in the interference between the flow and the volute tongue, whereby the periodical pressure pulsation is mitigated to lead to an abatement of the noise.
In the above prior art, however, there has been a problem that, when radius of the trailing edge of the vane of the impeller is varied in the direction of axis of rotation, the head or the efficiency thereof is reduced due to the fact that the ratio between radius of the trailing edge of the impeller vane and radius of the leading edge of the diffuser vane or radius of the volute tongue is varied in the direction of axis of rotation. Further, when the outer radius of the main shroud and the front shroud of the impeller are different from each other in association with the fact that the trailing edge radius of the impeller vane is varied in the direction of axis of rotation, an axial thrust occurs due to difference between the projected areas of the main shroud and the front shroud in the direction of axis of rotation. In the case where the peripheral position of the trailing edge of the impeller vane is varied in the direction of axis of rotation, although the peripheral distance between the trailing edge of the impeller vane and the leading edge of the diffuser vane or the volute tongue is varied, amount of such change has not been optimized. In the case where the peripheral position of the volute tongue is varied in the direction of axis of rotation and amount in such change is substantially equal to the peripheral distance between the trailing edges of the impeller vanes which are next to each other, the portion for effecting the pressure recovery in the volute casing becomes shorter where a sufficient pressure recovery cannot be obtained.
An object of the present invention is to provide a centrifugal fluid machine in which reduction in head and efficiency or occurrence of an axial thrust is controlled while noise and pressure pulsation are abated.
In the case of a diffuser pump, the above object may be achieved such that the trailing edge radius of the impeller vane and the leading edge radius of the diffuser vane are increased or decreased monotonously in the direction of axis of rotation and inclinations on a meridional plane of the trailing edge of the impeller and the leading edge of the diffuser are in the same orientation.
Alternatively, it may be achieved such that, of the trailing edge of the impeller vane, radius at the center in the direction of axis of rotation is made larger than radius at the two ends in the direction of axis of rotation and, of the leading edge of the diffuser vane, radius at the center in the direction of axis of rotation is made larger than radius at the two ends in the direction of axis of rotation.
Alternatively, it may be achieved such that, of the trailing edge of the impeller vane, radius at the center in the direction of axis of rotation is made smaller than radius at the two ends in the direction of axis of rotation and, of the leading edge of the diffuser vane, radius at the center in the direction of axis of rotation is made smaller than radius at the two ends in the direction of axis of rotation.
Alternatively, it may be achieved such that the trailing edge radius of the impeller vane and the leading edge radius of the diffuser vane are varied in the direction of axis of rotation and the ratio between the trailing edge radius of the impeller vane and the leading edge radius of the diffuser vane is made constant in the direction of axis of rotation.
Alternatively, it may be achieved such that the peripheral distance between the trailing edge of the impeller vane and the leading edge of the diffuser vane is varied in the direction of axis of rotation and difference between the maximum value and the minimum value of the peripheral distance between the trailing edge of the impeller vane and the leading edge of the diffuser vane is made equal to the peripheral distance between the trailing edges of the vanes next to each other in the impeller or to a part obtained by equally dividing that by an integer.
Alternatively, it may be achieved such that, when the leading edge of the diffuser vane and the trailing edge of the impeller vane are projected onto a circular cylindrical development of the diffuser leading edge, the leading edge and the trailing edge of the vanes are perpendicular to each other on the circular cylindrical development.
In the case of a volute pump, the above object may be achieved such that the trailing edge radius of the impeller vane and radius of the volute tongue of the volute casing are increased or decreased monotonously in the direction of axis of rotation and inclinations on a meridional plane of the trailing edge of the impeller vane and the volute tongue are set in the same orientation.
Alternatively, it may be achieved such that, of the trailing edge of the impeller vane, radius at the center in the direction of axis of rotation is made larger than radius at the two ends in the direction of axis of rotation and, of the volute tongue of the volute casing, radius at the center in the direction of axis of rotation is made larger than radius at the two ends in the direction of axis of rotation.
Alternatively, it may be achieved such that, of the trailing edge of the impeller vane, radius at the center in the direction of axis of rotation is made smaller than radius at the two ends in the direction of axis of rotation and, of the volute tongue of the volute casing, radius at the center in the direction of axis of rotation is made smaller than radius at the two ends in the direction of axis of rotation.
Alternatively, it may be achieved such that the trailing edge radius of the impeller vane and the radius of the volute tongue of the volute casing are varied in the direction of axis of rotation and the ratio between the trailing edge radius of the impeller vane and the radius of the volute tongue is made constant in the direction of axis of rotation.
Alternatively, it may be achieved such that the peripheral position of the trailing edge of the impeller vane is varied in the direction of axis of rotation and difference between the maximum value and the minimum value of the peripheral distance between the trailing edge of the impeller vane and the volute tongue is made equal to the peripheral distance between trailing edges of the vanes that are next to each other in the impeller or to a part obtained by equally dividing that by an integer.
Alternatively, it may be achieved such that, when the volute tongue of the volute casing and the trailing edge of the impeller vane are projected onto a circular cylindrical development of the volute tongue, the volute tongue and the trailing edge of the vane are perpendicular to each other on the circular cylindrical development.
In the case of a multistage centrifugal fluid machine, the above object may be achieved such that, for at least two impellers of the impellers of the respective stages each constituted by a main shroud, a front shroud and vanes, the trailing edge radius of the vane is varied in the direction of axis of rotation and the main shroud and the front shroud are formed into different radiuses; of the impellers of which the main shroud and the front shroud are formed into different radiuses, the outer radius of the main shroud of at least one impeller is made larger than the front shroud thereof and the main shroud of the remaining impellers is made smaller than the front shroud thereof.
Alternatively it may be achieved such that, for an even number of impellers of the impellers of the respective stages each constituted by a main shroud, a front shroud and vanes, the trailing edge radius of the vane is varied in the direction of axis of rotation and the main shroud and the front shroud are formed into different radiuses of the impellers of which the main shroud and the front shroud are formed into different radiuses, the main shroud of one half of the impellers is made larger than the front shroud thereof and the main shroud of the remaining half of the impellers is made smaller than the front shroud thereof. | {
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The present invention relates to a method and composition for treating multiple sclerosis, demyelinating diseases and other diseases belonging to the general category of immunodeficiency diseases.
Multiple sclerosis, one of the demyelinating diseases of unknown etiology, has been known as one of the most intractable diseases known in the world with no effective therapy having yet been developed for it (c.f. G. Kuroiwa, "Intractable Diseases-Study and Prospect", S. Okinaka, Ed., Tokyo Univ. Press, 1979, pp. 7-27, 1979).
For allergic demyelinating diseases in humans, however, a useful experimental model was developed in 1947 by three research groups independently but having recourse to the same technique. Feund et al. (J. Freund et al., J. Immunol. 57, 179, 1947), Kabat et al. (E. A. Kabat et al., J. Exp. Med., 85, 117, 1947) and Morgan et al. (I. M. Morgan et al., J. Exp. Med., 85, 131, 1947) disclosed the successful development of experimental allergic encephalomyelitis (EAE) in animals by injecting a homogenized emulsion of the animal brain employing Freund's complete adjuvant technique, and the death of the animals within two or three weeks of the treatment. Since, then, EAE has been utilized as an experimental model in studies of multiple sclerosis and other diseases influenced by cellular immunodeficiency. Indeed, it has served as a rare and useful system for in vivo-screening of curatives and treatments for demyelinating diseases and other immunodeficiency and autoimmune diseases.
Drugs for which EAE has been employed as a screening system include steroid anti-inflammatory agents, nonsteroid anti-inflammatory agents such as Flubiprofen, Cyclosporin A (cf. A. N. Davison and M. L. Cuzner, Ed. "The Suppression of Experimental Allergic Encephalomyelitis and Multiple Sclerosis", Academic Press, 1980), and E. N. 3638 (S. Levine and R. Sowinshi, J. Immunol. 120, 602, 1978; P. Y. Paterson and D. Drobish, Science, 165, 191, 1969), Cyclophosphamide (S. Levine and R. Sowinshi, J. Immunol., 120, 602, 1978), Nitridazole (P. Y. Paterson et al., J. Immunol., 118. p. 2151, 1977 and C. A. Bernard et al., Int. Arch. Allergy Appl. Immunol., 53, p. 555, 1977) and amino acid copolymer (R. Arnon and D. Teitelbaum, "The Suppression of Experimental Allergic Encephalomyelitis and Multiple Sclerosis", Academic Press. p. 105, 1980). The responses of EAE against these drugs in screening processes have probably been due to the immunosuppressive effects of the drugs. Of these drugs, however, those which presented any positive effects were of the steroid family.
In inflammatory or rheumatic diseases, some steroids also work remarkably well. However, undesirable secondary effects are almost always involved in their clinical application so that the drugs of this family are gradually being replaced by newly developed non-steroidal ones. For multiple sclerosis and other autoimmune diseases, the development of non-steroidal drugs that would act efficaciously but not be accompanied by adverse side effects in therapy is likewise desired.
As a result of recent researches, multiple sclerosis has come to be recognized as a disease caused by viral infection and/or the malfunction of thymus dependent lymphocytes (T-cell) in which the problem resides in a reduction in the number of "suppressor T-cells" (M. A. Bach, Lancet, Dec., P. 1221, 1980 and Reinherz et al., New Engl. J. Med., 303, p. 125, 1980). As for biosubstances involved in the control, differentiation and function of T-cells, some high molecular weight proteins such as thymosin have become known in recent studies.
In 1976, a nonapeptide having an amino acid sequence: p-Glu-Ala-Lys-Ser-Gln-Gly-Gly-Ser-Asn-Oh (p-Glu representing pyroglutamic acid) was isolated from a volume of pig serum by J. F. Bach et al., and was named Facteur Thymique Serique (FTS) or Serum Thymic Factor (J. F. Bach et al., Nature, 266, p. 55, 1977 and Jean-Marie Pleau et al., J. Biol. Chem. 252, p. 8045, 1977). The present invention then is directed to new uses and pharmaceutical compositions containing FTS. FTS has been thought to have the ability to efficiently induce T-cell differentiation and some researchers seem to think that there may be low molecular weight peptides in mice, humans and other animals which might have actions similar to FTS. The present inventors have for some years been conducting research relative to the low molecular peptide: FTS for applications to the therapy of multiple sclerosis and other immunodeficiencies. The discover of the in vivo effects of FTS in delaying the onset of neurological and clinical signs in EAE guinea pigs and monkeys, in alleviating the symptoms and greatly increasing survival time and in the cure-rate of treated animals led them to work out the present invention.
An EAE system utilizable in laboratory study can be obtained in almost any species of animals when they are immunized with an extract of the animal brain such as the myelin basic protein emulsified in the Freund's complete adjuvant formulation. The most frequently employed systems are those in guinea pigs, mice and monkeys. In guinea pigs that are immunized in this way, the clinical symptoms of EAE generally develop rather acutely. The animals cease to show notably body weight gain and, at about the tenth day after immunization, the animals being to lose weight. At about the twelfth day, ataxia and paralysis develop in the hind part of the bodies and death comes to each one thereafter. The observed symptoms are similar in mice although death does not necessarily follow and many have a chance to recover when diet and other conditions are improved.
In guinea pigs, recent progress in research has made it possible to develop, besides the rather acute type of EAE which causes the animals to die within ten to sixteen days after immunization, a more chronic type of EAE which manifests a retarded onset of the symptoms and the occurrence of death. This chronic type of EAE was developed by modifying the immunization technique and adjusting animal conditions including the selection of their age. A guinea pig in which such a rather chronic type of EAE is induced shows symptoms which more closely resembled multiple sclerosis of humans.
At this time, however, only the conventional, rather acute type of EAE animal system is generally employed by medical and pharmaceutical specialists for screening new drugs to be employed in the treatment of EAE. Even new curatives for treating EAE, including steroids, which have been developed under such circumstances continue to give only a limited contribution to the prolongation of the lives of animals suffering from demyelinating diseases or other diseases of this category. | {
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It is often necessary for trained personnel to provide a variety of gases of medical quality in a medical facility. Examples of such gases include medical air, oxygen, nitrogen, nitrous oxide, and carbon dioxide. Systems are also often installed in medical facilities which provide vacuum or gas evacuation. Gas service may be provided through a system which delivers the gas throughout a facility or portions or zones thereof. A number of primary supply sources of gas are used to deliver gas through outlet ports positioned at locations within the medical facility. The delivery system for each type of gas commonly includes manifolds with appropriate shut-off valves and pressure gauges. The delivery system also commonly includes at least one pressure regulator, check valve, and piping supply lines connecting the elements of the system. The primary supply source for each gas may be located in a secure area in the interior of the medical facility. Alternatively a primary supply source may be located at the exterior of the facility for maintenance by outside vendors providing the various gases.
It is critically important that the correct gas at the proper pressure be supplied when required from a medical gas supply system. Great effort is taken to assure that the various gases supplied are clearly marked at all locations. The possibility for delivery of the wrong gas at an incorrect location should be minimized. The pressure of each gas delivered may also be appropriately monitored throughout the system.
There are occasions which may require a secondary gas source to be connected to the gas delivery system of a medical facility. These instances might involve an emergency, a need for maintenance, a requirement of inspection, certification testing or service. One method of connecting the secondary gas source involves connecting the secondary gas source to the system through a hose to a conduit in the facility which normally serves as an outlet. Such an arrangement, known as backfeeding in the industry, is unacceptable according to the National Fire Protection Association (NFPA), the regulatory agency responsible for medical gas piping standards. Such a connection, according to NFPA, puts the system and possibly users thereof at risk of injury or damage.
Gases delivered by medical gas systems are generally at relatively low pressures. Typical desired pressure levels are 50 psi for oxygen, nitrous oxide, carbon dioxide and medical air, 180 psi for nitrogen, and 15 in/Hg to 25 in/Hg for vacuum or gas evacuation. Bottled gases by comparison have considerably higher pressures, commonly about 2000 psi. If the wrong gas were delivered to the wrong supply line through backfeeding, incorrect pressure or flows in portions of the system may occur. Such incorrect pressures and flows may place equipment and personnel at risk.
The medical system for each gas type is designed to provide gas flow from the primary source toward the various outlets and devices which utilize the gas within the medical facility. Gas should not be allowed to flow in a direction opposite to that for which the equipment was designed. Reverse operation requires a user to thoroughly understand every component of the system and what is necessary to safely accomplish reverse flow. It is often difficult to conduct such an analysis when many types of devices may be connected to the system.
For these reasons NFPA has disapproved of the practice of backfeeding of gas supply lines. Despite the NFPA position, personnel in medical facilities when faced with the necessity of keeping gas systems in operation are forced to use such backfeeding connections. In 1996 NFPA took the position that emergency service of an oxygen supply could be provided by a low pressure inlet located in the main supply line. This inlet is required to be located at the exterior of the medical facility. The use of such an inlet is authorized only for use to achieve an emergency supply of oxygen and is not to be used in the case of inspection/certification. Since this emergency inlet port is not required to be retrofit into existing "grandfathered" systems, most medical facilities are not equipped with this capability. Such an arrangement is of no help when the problem in the system is something other than the main supply, such as a system break inside the medical facility. In addition, gas delivery systems are normally divided into zones. This port does not allow gas service to be selectively supported or inspection/certification activities to be performed by selected zones. As a result, even in oxygen systems which have such a port the practice of backfeeding is sometimes necessary.
Thus there exists a need for an apparatus and method for connecting a secondary supply of a medical gas to a medical gas supply system. There further exists a need for an apparatus and method of connecting such a secondary supply of medical gas in a quick and reliable manner, which can be connected to selected zones of the supply system and which does not require backfeeding of any portion of the gas supply system. | {
"pile_set_name": "USPTO Backgrounds"
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1. Field of the Invention
The present invention relates to an Internet telephone apparatus that realizes a telephone call via the Internet, a adapter and a server that are used for the Internet telephone communication, an Internet telephone system, and a control method for the Internet telephone apparatus.
2. Description of Related Art
A conventional network that is used by so-called Internet telephone has been configured as follows.
Taking an Internet telephone system using H.323 protocol as an example, a managing server (referred to as gatekeeper) is provided within an Internet telephone network. This gatekeeper has functions to receive a phone number of a destination to be called, from each telephone in a unified way, to convert the phone number into a corresponding IP address, and to return the phone number back to the caller telephone.
When an operator inputs the desired phone number to be called, the number is called. When the telephone receives the IP address that corresponds to the telephone number from the gatekeeper, the telephone can access, based on the IP address, a telephone of the desired destination to be connected via the gatekeeper, or directly access the telephone without involving the gatekeeper. Accordingly, the telephone call can be made available via the Internet (see Related Art 1).
In addition, a router is normally involved between a gatekeeper and each telephone. A plurality of Internet telephones are connected to such a router, configuring a group in a network. Telephones within the same group have IP addresses having a common network address. In a normal corporate office setting, telephones within the same department are configured as the same group on the network.
FIG. 9(a) illustrates a network configuration of a commonly used Internet telephone system. In the network of FIG. 9(a), router A 902 and router B 903 are connected to management server 901. Internet telephones A1-A4 are connected to router A 902, configuring group (A), while Internet telephones B1-B4 are connected to router B 903, configuring group (B).
FIGS. 9(b) and (c) illustrate management charts that register telephone numbers assigned to each Internet telephone and IP addresses corresponding to the numbers. FIG. 9(b) and (c) respectively illustrate management charts of group (A) and group (B). In this example, telephone numbers are extension numbers used in a corporate setting.
As shown in FIG. 9(b), telephone numbers 1001-1004 are respectively assigned to Internet telephones (terminals) A1-A4, thereby having IP addresses of (192. 168. 1. 1)-(192. 168. 1. 4). Thus, network address (192. 168. 1) is commonly used for the above IP addresses of group (A) terminals.
As shown in FIG. 9(c), telephone numbers 2001-2004 are respectively assigned to Internet telephones (terminals) B1-B4, thereby having IP addresses of (192. 168. 2. 1)-(192. 168. 2. 4). Thus, network address (192. 168. 2) is commonly used for the above IP addresses of group (B) terminals.
[Related Art 1]
Japanese Patent Laid Open Publication 2002-101198 (Pages 4-5, FIG. 1)
The above described conventional art has the following shortcomings.
In a case where a call is place to a telephone in a department and the telephone is busy, the caller must hang up the phone and dial another number of a telephone, which is in close proximity to the unavailable telephone, if it is for an urgent matter. Therefore, such a calling operation has been very cumbersome to the caller.
The above network configuration is further described using the example of terminal A1 placing a call to terminal B1. FIG. 10 is a sequence chart illustrating an operation of a conventional Internet telephone system.
As shown in FIG. 10, when a call is placed from terminal A1 to terminal B1, the caller first input telephone number (2001) of terminal B1. Upon receiving the telephone number input, terminal A1 requests for an IP address of terminal B1 from server 901. Then, server 901 provides the IP address of terminal B1. Based on the provided IP address, terminal A1 places a call to terminal B1.
In this example, terminal B1 is busy, thus the connection to terminal B1 is unsuccessful and terminal A1 sounds a busy tone. Upon confirming the busy tone, the caller hangs up the telephone first, and inputs telephone number (2002) of terminal B2. Similar to the situation of calling terminal B1, terminal B2 is called when terminal A1 receives an IP address of terminal B2 from server 901.
In this example, terminal B2 is also busy, thus the connection to terminal B2 is unsuccessful and terminal A1 sounds a busy tone. Upon confirming the busy tone, the caller hangs up the telephone, and inputs telephone number (2003) of terminal B3. Similar to calling terminal B1 and terminal B2, terminal B3 is called when terminal A1 receives an IP address of terminal B3 from server 901.
In this example, terminal B3 is not busy, thus the connection between terminals A1 and B3 is successful. Therefore, a message to the operator of terminal B1 is delivered to the operator of terminal B3. As described above, when one terminal in a department is busy, the operator must dial another number of an adjacent terminal. | {
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Embodiments relate to a multi-phase generator. In particular, exemplary embodiments relate to a multi-phase generator for generating a signal having various phases.
Demand for high-picture quality, high resolution, multi-function, and high-speed semiconductor devices has increased. Further, semiconductor devices need various operating frequencies to drive internal circuits. In particular, when a semiconductor device performs a high-speed operation such as operational processing, an oscillator that operates at high speed is required to generate a high operating frequency. In addition, a large-size circuit is separately required in order to generate a signal having various operating frequencies or phases. | {
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Wireless communication systems have developed into a high speed and high quality of radio packet communication systems in order to provide data service and multimedia service out of the initial voice-oriented service. In order to provide a high speed and high quality of data service in the wireless communication system, multiple-input multiple-output (MIMO) schemes have been proposed in various ways.
The MIMO schemes can be classified into spatial diversity scheme for increasing transmission reliability by employing multiple paths and spatial multiplexing scheme for improving the data rate by transmitting multiple data streams at the same time. Further, active research has recently been done on a method of obtaining the advantages of the two schemes by properly combining them.
The MIMO schemes can also be classified into open-loop transmission scheme in which channel information is used to schedule user data and closed-loop transmission scheme in which channel information is not used to schedule user data. In the open-loop transmission scheme, a transmitter and a receiver can be constructed relatively simply without uplink radio resources for transmitting channel information since the transmitter does not need channel information. However, the open-loop transmission scheme is disadvantageous in that its performance is degraded when channel correlation is increased or multiples channels are subject to deep fading at the same time because this scheme cannot cope with a channel change adaptively. On the other hand, in the closed-loop transmission scheme, a receiver estimates a channel and then re-transmits an estimated channel to a transmitter, and the transmitter acquires channel information. The transmitter performs pre-processing adapted to a channel in consideration of a channel state every moment, so the capacity of a system can be maximized.
In the closed-loop transmission scheme, system performance can be maximized when all channel information is known. But as channel information increases, radio resources for transmitting the channel information increase. Moreover, channel information for MIMO schemes increases as the number of antenna increases. If radio resource for channel information is allocated too much, radio resources for data may be insufficient. It may result in low data rate.
Thus, there is a need for method of maximizing the data rate while minimizing the amount of feedback information. | {
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This invention relates to moving carriage type thermal ink jet printers, and more particularly, to a thermal ink jet printhead and replenishable reservoir which travels therewith having means to sense the ink content thereof so that it may be refilled at predetermined ink content levels.
Thermal ink jet printing systems use thermal energy selectively produced by resistors located in capillary filled ink channels near channel terminating nozzles or orifices to vaporize momentarily the ink and form bubbles on demand. Each temporary bubble expels an ink droplet and propels it toward a recording medium. The printing system may be incorporated in either a carriage type printer or a pagewidth type printer. A carriage type printer generally has a relatively small printhead containing the ink channels and nozzles. The printhead is usually sealingly attached to an ink supply cartridge and the combined printhead and cartridge assembly is reciprocated to print one swath of information at a time on a stationarily held recording medium, such as paper. After the swath is printed, the paper is stepped a distance equal to the height of the printed swath, so that the next printed swath will be contiguous therewith. The procedure is repeated until the entire page is printed. In contrast, the pagewidth printer has a stationary printhead having a length equal to or greater than the width of the paper. The paper is continually moved past the pagewidth printhead in a direction normal to the printhead length at a constant speed during the printing process. Moving carriage type ink jet printers must either carry the ink reservoir along with the printhead or provide a flexible ink supply line between the moving printhead and a stationary ink reservoir. In addition, thermal ink jet devices require a small negative pressure at the printhead in order prevent ink from weeping from their droplet expelling nozzles.
Generally, thermal ink jet printers of the moving carriage type use a relatively large stationary ink reservoir and a flexible supply line arrangement to a movable small ink reservoir that is attached to the moving printhead. This is because the carriage providing the printhead motion is subjected to periodic accelerations at the ends of scan. Therefore, a large carriage mounted ink reservoir would require a large drive motor along with robust structure in order to achieve rapid carriage accelerations and accurate control of the printhead position. Small carriage mounted disposable ink reservoirs suffer the disadvantage of requiring frequent replacement. Such disposable ink reservoirs generally are bundled with the ink jet printhead so that both are discarded when the cartridge is empty.
U.S. Pat. Nos. 3,967,286; 4,677,448; and 4,757,331 disclose a recording apparatus with a carriage mounted ink tank and a second tank that is fixed. The second tank remains disconnected from the first tank during recording and intermittently is connected to the first carriage mounted tank when the ink is to be supplied from the second tank to the first.
U.S. Pat. No. 4,737,801 discloses an ink supply device comprising a first ink tank and a second ink tank for supplying ink to the first tank. A liquid level sensor is mounted in the first tank. The ink supply system also comprises an overflow sensor.
U.S. Pat. No. 4,788,861 discloses an apparatus for monitoring the ink supply of an ink printing device. The apparatus comprises three electrodes for measuring resistance. A first electrode pair is constantly moistened by the ink to provide an ink comparison resistance. An additional electrode with one of the first pair serves for measuring the resistance change due to fluid level. This arrangement can determine a high and low ink level.
U.S. Pat. No. 4,432,005 discloses an ink control system for an ink jet color printer. The printer comprises three long tubular supply sacks connected to three secondary ink reservoirs mounted on a printhead through flexible umbilical tubes.
U.S. Pat. No. 4,929,969 discloses an ink supply construction for an ink jet printer which uses a foam-filled ink reservoir. The foam structure comprises a network of fine filaments to reduce drooling of the ink and provide a slight negative pressure to the ink at the printhead. While it is known to provide a small foam-filled replenishable ink reservoir attached to a carriage-mounted printhead for movement therewith, such disclosures and prior art printers do not have a reliable, cost effective way to ensure that the printhead replenishable reservoir maintains a sufficient supply of ink by monitoring the ink content in the replenishable reservoir and refilling it at predetermined levels, while concurrently ensuring that the replenishable reservoir is not overfilled. | {
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Skin performs very important functions as a barrier against the external environment, protecting from biological, chemical and physical attacks of microorganisms, chemical substances, ultraviolet rays, etc. and preventing loss of biologically essential components such as moisture. It is a stratum corneum having a thickness of about 20 μm, the outermost layer of the epidermis, that functions as the barrier. The stratum corneum is made up of flat corneous cells laid like bricks cemented with intercellular lipids. It is known that ceramides act as a key component of the intercellular lipids for making up the lipid barrier, playing an important role in keeping skin soft and fresh (see Downing D. T., et al., J. Lipid Res., vol. 24, p. 759 (1983) and Dowing D. T., et al., J. Invest. Dermat., vol. 84, p. 410 (1985)). It has been revealed that the skin of those suffering from rough skin, dry skin or atopic dermatitis has a noticeably reduced ceramide content in the intercellular lipids as compared with healthy skin. Attempts to improve skin conditions by supplementing rough skin with the intercellular lipids containing ceramides have been made. For example, external preparations containing ceramides or ceramide-containing intercellular lipids for application to the skin have been proposed.
However, ceramides are highly crystalline high-melting compounds and, because of their peculiar amphiphatic structure, have extremely low solubility in most of oil-soluble or water-soluble bases (solvents) for cosmetics. For this it has been difficult to formulate ceramides into stable preparations. That is, preparations having a high ceramide content easily undergo precipitation, or some lubricants which are used to dissolve a larger amount of a ceramide are unfavorable for safety.
It has recently been demanded to supply ceramides in the form of a clear solution for use in cosmetics or pharmaceuticals. To meet the demand JP-A-9-315929 (the term “JP-A” as used herein means an “unexamined published Japanese patent application”) proposes a clear lipid composition comprising a sphingolipid, a lysophospholipid, and a polyhydric alcohol, the ratio of the sphingolipid to the lysophospholipid being 2/1 or less. This composition is a water-free mixture, however. JP-W-9-505065 (the term “JP-W” as used herein means a “world patent application (PCT) transfer originating from abroad”) discloses a lipid composition in which a phytosphingosine-containing ceramide is stably suspended in a C6-C100 ester base and solubilized in a C8-C22 monofatty acid ester. It is desired for this composition to be free from water. In other words, the compositions of JP-A-9-315929 and JP-W-9-505065 have difficulty in keeping clear when mixed with water as is frequently used in formulation into final products, or in providing a clear preparation upon dilution with water to an arbitrary concentration.
Japanese Patent 3008212 teaches transparent or translucent cosmetics comprising (A) an amphiphatic lipid, (B) a nonionic surface active agent, (C) an ionic surface active agent, and (D) an aqueous medium, the ratio of (A) to [(B)+(C)] being 0.2 to 10. However, the amphiphatic lipids that are actually used are pseudoceramides. In addition, there is a fear of skin irritation due to the ionic surface active agent which is not preferred for cosmetics. | {
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1. Field of the Invention
The present invention relates to a transport roll and a train of transport rolls for transporting a metal body in a hot state while the heat radiation therefrom is being prevented, and more particularly, to a transport roll and a train of transport rolls for transporting a hot slab or ingot emerging from a mold or a heating furnace.
2. Description of the Prior Art
The conventional transport roll for the transport of a steel ingot or slab heretofore used in steel making and rolling works has been of a heat-resistant, solid or hollow cylindrical type roll.
In transport rolls which transport a very hot and heavy material such as a hot slab emerging from the continuous casting process or a hot slab or bloom emerging from a heating or slabbing step to a subsequent processing step, several difficult problems are encountered. The train of transport rolls tends to incur thermal fatigue from the heat conducted directly from the hot material and from the radiant heat absorbed thereby; the rolls draw off heat from the hot material causing it to drop considerably in temperature; and the roll surfaces undergo severe deterioration.
Quite recently, with a view to attaining energy saving as well as high productivity, much work has gone into the development of a direct rolling process wherein the hot casting emerging from a continuous casting mold or the hot slab or bloom emerging from a slabbing step is delivered directly to a subsequent rolling step.
Such a hot casting, slab or bloom (referred to as "hot material" hereinafter) is continuously transported by the transport apparatus between prior and subsequent steps and, for carrying out the direct rolling step, it is of primary importance that the temperature drop of the hot material during its travel through the transport apparatus should be held to the minimum possible.
Since the hot material comes in direct touch with the transport rolls employed in the transport apparatus, its heat is conducted to the low temperature cold transport rolls and is radiated in all directions. As a result, the hot material falls in temperature so sharply that it is very difficult to transport it as far as the rolling stand before its temperature drops below the minimum required for the rolling step. No transport roll satisfactory for such a direct rolling process has been proposed heretofore.
Thus, the inventors of the present invention attempted to make the circumferential area of the transport rolls which comes in direct touch with the hot material as small as possible by providing grooves on the circumferential surface of the roll. The result was not, however, so remarkable as we had expected. We consider that this result occurred probably because cold air currents are generated in the grooves around the transport roll when the rolls rotate and these currents act to cool the hot material. Moreover, another unexpected problem came to light. It was found that cracks tend to occur at the bottom of the grooves, reducing the service life of the transport rolls. No doubt, these cracks occur because the bottom of the groove is subject to repeated thermal stresses. Next, we tried adhering heat resistant tape to the bottom of the grooves with a view to lessening the thermal shock. Although this was somewhat effective for preventing the occurrence of cracks, it did not eliminate the air currents which cool the hot material. | {
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Many methods for peptide synthesis are described in the literature (for examples, see U.S. Pat. No. 6,015,881; Mergler et al. (1988) Tetrahedron Letters 29:4005-4008; Mergler et al. (1988) Tetrahedron Letters 29:4009-4012; Kamber et al. (eds), Peptides, Chemistry and Biology, ESCOM, Leiden (1992) 525-526; Riniker et al. (1993) Tetrahedron Letters 49:9307-9320; Lloyd-Williams et al. (1993) Tetrahedron Letters 49:11065-11133; and Andersson et al. (2000) Biopolymers 55:227-250. The various methods of synthesis are distinguished by the physical state of the phase in which the synthesis takes place, namely liquid phase or solid phase.
In solid phase peptide synthesis (SPPS), an amino acid or peptide group is bound to a solid support resin. Then, successive amino acids or peptide groups are attached to the support-bound peptide until the peptide material of interest is formed. The support-bound peptide is then typically cleaved from the support and subject to further processing and/or purification. In some cases, solid phase synthesis yields a mature peptide product; in other cases the peptide cleaved from the support (i.e., a “peptide intermediate fragment”) is used in the preparation of a larger, mature peptide product.
Peptide intermediate fragments generated from solid phase processes can be coupled together in a liquid phase synthetic process (herein referred to as “solution phase synthesis”). Solution phase synthesis can be particularly useful in cases where the synthesis of a useful mature peptide by solid phase is either impossible or not practical. For example, in solid phase synthesis, longer peptides eventually may adopt an irregular conformation while still attached to the solid support, accordingly resulting in partial or entire loss of activity in the final product. Also, as the peptide chain becomes longer on the support resin, the efficiency of process steps such as coupling and deprotection may be compromised. This, in turn, can result in longer processing times to compensate for these problems, in addition to incremental losses in starting materials, such as activatable amino acids, co-reagents, and solvents. These problems can increase as the length of the peptide increases, and therefore, it is relatively uncommon to find mature peptides of greater than 30 amino acids in length synthesized using only a solid phase procedure.
In solution phase coupling, two peptide intermediate fragments, or a peptide intermediate fragment and a reactive amino acid, are coupled in an appropriate solvent, and usually in the presence of additional reagents that promote the efficiency and quality of the coupling reaction. The peptide intermediate fragments are reactively arranged so the N-terminal of one fragment becomes coupled to the C-terminal of the other fragment, or vice versa. In addition, side chain protecting groups, which are present during solid phase synthesis, are commonly retained on the fragments during solution phase coupling to ensure the specific reactivity of the terminal ends of the fragments. These side chain protecting groups are typically not removed until a mature peptide has been formed.
For the synthesis of very large peptides, it is not uncommon for multiple solution phase coupling steps to be performed using three or four or more peptide intermediate fragments. While the general concept of end-to-end coupling reactions in solution phase reactions is generally theoretically straightforward when multiple peptide intermediate fragments are used, in practice this is rarely the case. Various factors, such as impurities and peptide yield, can have a significant affect on the quality and yield of a full-length peptide. Therefore, peptide synthesis using hybrid schemes are often challenging, and in many cases it is difficult to predict what problems are be inherent in a synthesis scheme until the actual synthesis is performed.
In some cases, solution phase synthesis can be affected by a lack of purity of the peptide intermediate fragments following solid phase synthesis. In this regard, it may be necessary to subject peptide intermediate fragments to a purification step prior to coupling the fragments in a solution phase process. The purification, in turn, can cause a reduction in the yield of the peptide intermediate fragment, and accordingly, the final peptide product.
Also, the yield of the mature peptide is inversely proportional to the number of solution phase steps that are required to synthesize the mature peptide. In some cases, three, four, or more than four solution phase steps utilizing peptide intermediate products may be required to generate a mature peptide. Every additional solution phase coupling step can result in a diminished return of full-length peptide product. Therefore, to improve the overall yield, it is generally desirable to minimize the steps that are involved in coupling.
Modest improvements in one or more steps in the overall synthetic scheme can amount to significant improvements in the preparation of the mature peptide. Such improvements can lend to a large overall saving in time and reagents, and can also significantly improve the purity and yield of the final product.
While the discussion of the importance of improvements in hybrid synthesis is applicable to any sort of peptide produced using these procedures, it is of particular import in the context of peptides that are therapeutically useful and that are manufactured on a scale for commercial medical use. While the synthesis of small molecule pharmaceuticals can be relatively inexpensive, the cost of synthesis of larger biomolecular pharmaceuticals, such as therapeutic peptides, in comparison can be vastly higher. Because of the cost of reagents, synthesis time, in addition to other factors, very small improvements in the synthetic process of these larger biomolecular pharmaceuticals can have a significant impact on whether it is even economically feasible to produce such a pharmaceutical. Such improvements are necessary due to these high production costs for larger biomolecular pharmaceuticals as supported by the fact that, in many cases, there are few, if any, suitable therapeutic alternatives for these types of larger biomolecular pharmaceuticals.
This is clearly seen in the case of therapeutic peptides that are used for the treatment of immunodeficiency diseases caused by retroviral infection. Peptides having anti-retroviral activity can act in different ways, including by preventing fusion of the viral particle with the host immune cell. There is a great need for these novel and effective therapeutic peptides because, in many cases, traditionally used anti-virals become ineffective for the treatment of these diseases because of viral resistance due to mutation.
One promising class of therapeutic peptides useful for combating immunodeficiency diseases is fusion inhibitors. These types of therapeutic peptides can reduce viral titer, and significantly improve the quality of life in patients having immunodeficiency diseases. For example, the FUZEON® peptide (also known as enfuvirtide or T-20), which is a synthetic, 36-amino-acid peptide, the hybrid peptide T-1249, and derivatives and counterparts of these peptides, have proven beneficial as fusion inhibitors in the treatment of the human immunodeficiency virus (HIV) and the acquired immune deficiency syndrome (AIDS). The FUZEON® peptide and its derivatives are the first inhibitors of HIV to demonstrate consistent, potent activity in persons infected with HIV. Kilby et al. (1998) Nat Med 4:1302 and Kilby et al. (2002) AIDS Res Hum Retroviruses 18:685.
Fusion inhibitors such as the T-20 and T-1249 peptides bind to a region of the glycoprotein 41 envelope of HIV type 1 (HIV-1) that is involved in the fusion of the virus with the membrane of the CD4+ host cell. Wild et al. (1993) AIDS Res. Hum. Retroviruses 9:1051. Fusion inhibitors remain outside the cell and block HIV-1 prior to HIV-1 entering the cell. The FUZEON® peptide and its derivatives minimize drug interactions, side effects and cytotoxicity by potently and selectively inhibiting HIV-1 in vitro.
In addition to these concerns, issues relating to product recovery and product purity for the large-scale production of peptides, as well as reagent handling, storage and disposal, can greatly impact the feasibility of the peptide synthesis scheme. Thus, there is a continuing need for peptide synthesis processes capable of efficiently producing peptide materials of commercial interest in large batch quantities with improved yields. Recovery of cleaved peptide from a support resin after solid phase synthesis of the peptide is one aspect of the synthesis in which improvement is needed. | {
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Multimedia decoding components found in, for example, DVD players and set-top boxes typically utilize a decoder to decode encoded multimedia data (e.g., MPEG video and audio data). The multimedia decoding components then provide the decoded multimedia data for formatting for display as video and audio content. To reduce cost and complexity, many of these multimedia decoding components have limited capabilities. Moreover, these components often implement limited types of interfaces that may be used to connect to other components. Frequently, the only device interface provided by such components is a single mass storage device interface through which the components connect to one or more mass storage devices for the storage of and access to multimedia data. The limited interface capabilities of these multimedia decoding components typically inhibits the ability to connect other components in a conventional manner so as to increase the capabilities and functionality of multimedia processing components implementing a decoder. Accordingly, a system and technique for interfacing with such multimedia components would be advantageous. | {
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Messaging is a convenient and popular means for people to engage in local or remote communication. Through the use of devices, such as computers, personal digital assistants (“PDAs”), and cellular phones enabled by associated software and hardware providing user-friendly interfaces, people routinely engage in messaging through what are typically known as instant messaging (“IM”) or text-messaging services.
IM is a type of messaging service that enables a person to create a kind of private chat room with another individual in order to communicate in real time over the Internet, and is analogous to a telephone conversation except that communication is text-based, not voice-based. Typically, an instant messaging system alerts a person whenever somebody on the person's private list, e.g., a “buddy list,” is online. The person can then initiate a chat session with that particular individual. Many commercial providers exist for individuals to engage in IM, and popular IM service messaging systems include, for example, Lotus® Sametime®, American Online® (“AOL®'s”) AIMSM, MSN®, and Yahoo!®. Normally, these IM service messaging systems are installed to the devices used by individuals that engage in instant messaging.
Text messaging, like instant messaging, involves sending text messages to a device such as a cellular phone, PDA or pager. However, text messaging is used for messages that are no longer than a few hundred characters. The term is usually applied to messaging that occurs between two or more mobile devices. Like IM service messaging systems, the devices permitting text messaging have software installed to the devices used by the individuals engaging in text messaging.
Whether using an IM or text-messaging service, oftentimes, the hardware and software used to enable these systems include a myriad of useful preferences that govern an individual's messaging session with another. Examples of such preferences include automatically or not logging the textual communication occurring during the messaging session, setting styles and colors of font, enabling emoticon capabilities, enabling sound capabilities for certain messages, enabling or not enabling picture capabilities, setting filtering capabilities, such as those desired by parents, enabling or prohibiting webcam viewing capabilities, and so forth. Typically, a user of a messaging service system sets messaging preferences based solely on the user's preferences. That is, the preferences are strictly a matter of personal taste.
Despite advances in messaging, problems remain. For one, although a user of a messaging service system often pre-configures preferences for use while engaging in messaging, a remote user of the system is unaware of the user's preferences in effect while a messaging session occurs between them. Unawareness of another user's preferences may lead to disconcerting results. For instance, suppose a user desires that none of the user's messaging sessions are ever logged. Suppose further that the user begins a messaging session with another user of an IM service system, and the user textually communicates the preference that the user's messaging session not be logged. Even if the other user communicates that no logging will occur, the other user may surreptitiously decide to log the messaging session anyhow in accordance with that user's preferences. By this example, further problems are borne out. That is, there is no effective means to ensure enforcement of each user's preferences, and there is no effective means to discuss modifications to each other's preferences before each user decides to commence with the messaging session.
A need, therefore, exists, for methods, systems, and media for users of messaging systems to engage in messaging sessions with awareness of another user's preferences, to enable means for modifying one or more of at least one user's preferences, and to enforce a user's preferences, whether modified or not, prior to commencing a messaging session. | {
"pile_set_name": "USPTO Backgrounds"
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1. Field of the Invention
This invention relates to a spark coil control device for an internal combustion engine equipped with electronic ignition advance.
2. Description of the Prior Art
In any inductive coil system, spark generation is provided by breaking a high current in the primary of a high voltage coil, thereby inducing a surge of current to the secondary tied into the spark plugs. The energy stored in a coil has the form 1/2 LI.sup.2 where L is the coefficient of self-induction and I.sup.2 is the square of the intensity of the current circulating in the primary immediately before being open circuited. In conventional spark coils where the rupture is provided by contact points, the cyclical relationship of the contact point closure is maintained at a constant 66% of the period, and spark generation under all circumstances results from a compromise between a coil being heated by the Joule effect when the motor is at idle and a sufficient quantity of stored energy to provide spark at higher rpms.
In an electronic ignition system for an internal combustion engine with programmed spark cartography, it is advisable to set aside space in the memory to make it possible to engender an angle for initial coil conduction which varies in accordance with the speed of rotation of the motor, thereby eliminating that compromise. It is also possible to use the value for the speed of rotation to take into account the lower battery power during the starting phase.
In most known ignition systems involving an electronic calculator, a counter under a load which is the 180.degree. complement of the angle of ignition advance is decremented for each degree of rotation of the crankshaft and controls the zero resetting of a bridge which commands the circulation of electrical current in the primary of the coil. The high logical state of the bridge is commanded by the coincidence output from a logic comparator which is connected, on the one hand, to the outputs of the counter and, on the other hand, to the memory providing the value of the angle for initiating coil conduction. The drawback of such a system is that it is incapable of inducing coil conduction when the value of the conduction angle is greater than the 180.degree. complement to the angle of advance.
The major drawback stems from the quality of the decrementaiton signal. Indeed, it is difficult to devise a mechanical method for large-scale production of targets and of primary elements providing resolution of a crankshaft degree. Targets are generally manufactured with a number of teeth of less than 50, and interpolation is used to initiate 360 impulses for each revolution of the crankshaft. The interpolation systems have sufficient precision when the motor is operating at a steady speed but when it is operating at variable speeds, in particular when it is being started in intense cold, the number of impulses restored per half revolution generally differs substantially from 180, which induces an error in the value of the spark advance angle equal to the differences between the value restored over a half revolution and the theoretical number. One solution consists in bringing about the release of a spark when a reference mark connected with the flywheel passes by a primary element on the crankshaft of the flywheel so long as the speed of rotation of the motor is below a certain threshold, but this solution does not permit taking maximum advantage of the flexibility offered by the electronic generation of a spark advance law. | {
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As medical technology has advanced, it is increasingly common for practitioners to interpret data received from one or more medical imaging devices. Different types of imaging devices (e.g., x-ray images, computed tomography scans, magnetic resonance imaging (“MRI”) scans) produce different types of output images, and medical practitioners receive extensive training in performing diagnoses based on these images. However, analysis of these images may involve various time consuming processes, such as manual labeling of elements within an image. For example, a practitioner might spend a significant amount of time manually applying labels to vertebrae in a spinal x-ray or MRI scan in order to report a spinal problem. These manual processes may delay patient results and reduce the availability of the practitioner to perform other tasks. User errors during these processes may result in incorrect or delayed reports. Through applied effort, ingenuity, and innovation, applicant has solved many of these identified problems by developing a solution that is embodied by the present invention, which is described in detail below. | {
"pile_set_name": "USPTO Backgrounds"
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1. Field of the Invention
The present invention pertains to the art of power generation and power generation control systems and, more particularly, to power generation and power generation control systems that can be easily installed in a consumer household, a business or other end-user establishment.
2. Discussion of the Prior Art
In general, large centralized grids or networks are utilized to provide power to multitudes of consumer households, businesses and other end-users. Distribution of electric power from power plants to households and businesses is conducted over a network of utility lines connected to each residence and business. A standard consumer household, business or end user establishment has a consumer circuit that includes an end user circuit breaker that controls power to numerous individual circuits, each with its own circuit breaker. Generally, three-phase power is split into two sets of circuit breakers, one per phase, or two separate power phase groupings of circuit breakers. Should something happen to a specific circuit, that individual breaker opens and halts the flow of power to the device that failed. Should that individual circuit breaker fail, an upstream breaker opens and cuts the flow of power to all the circuits in the home business or end-user establishment.
Each of the large centralized grids is interconnected with various generating stations and substations that supply power to various loads and monitor utility lines for problems. Each of the large grids has a number of disadvantages, including reliance upon certain vital connections to power plants, as well as distribution difficulties during peak power demand periods. One solution to power supply problems is to install one or more power generating devices at a consumer's residence or business. In some instances, it is desirable to feed extra power generated by such devices back into the centralized grid, where the power may be shared. Such devices preferably include photovoltaics, wind power, hydroelectric generators and fuel cells, along with conventional and variable speed diesel engines, Stirling engines, gas turbines, micro-turbines and hybrid vehicles. Additionally, storage systems, such as batteries, super-conducting, flywheel, pumped water and capacitor types, may also provide power during outages. However, there are a number of problems associated with utilizing such power generation and storage devices. For example, the engineering, permitting and installation costs for a solar panel power generation and control system can be as much as the cost of the equipment being installed. Much of the installation cost results from the necessity of developing engineering documents, obtaining permits and hiring a qualified installer or electrician to connect the system to the centralized power grid based on particular engineering and building code specifications. Each end-user electrical system typically has the same components: a power generation system, a connection to the utility grid, safety systems and, preferably, an energy storage device. Although most end-user electrical systems are conceptually the same, each one requires a custom installation. Household appliances such as lamps, radios, stoves, etc. are also connected to the power grid but, unlike power generation systems, any consumer can buy and install such appliances without the need for developing engineering documents and hiring qualified installers such as an electrician.
Although there are many reasons why end-user power generation systems require a custom installation, one major reason they are not “plug and play” in the same way as appliances is that, if during a power grid outage, the end-user power generation system was to feed power back to the grid, it would become a danger to utility workers handling power lines. Household appliances such as lamps, radios, stoves, etc. present no such risk because they do not generate or provide power and, therefore, consumers may install them without developing engineering documents, obtaining permits or hiring an electrician. More specifically, when a utility line needs maintenance or repair, the lines are disconnected from the power grid and the utility workers assume that no power is being supplied to the line. If there is end-user power supplied to the line downstream of a disconnect point, that assumption could be fatal.
One such scenario is depicted in FIG. 1, showing a consumer household, business or other end-user establishment 20 including an end-user electric power generation system 25 in communication with a power grid 26 via a power line 28. A standard main circuit breaker 30 is provided between end-user electric power generation system 25 and power line 28, which connects to the main power grid 26 through switch 48. As depicted, households 40 are supplied with power 44 produced by a power plant 46. When an outage occurs, power 44 is blocked at switch 48 in order for a utility worker 50 to work on power line 28. However, end-user supplied power indicated by arrow 55 from electric power generation system 25 may continue to flow through power line 28, endangering the utility worker 50, and may even flow into an end-user establishment 60. This situation shows the importance of hiring a qualified electrician 61 when installing prior art electric power generation system 25.
One solution to such a problem is set forth in U.S. Patent Application Publication No. 2002/0036430 directed to a local area grid for distributed power. The '430 document notes that a utility can impress a “kill” signal on main power grid lines for power conditioning unit disconnect from a grid for servicing. This connection allows power utilities to monitor and track power flow. However, such a system requires expensive installation by trained professionals and relies on an external signal to be sent by the utility in order to provide a measure of safety for utility line workers.
Based on the above, there is a need for an end-user power generation and control system allowing for the transfer of power between an end-user installable power generator and a power line that eliminates the possible danger to utility workers and can be quickly and inexpensively installed. | {
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Animals' viral infectious diseases such as highly pathogenic avian influenza, newcastle disease and infectious bursal disease, harm the development of livestock husbandry seriously, cause great economic loss and has received extensive attention of the world. Immunization is the best measure to prevent and control the outbreak of these diseases. However, inoculation of vaccine solely usually produces relative weak immunity. Immune adjuvant can enhance immune effects of the vaccine, and prolong protection time. Many immune adjuvants, such as freund's adjuvant and lipopolysaccharide, are easy to cause systematic responses (such as nausea, fever, anaphylaxis, eosinophilia, toxicosis, paralysis and autoimmune disease) and local inflammatory responses (such as inflammation, pain, swelling, necrosis, ulceration and abscessus), so the extensive application is limited, Therefore, the development of efficient and safe new immune adjuvant has become the hotspot of preventing and controlling animal-borne disease. It is proved many traditional Chinese medicines have immunological enhancement, efficient and safe. However, most of them have complicated components and inconvenient administration. With the development of intensive livestock farming, drinking and administration of animal population has more obvious advantages. The invention carries out component medicine screening, prescription screening, and dose screening, combined some aspects such as convenient for application, to perform comprehensive comparison, and the immunopotentiator prepared from mulberry leaves polysaccharide and eucommia polysaccharide is developed ultimately. | {
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1. Field of the Invention
The invention relates generally to devices for directly converting thermal energy to useful electric energy, wherein the invention may also be utilized for directly pumping heat from a colder source to a higher temperature sink. More specifically, the invention relates to a device for utilizing with high efficiency the electric fluctuation energy of small circuits thermally insulated from other small circuits at a different temperature so as to produce useful electric energy. The same device also efficiently pumps heat from lower to higher temperature regions.
2. Description of the Prior Art
Devices for converting thermal energy directly into electric energy have been extensively investigated and the most commonly utilized devices have been the thermionic converters working from high temperature sources and silicon cells utilizing the input thermal energy of solar radiation. The present state-of-the-art has been limited to achieving efficiencies of 15% for thermionic converters and 16% for silicon solar cells. In addition to these limitations on efficiencies, the temperature range over which these devices can work efficiently has been limited to high temperatures in the range of 1400.degree. to 2200.degree. K for the emitter and 500.degree. to 1200.degree. K for the collector of the thermionic converters and to moderate operating temperatures in the range of less than 400.degree. K for the temperature of the silicon solar cells.
The present invention removes these limitations along with providing other improvements in the performance of the direct conversion of thermal energy to electric energy. The thermal converter of this invention eliminates the electron cooling, radiation losses and lead losses of thermionic diode converters and operates reversibly as a heat pump over a wide temperature range. The efficiency for each working temperature range is determined by the physical dimensions of the circuits. The small circuits of this invention yield increased efficiency and power output or heat pump output. The efficiency of the small circuit devices of this invention also improves the efficiency when the input thermal energy is in the form of thermal radiation from a heated source such as solar radiation from the sun which is to be converted to useful power. The Carnot cycle efficiency obtainable from a heat source at solar temperature working with a heat sink at the ambient temperature on earth is over 90%. This invention achieves this efficiency as it is not limited by the heat losses resulting from the diffusion and thermal conduction processes of solar cells. The invention also improves on the efficiency obtainable from the small circuits of the prior art. A typical prior art device is disclosed in U.S. Pat. No. 3,760,257 issued Sept. 18, 1973, which discloses a device used with a directional wide band antenna system to convert radiation energy to useful output power. The improvement of the invention herein over the prior art results generally from minimizing or eliminating the losses resulting from eddy current losses on the receiving antenna surfaces. Also, the efficiency of converting the wide bandwidth radiation such as solar radiation is increased in the instant invention by minimizing or eliminating the losses that occur from impinging stray radiation from other directions and the losses resulting from incompletely utilized voltages from antenna element spacings approaching one wavelength, or from antenna element spacings less than one half wavelength. | {
"pile_set_name": "USPTO Backgrounds"
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1. Field of the Invention
The present invention relates to a cleaning apparatus for cleaning semiconductor wafers, glass for photomasks and the like (hereinafter referred to as substrates) and, more specifically, to a cleaning apparatus provided with a contact buffer apparatus.
2. Description of Related Art
A cleaning apparatus of interest to the present invention is disclosed in, for example, Japanese Patent Laying-Open Gazette No. 90941/1982. FIG. 1 is a side view of the cleaning apparatus shown in the gazette. The cleaning apparatus shown therein is called a swing type cleaning apparatus, since an arm provided with a cleaning brush is swingable.
Referring to FIG. 1 of the prior disclosure, the conventional cleaning apparatus comprises a cleaning portion 121 for cleaning a substrate 141, and a supporting portion 122 for supporting the cleaning portion 121. The cleaning portion 121 comprises: a rotary cleaning brush 102 for cleaning the substrate 141; a swing arm 101 for supporting the rotary cleaning brush 102 swingable in a horizontal direction; a driving motor 103 for rotating the cleaning brush, which rotatably drives the cleaning brush 102; and a transmission belt 104 for transmitting the drive of the driving motor 103 to the rotary cleaning brush 102. The support portion 122 comprises: an arm support 105 for supporting the cleaning portion 121 enabling rotation and elevation of the cleaning portion 121; a rotary driving apparatus 111 for rotating the arm support 105; an elevating apparatus 117 for elevating the arm support 105; a rotating position detecting sensor 115 for detecting the rotating position of the cleaning brush 102; and a stop 107 for adjustably setting the position to which the swing arm 101 is lowered. The rotary driving apparatus 111, the elevating apparatus 117, the rotating position detecting sensor 115 and the stop 107 are mounted on a base 140 by means of brackets and the like. The rotary driving apparatus 111 comprises a rotary driving motor 112 for rotating the arm support 105 through the transmission belt 114, and the elevating apparatus 117 comprises an output rod 119 being in contact with a lower end portion of the arm support 105 for elevating/lowering the arm support 105. When the rotary cleaning brush 102 is located in the position illustrated in FIG. 1, a spin chuck 142 for holding the substrate 141 is provided therebelow. A rotating position detecting apparatus 115 comprises three rotating position detecting sensors 115A, 115B and 115C which detect that the rotary cleaning brush 102 is at a standby position A, a central position B of the substrate 141 and the peripheral position C of the substrate 141 shown in FIG. 1, respectively.
The operation of the swing type cleaning apparatus will be described in the following. When the substrate 141 is to be cleaned, first, the arm support 105 is raised by the elevating apparatus 115 at the standby position A shown in FIG. 1, so that the swing arm 101 is raised. Thereafter, the rotary driving motor 112 is rotated, the swing arm 101 is swung through the arm support 105, and the cleaning brush 102 is moved to a position above the central position B of the substrate 141. The cleaning brush 102 is rotated about its axis at the position B and the swing arm 101 is lowered under control of the stop 107 through the arm support 105. After the rotary cleaning brush 102 is brought into contact with the surface of the substrate 141, the rotary cleaning brush 102 is swung about the arm support 105 from the central position B to the peripheral position C of the substrate 141, so that the substrate 141 is cleaned by means of the rotary cleaning brush 102.
Usually, very fine circuit patterns are formed on the surface of the substrate 141 before or after the step of cleaning. Therefore, the substrate must be handled delicately in cleaning so as to prevent any minute damage on the surface of the substrate. As the degree of integration of the IC circuits has been increased, it has become necessary to more delicately treat the substrate to prevent any damage on the substrate, to remove dust more completely, etc.
In the above described conventional cleaning apparatus, when the cleaning brush 102 is brought into contact with the substrate 141, the brush is lowered at the operational velocity of the output rod 119 of the elevating apparatus 117. Consequently, the edge of the cleaning brush 102 strikes the surface of the substrate 141 with relatively large energy. Especially, when the brush has a smaller contact area, the shock at the time of contact becomes larger. Consequently, the surface of the substrate is damaged and the above described strict conditions of cleaning are not satisfied. | {
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1. Field of the Invention
The present invention relates to novel pharmaceutical compositions and methods of treatment that utilize or comprise tetrac (3,3xe2x80x2,5,5xe2x80x2-tetraiodothyroacetic acid), a natural metabolite of the thyroid hormone T4 (L-thyroxine). Pharmaceutical compositions of the invention are capable of suppressing the secretion of thyroid stimulating hormone (TSH) while reducing or avoiding the thyromimetic stimulation of peripheral tissues as compared to an equivalent TSH-suppressive dose of L-thyroxine.
2. Background
The thyroid is a bilobal gland located at the base of the neck in front of the windpipe. It produces a variety of hormones that regulate body metabolism and organ function and thus affects such things as heart rate, cholesterol level, body weight, energy level, muscle strength and skin condition, among other things. The thyroid hormones bind to protein receptors closely associated with DNA in the nucleus of the cells of the body thereby regulating the transcription of DNA and the translation of RNA. Therefore, the metabolic effects of the thyroid hormones derive from their ability to regulate the turnover of enzymes and proteins in the body.
The amount of thyroid hormone present in the body is carefully regulated by a feedback mechanism involving the hypothalamus, pituitary and thyroid glands. The hypothalamus produces thyrotropin releasing hormone (TRH) which causes the pituitary to produce thyroid stimulating hormone (TSH). TSH stimulates the thyroid to produce T4 (thyroxine) and T3 (3,3xe2x80x2,5-triidodothyronine), the two major thyroid hormones (FIG. 1). The levels of T4 and T3 in the blood are monitored by the pituitary which will produce more TSH if the thyroid hormone levels are too low and less TSH if the levels of T3 and T4 are too high.
T4 is the principal secretory product of the thyroid gland while T3 is the most potent thyroid hormone due to its high binding affinity for the thyroid hormone nuclear receptors. Secretion of TSH from the pituitary gland is exquisitely sensitive to inhibition by T3. Although T3 is only secreted by the thyroid gland in small amounts, its principle source in the pituitary gland is through the local conversion of T4 to T3 by the pituitary specific enzyme, monodeiodinase type II. The control of pituitary TSH secretion therefor depends on the activity of this monodeiodinase. As the circulating concentrations of T4 approach normal levels, T4 suppresses the activity of the pituitary specific monodeiodinase type II thus reducing T3 generation and effectively releasing the pituitary from further suppression. The ability of T4 to control the suppression of TSH secretion accounts for the feedback regulation of T4 on its own secretion and the normal set-point of the thyroid-pituitary axis.
The presence of too much or too little thyroid hormone in the body leads to abnormalities which can become life-threatening if left untreated. The presence of too much thyroid hormone leads to hyperthyroidism. Hyperthyroidism, or overactivity of the thyroid gland, has several causes and amongst other symptoms causes anxiety, insomnia, weight loss and rapid heart rate. Hyperthyroidism is treated by destruction of all or part of the thyroid gland by surgical removal, treatment with radioiodine, or both, and with drugs that block the synthesis of the thyroid hormones.
The presence of too little thyroid hormone leads to hypothyroidism which is more common than hyperthyroidism. Hypothyroidism, or underactivity of the thyroid gland, has several causes and amongst other symptoms causes lassitude, weakness, weight gain and slow heart rate. Hyperthyroidism is treated by lifelong replacement with synthetic thyroid hormones, usually L-thyroxine.
Abnormal growths or cancers of the thyroid gland are presently treated by surgical removal of the gland followed by radioiodine to destroy any remaining thyroid tissue. This is followed by chronic treatment with supraphysiologic doses of T4 to suppress the secretion of TSH from the pituitary gland, thereby preventing stimulation of residual thyroid cancer cells expressing the TSH receptor. These supraphysiologic suppressive doses of T4 unavoidably lead to mild hyperthyroidism.
Other metabolites of the thyroid hormones are tetrac (3,3xe2x80x2,5,5xe2x80x2-tetraiodothyroacetic acid) and triac (3,3xe2x80x2,5-triiodothyroacetic acid) which are produced by the deamination of T4 and T3, respectively (FIG. 1). Tetrac is a prohormone of triac and is converted by two enzymes, the same monodeiodinase type II found in the pituitary and to some extent elsewhere in the brain and at low expression in the heart and thyroid gland and monodeiodinase type I found in the liver and other peripheral tissues that converts T4 to T3. Triac is also a potent inhibitor of TSH secretion and has been investigated as a substitute for T4 in treating thyroid patients after thyroidectomy. However, because of its potent thyromimetic activity in peripheral tissues and very short plasma half-life, triac was found to be an unsuitable substitute for T4 for this purpose. However, triac has been found to be useful in treating a rare form of thyroid hormone resistance.
Thus, it would be extremely desirable to develop novel pharmaceutical compositions capable of suppressing TSH secretion while reducing or avoiding the iatrogenic hyperthyroidism induced by comparable TSH-suppressive doses of T4 (L-thyroxine).
See also: Bracco, D., et al. J. Clin. Endocrinol. Metab., 77: 221-228 (1993); Burger, A. G. and Vallotton, M. B., xe2x80x9cThe metabolism of tetraiodothyroacetic acid and its conversion to triiodothryoacetic acid,xe2x80x9d Thyroid Hormone Metabolism, pages 223-239, W. A. Harland and J. S. Orr, editors, Academic Press, London, New York, San Francisco, (1975); Burger, A. G. et al. Acta Endocrinologica, 92: 455-467 (1979); Goolden, A. W. G., et al. The Lancet, 1: 890-891 (1956); Green, W. L. and Ingbar, S. H. J. Clin Endocr., 21: 1548-1565 (1961); Lerman, J. and Pitt-Rivers, R. J. Clin. Endocrinol. Metab., 16: 1470-1479 (1956); Lerman, J., J. Clin. Endocr., 21: 1044-1053 (1961); Liang, H., et al. Eur. J. Endocrinol., 137: 537-544 (1997); Menegay, C., et al. Acta Endocrinol. (Copenh), 121: 651-658 (1989); and Richardson-Hill, S., et al. J. Clin. Invest., 39: 523-533 (1960).
The present invention provides novel pharmaceutical compositions comprising tetrac which are capable of suppressing TSH secretion while reducing or avoiding the thyromimetic stimulation of peripheral tissues induced by a dose of L-thyroxine which produces an equivalent TSH-suppressive effect. The invention further provides pharmaceutical composites that comprise a combination of tetrac and L-thyroxine (T4).
Preferred pharmaceutical compositions are capable of suppressing TSH secretion while reducing or avoiding the thyromimetic stimulation of the tissues of the heart, liver, kidneys, muscle and bone as compared to the stimulation of said tissues induced by a dose of L-thyroxine which produces an equivalent TSH-suppressive effect.
The compositions of the present invention are capable of suppressing TSH secretion without suppressing the activity of the pituitary specific type II monodeiodinase.
The invention provides a method for suppressing TSH secretion while reducing or avoiding the thyromimetic stimulation of peripheral tissues induced by a dose of L-thyroxine which produces an equivalent TSH-suppressive effect comprising administration of a pharmaceutical composition comprising tetrac.
The method of the present invention may be used to treat patients suffering from malignancies or other abnormal growths of the thyroid gland. The method of the present invention is particularly useful for suppressing the growth of residual thyroid tissue in a thyroid cancer patient post thyroidectomy.
Tetrac is a natural metabolite of thyroxine (T4), the main secreted thyroid hormone. The thyromimetic potency of tetrac is less than triac because of its lower binding affinity for the thyroid hormone nuclear receptors. Additionally, tetrac is locally converted to triac, a potent inhibitor of TSH secretion, by the pituitary specific type II monodeiodinase. Due to its long half-life, tetrac assures a constant supply of triac and the small amounts of locally produced triac in the pituitary and its rapid metabolic half-life limits the thyromimetic activity of triac in other tissues of the body. Moreover, tetrac, unlike T4, does not suppress the activity of the pituitary specific monodeiodinase as its concentration in the plasma is increased. Therefore, following conversion to triac, tetrac is capable of suppressing TSH in an unrestrained fashion. In addition, tetrac is less thyromimetic in peripheral tissues as compared to T4 and is pharmaceutically more elegant than triac because of its longer plasma half-life.
Other aspects of the invention are disclosed infra. | {
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Broadband communication networks provide high-speed data communication to many residential neighborhoods and commercial locations. To achieve efficient and reliable data transmission over a broadband communication link, sampling clocks used to sample and receive data must acquire synchronization with the transmitted data stream. In many broadband communication systems, downstream data is broadcast from a central office to all network units served by the central office. A particular network unit will decode only those portions of the downstream data which are addressed to it. As such, the downstream data link is relatively long-lived and the time to initially acquire sampling clock synchronization will have negligible effect on the performance of the downstream data link.
However, many broadband communication systems do not provide a similar long-lived data link for upstream data. Instead, the upstream data link is shared such that each network unit served by the central office is assigned a particular window during which the network unit may transmit its upstream data. The sampling clocks used to sample and receive data sample on the upstream data link must, therefore, resynchronize with each network unit each time the network unit's transmission window begins. Because the transmission windows are usually not long-lived, the time to acquire resynchronization may have a significant impact on the performance of the upstream data link. | {
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Electronic article surveillance (EAS) systems are often used to prevent unauthorized removal of articles from a protected area, such as a library or retail store. An EAS system usually includes an interrogation zone or corridor located near the exit of the protected area and markers or tags attached to the articles to be protected. EAS systems have been based on magnetic, RF, microwave and magneto-strictive technologies. Regardless of the particular technology involved, the EAS systems are designed such that the tag will produce some characteristic response when exposed to an interrogating signal in the corridor. Detection of this characteristic response indicates the presence of a sensitized tag in the corridor. The EAS system then initiates some appropriate security action, such as sounding an audible alarm, locking an exit gate, etc. To allow authorized removal of articles from the protected area, tags that are either permanently or reversibly deactivatable (i.e., dual status tags) are often used.
In the ideal case, the EAS system initiates an alarm sequence only when a sensitized tag is present in the corridor. However, EAS systems are sensitive to electromagnetic interference in their operating environment which can interfere with detection of a sensitized tag or can cause false alarms. The degree of sensitivity to interference depends on a variety of factors, such as the type of EAS system, the operating bandwidth of the system, the bandwidth and statistical characteristics of the interference, and the system receiver design. Many EAS systems operate at a frequency of approximately 10 to 40 KHz. This frequency band may contain significant asynchronous interference in a library environment, principally from CRTs and TVs. Depending on their distance from the EAS system, these sources of interference can impair or disable detection ability.
Synchronous interference can be synchronous with either the power line signal or with the EAS system itself. Interrogation synchronous interference occurs when the drive field signal generated during an interrogation activates other objects in the environment, such as metal door frames, metal wall studs, metal gates or other metal objects. These objects then emit a signal which is often similar to the characteristic response of a magnetic tag. Power line synchronous interference is noise that tends to occur during the same point relative to the phase of the power line signal. Both interrogation and power line synchronous interference can reduce the ability of an EAS system to detect a sensitized tag or can cause false alarms.
When noise is spectrally overlapping, as with the types of interference described above, it is very difficult to suppress using conventional linear filtering methods. Because the spectral signature of the magnetic tag is broadband, any in-band filtering of the received signal to remove interference will distort the signal of interest. In a linear filtering scheme, a trade-off exists between filtering the noise and distorting the signal of interest. Thus, a linear filtering scheme alone may not increase the reliability of an EAS system. | {
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One conventional manner of fabrication of a zener diode on an integrated circuit is to form the zener diode during the same processing steps used to form the bipolar transistors on the silicon wafer. Referring to FIGS. 1 and 2, the P+ anode region 11 of the diode is formed in the N epitaxial region 12 during the base diffusion of the bipolar transistor and the cathode region 13 is formed during the emitter diffusion, the diode structure also including the N+ buried layer region 14 and the isolation regions 15. At the time of diffusion of the cathode region 13, an N+ contact region 16 is diffused into the N epitaxial layer 12. A metallic interconnect 17 extending over the oxide layer 18 connects the region 13 with the epitaxial layer contact 16; a metal contact 19 is also provided for the anode region 11. The contact 17 is connected to the positive source of voltage supply and contact 19 is connected to the negative side.
As the voltage across terminals 17 and 19 increases, a point is reached where the zener diode avalanches and the current rapidly increases from zero to some maximum level. A typical voltage at which avalanche occurs is 6-7 volts.
One major problem with such forms of zener diode is that the voltage at which the avalanche occurs drifts with time. This is due to the fact that the junction avalanche initially starts at the point where the junction 20 abutts the oxide layer 18, i.e. at the surface of the semiconductor body. There is a fringing of the electric field at this point along the surface and any factor that influences this electric field will influence the zener voltage. The oxide will usually contain contaminants, for example sodium atoms; these sodium atoms have a plus charge and are very mobile in the oxide 18 even at room temperature. If these sodium atoms come near the junction 20, they bend the depletion layers at the surface and affect the breakdown voltage. Therefore, the breakdown voltage is a function of the electric field at the surface and may increase as a function of time, and the circuit may drift out of specification existing at first use.
A second disadvantage is that the zener voltage is dependent on the diffusion depths and other parameters of the diffused areas 11 and 13, and these in turn are a function of the deposition steps used to make the other transistors on the IC. Therefore the zener diode specifications are principally determined by considerations other than good zener diode parameters. | {
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1. Field of the Invention
The present invention relates to an organic electroluminescent device and organic electroluminescent display device having enhanced efficiency.
2. Discussion of the Related Art
With the advent of the information era, the field of displays, which visually display electrical information signals, has rapidly developed. In line with such trend, a variety of ultra-thin and light flat display devices with low power consumption have been developed.
Examples of such flat display devices include, but are not limited to, a liquid crystal display (LCD) device, a plasma display panel (PDP) device, a field emission display (FED) device, and an organic light emitting device (OLED).
In particular, OLEDs are self-emissive and have faster response time, higher luminous efficacy, higher brightness and wider viewing angle than other flat display devices. An OLED includes an anode, a hole injection layer, a hole transport layer, an emission layer, an electron transport layer, an electron injection layer, and a cathode.
Such OLEDs include, between first and second electrodes, a single light emitting unit including a hole injection layer, a hole transport layer, an emission layer, an electron transport layer, and an electron injection layer. However, recently, multiple light emitting units are formed between first and second electrodes.
However, blue light emitting units included in conventional multiple light emitting units include fluorescent blue emission layers. In this regard, a blue emission layer has a lower efficiency than emission layers that realize other colors and thus total panel efficiency is also reduced. | {
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(a) Field of the Invention
The present invention relates to an optical system for endoscopes provided with a relay lens comprising an inhomogeneous lens whose refractive index reduces progressively in going from a center portion toward a periphery.
(b) Description of the Prior Art
Since an inhomogeneous lens has a refracting power in medium per se and retains an imaging function only in the configuration of a tiny rod-shaped member even though its end surface is not ground to a spherical surface, it is used as an image transmitting optical system for extremely fine endoscopes. An example of the optical system for endoscopes provided with the image transmitting optical system of the type is given in FIG. 1. In this figure, reference numeral 1 denotes an objective lens unit composed of two plano-convex lenses whose convex surfaces are arranged in such a manner as to face to each other and forming an image M.sub.1 of an object M on a plane of exit thereof. To this plane of exit is cemented an inhomogeneous rod lens 2 having a length of nP (P is the pitch of an inhomogeneous medium which brings about, for example, twice relay functions, namely, imaging functions with a length of 1P and n is the positive integer) and on an exit end face of the inhomogeneous rod lens is cemented a cover glass 3 keeping dirt off the exit end face and preventing an object image M.sub.2 formed on the exit end face from being viewed together with dirt. The optical arrangement on the rear side of the cover glass 3 comprises a relay lens unit 4 for erecting the object image M.sub.2 formed by the inhomogeneous rod lens 2 and correcting chromatic aberration of magnification and axial chromatic aberration which are generated through the inhomogeneous rod lens 2, an aperture stop 5 arranged in an pupil position of the relay lens unit 4 and allowing the reduction of flare as well as the adjustment of a depth of field and the uniformity of brightness in a visual field, a field lens 6 arranged on the rear side of the relay lens unit 4 and adjusting the position and size of an eye point ExP, a field stop 7 disposed in an imaging position of an image M.sub.3 formed through the relay lens unit 4 and the field lens 6, an eyepiece 8 arranged behind the field stop 7 and magnifying the image M.sub.3 defined by the field stop 7, and a cover glass 9 disposed behind the eyepiece 8.
In such an optical system, although individual optical components are arranged so that the object image produced through the objective lens unit 1 is formed on an entrance end face and exit end face of the inhomogeneous rod lens 2, a problem has been encountered that it is difficult for the inhomogeneous rod lens 2 to prevent the periphery of the entrance and exit end faces from being damaged into fine flaws (a so-called burr) when the end faces are polished and as such, in the above arrangement, the burr will be viewed together with the object image and will bring troubles of observation. Further, another problem has arisen that, during the assembly of the optical system, if minute dust adhering to a lens frame and the like and dirt such as cutting chips of metal parts are attached to the entrance end face of the inhomogeneous rod lens 2, they will be viewed together with the object image and will cause observation to be difficult. In addition, there also has been a problem that since the relay lens unit 4 consists of two lens groups, the manufacturing cost of the entire optical system is high.
An optical system disclosed in, for example, Japanese Utility Model Preliminary Publication No. Sho 55-147013, proposed with the intention of solving these problems makes use of an inhomogeneous rod lens 10, as shown in FIG. 2, with a length of (n/2)P somewhat different (the rod lens shown is some shorter than (n/2)P from that of FIG. 1 and is designed so that the image M.sub.2 transmitted through the rod lens is formed in front or rear of the exit end face of the inhomogeneous rod lens 10 and so that the image is directly observed through the eyepiece 8. According to this structure, although the dirt and flaws on the exit end face of the inhomogeneous rod lens 10 are not viewed, a problem has been posed that the dirt and flaws on the entrance end face are still viewed along with the object image and as such observation is difficult. Also, there has been a problem that since the structure fails to include any optical system for correcting the chromatic aberration produced through the inhomogeneous rod lens 10, the image will suffer considerable deterioration. Further, although it is considered that the aperture stop is disposed on the side of the objective lens unit 1, namely, at a point A indicated in FIG. 2 because there is no space sufficient to place the aperture stop on the rear side of the inhomogeneous rod lens 10, it has been extremely difficult for the accuracy and making of parts to provide a doughnut-shaped stop in the objective lens which is no more than 1 mm in diameter. | {
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The present invention relates generally to the manufacture of metallic containers, and more particularly to an integrated machine station for forming cans from metallic blanks and trimming and cleaning them.
Many different methods and apparatus for manufacturing metallic containers such as cans have long been known. In past years cans were typically of the "three piece" variety, i.e., a sidewall, and two separate end members. Such cans were formed by rolling flat stock into a hollow cylinder, forming and sealing an axial seam, applying and seaming a bottom end, then filling the container and applying a top. In recent years more and more cans of the drawn and ironed variety have been produced. Cans of this type are formed by drawing a disk-like blank into a shallow cup, then forcing the cup through a set of annular dies of decreasing diameter so that the cup is stretched and deepened to form a can. The lip about the open end of the can is typically irregular and ragged, and accordingly must be trimmed to form a regular upper edge, simultaneously sizing the height of the can. Finally, metal particles, lubricants and other foreign matter must be removed from the cans before printing or filling, and accordingly such cans are typically transported through elongate chambers where they are washed, rinsed with deionized water or the like, then dried and finally printed.
Despite advances in apparatus for forming the cans, such as for instance the draw-and-ironing machine disclosed in U.S. Pat. No. 4,007,620 issued Feb. 15, 1977, transportation of cans from one stage to another has continued to be a problem. In fact, more cans are damaged during transfer than during the actual processing or manufacturing operations. Although conveyors per se have been improved and newer forms thereof introduced, the basic approach to transporting numerous small articles, such as cans, has remained substantially the same. Cans produced by one stage are accumulated upon a conveyor, and fed to a subsequent stage. Each conveyor commonly provided buffering areas wherein cans could be accumulated in the event that a preceding stage produced more than could be accommodated by a succeeding stage. Such buffering areas absorb valuable floor space, necessarily increasing the overall size of the requisite manufacturing areas and moreover increasing the likelihood of damage to the cans.
Further, the apparatus used for cleaning newly-manufactured cans has typically taken the form of a tunnel-like flow through system wherein cans are transported through an elongate zone wherein they are progressively washed, and then dried. Conveyors having buffering areas are typically associated with either or both ends of the cleaning stage, further adding to the amount of space occupied by the apparatus.
From the foregoing, it will be understood that it would be highly advantageous to provide a unitized system for manufacturing cans, which eliminates the deficiencies of the usual prior art arrangements.
It is accordingly an object of the present invention to provide a unitized work station for manufacturing drawn and ironed can bodies.
Another object is to provide means for manufacturing cans, which occupies significantly less floor space than prior art apparatus.
Still another object is to provide a compact washer-dryer stage which may be used in direct juxtaposition with other manufacturing apparatus.
Another object is to provide a unitized can manufacturing station including a cleaning stage arranged in vertical tiers.
Yet another object is to provide a method of manufacturing metal cans which optimizes available floor space. | {
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In the manufacture of semiconductor products such as integrated circuits, individual electrical devices are formed on or in a semiconductor substrate, and are thereafter interconnected to form circuits. Interconnection of these devices is typically accomplished by forming a multi-level interconnect network in and through one or more dielectric or non-conductive layers that are formed over the electrical devices to electrically isolate the devices from one another. A conductive material, such as copper, is deposited into vias and/or trenches formed within these dielectric layers to connect the devices and thereby establish the multi-level interconnect network.
MIM (metal insulator metal) capacitors are semiconductor devices that are formed by sandwiching a thin layer or film of dielectric material between two layers of conductive material, usually metals. The metal layers can be said to comprise some or all of top and bottom electrodes, respectively, of the capacitor. Generally the bottom electrode is in contact with a conductive copper via or trench, which can also be said to comprise some of the bottom electrode of the capacitor. At times, however, the copper can diffuse from one electrode through the dielectric layer to the other electrode and “short out” or provide a conductive pathway between the two metal layers. This can substantially compromise the capacitor's ability to perform its intended function of storing charge. This deleterious effect is only enhanced through normal operation of the capacitor as the electric field induced during operation naturally enhances the undesired transport of copper from one electrode to the other. It is therefore necessary to ensure that the MIM capacitor is designed in such a manner that the functionality of the capacitor is maintained for the required lifetime of the device and that the diffusion and/or transport of copper through the dielectric layer is sufficiently controlled or eliminated to ensure such required lifetime.
It can be appreciated that several trends presently exist in the electronics industry. Devices are continually getting smaller, faster and requiring less power, while simultaneously being able to support and perform a greater number of increasingly complex and sophisticated functions. One reason for these trends is an ever increasing demand for small, portable and multifunctional electronic devices. For example, cellular phones, personal computing devices, and personal sound systems are devices which are in great demand in the consumer market. These devices rely on one or more small batteries as a power source and also require an ever increasing computational speed and storage capacity to store and process data, such as digital audio, digital video, contact information, database data and the like.
Accordingly, there is a continuing trend in the semiconductor industry to manufacture integrated circuits (ICs) with higher densities. To achieve high densities, there has been and continues to be efforts toward scaling down dimensions (e.g., at submicron levels) on semiconductor wafers. In order to accomplish such high densities, smaller feature sizes, smaller separations between features and layers, and/or more precise feature shapes are required. The scaling-down of integrated circuit dimensions can facilitate faster circuit performance and/or switching speeds, and can lead to higher effective yield in IC fabrication by providing more circuits on a semiconductor die and/or more die per semiconductor wafer, for example.
As device sizes continue to shrink, however, the close proximity of certain areas can lead to undesirable results. With regard to MIM capacitors, for example, bringing the metal layers closer together by reducing the thickness of the thin dielectric film can allow diffused copper to more readily short out the capacitor thereby compromising the capacitor's reliability and useful life. Still, a thin dielectric layer remains desirable as the capacitance, or ability of a capacitor to store charge, changes as a function of the distance between the metal plates, among other things. In particular, the capacitance goes up as the plates are brought closer together, but decreases as the plates are moved further apart. Accordingly, it would be desirable to fabricate a MIM capacitor in a manner that mitigates adverse effects associated with copper diffusion while concurrently allowing the size of the device to be reduced. | {
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A table saw can be used for cutting materials such as porcelain tile, ceramic tile, and so on. As shown in FIG. 1, a conventional table saw mainly comprises a base 11, a work table 12 supported on the base 11, a tank 13 arranged below the work table 12 for accommodating a cooling liquid, a blade 14 driven by a motor, and a guard assembly 15 mounted on the base 11.
During the cutting operation, the blade 14 is driven by the motor to perform a high-speed rotating motion, and a workpiece is positioned on the work table 12. Then the workpiece is pushed toward the blade 14 gradually by the operator to perform the cutting operation. When the blade 14 rotates at high speed, the cooling liquid in the tank 13 will be brought to a cutting area on the work table 12 by the blade 14. Thus, there is a lot of cooling liquid splashing around the cutting edge of the blade 14. In the prior art, the guard assembly 15 is used to block the splashing cooling liquid. However, the guard assembly 15 can only cover a part of the blade 14, and there is still another part of the blade 14 exposed. Therefore, the guard assembly 15 can only block a part of the cooling liquid brought by the blade, and most of the cooling liquid will splash to the operator and flow to the work table and the workpiece, as shown by arrows in FIG. 1. As a result, the clothes of the operator would be stained by the cooling liquid brought by the blade. Further, the cooling liquid blocked by the guard assembly falls on the work table or the workpiece, and stains the work table and the workpiece. | {
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Optical attenuators serve two primary purposes. The first purpose is to reduce the optical power transmitted in a system to allow for transmitter to detector balance. There is some loss of optical power over the length of a fiber optic cable. Additional optical power losses occur in each connector interface. An optical signal that travels a substantial distance between a transmitter and a detector or that travels through a number of connector assemblies will lose substantial optical power before the signal reaches a detector. Due to this loss of optical power, optical attenuators may be undesirable. On the other hand an optical signal that travels a relatively short distance through a relatively small number of connectors may have optical power at the detector that exceeds the detectors optimum optical power range. In situations in which signals with very high optical power reach a detector, it may be necessary to reduce the optical power with an optical attenuator to obtain optimum detector performance. The second purpose for employing optical attenuators is to test system performance. To test optical signal transmission systems the optical power must be reduced by a measurable quantity. Such tests can be used to test the system limits. To determine if an optical system will work when the optical power is reduced by 50% or some other selected amount, the optical power has to be reduced by 50% or another selected amount. Such a reduction is preferably made without changing the transmitter or the detector. To test the system performance as if under adverse conditions, it is necessary to degrade the system by a known quantity and then test for function. This will insure that the system will function under all conditions.
Optical attenuators that are currently used in operating optical systems either change the gap between two fiber optic cable ends or change the alignment between two fiber optic cable ends. The amount of attenuation obtained by these procedures depends on a number of different factors. These factors include fiber optic cable end shape and surface finish. Currently the ends of fiber optic cables in high performance systems are ground and polished. No two ground and polished fiber optic cable ends are exactly the same even when made in a laboratory. The variations in fiber optic cable end shapes make control of the gap between two cable ends difficult. It has not been possible to provide large air gaps in connectors that normally have abutting termini. Fiber optic cable connection end misalignment is difficult to control and measure. The misalignment angle, cable center line alignment, the gap between two cable ends, cable end shape and cable end surface condition all make a difference. Control of all these factors in the field is impossible. | {
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It is well known in the polycondensation catalyst field that there are three primary polycondensation catalysts, based on the metals titanium, antimony and germanium. Titanium (Ti) displays the highest activity but it has the disadvantage that it generates a large range of undesirable side reactions which produce a polymer with a problematic yellow discoloration. For instance, in the case of polyethylene terephthalate polymers, once the polymer is formed, it is very difficult to colour correct.
An antimony (Sb) based catalyst, such as antimony trioxide, is the most commercially used type of catalyst. However, it too requires color correction. This is believed to be due to the fact that particulate antimony remains in the polymer thereby resulting in a grey discoloration in the polymer. There is a growing health concern issue that relates to the use of antimony in manufacturing polymers that will contact food. Such food may thereby absorb antimony. Additionally there are significant environmental concerns regarding the disposal of an antimony-containing distillate which is an inevitable by-product of the polycondensation reaction. Finally, there are considerable environmental issues relating to up-stream processing of antimony catalysts.
Germanium (Ge), from a chemical and polymer discoloration viewpoint, has no negative implications as a polycondensation catalyst. However, germanium is costly and its cost is prohibitive to all but the highest quality polymer producers. Significant research has been invested in the discovery of catalyst formulations which combine the benefits of the three catalyst elements described above whilst at the same time eliminating undesirable characteristics. In the case of germanium, this essentially has led to the incorporation of additional active elements or compounds which maintain catalytic reactivity but reduce cost without adversely affecting the polymer quality. In much of the prior art, germanium has traditionally been used as a component to increase the quality of polymer produced by catalysts such as titanium or antimony.
Prior literature discloses many ways of adding germanium to a polycondensation reaction. For example Japanese patent JP 2001019753A2 published Jan. 23, 2001, assigned to Meldform Metals, details the complexing of germanium dioxide with a range of carboxylic acids, to produce an aqueous solution containing germanium dioxide in a concentration of 10 to 20 wt. %.
Other patents have disclosed the use of synergistic catalyst enhancers, containing carboxylic acids, in combination with titanium-containing catalysts. For instance, U.S. Pat. No. 6,372,879 B1, granted Apr. 16, 2002, assigned to ATOFINA Chemicals Inc., describes a range of synergistic combinations with a titanium-containing catalyst and lithium, sodium, potassium, rubidium, cesium, beryllium, magnesium, calcium, strontium, barium and ammonium salts.
U.S. Pat. No. 6,258,925 B1, granted Jul. 10, 2001, assigned to ATOFINA, discloses a titanyl oxalate catalyst and a catalyst enhancer such as a metallic oxalate, for example, lithium oxalate.
WO 00/71252 A1, published Nov. 30, 2000, assigned to ACMA Limited, discloses a catalyst composition for use in the preparation of esters, comprising an organometallic compound which is a reaction product of an orthoester or condensed orthoester of titanium, zirconium or aluminium, used in combination with a compound of germanium, antimony or tin. In this case, the preferred orthoester has the formula M(OR)4 or Al(OR)3 where M is titanium or zirconium and R is an alkyl group, and the condensed orthoester typically being of the formula R1O[M(OR1)2O]nR1. These organometallic compounds are prepared by reacting the orthoester and the metallic compound in the presence of, preferably, a dihydric alcohol such as 1,2-ethanediol.
U.S. Pat. No. 6,365,659 B1, granted Apr. 2, 2002, assigned to Toray Industries Inc., discloses a polyester composition comprising a polyester and a compound oxide of titanium as an essential element and a metal element selected from the group consisting of aluminium, zirconium germanium, tin and silicon. Specific particle size distribution for these catalysts in the polyester is stated.
WO 0156694 A1, published Aug. 9, 2001, assigned to ACMA Limited, discloses the combination of an organometallic compound containing either titanium or zirconium with a second metal from the group consisting of germanium, tin and antimony and a carboxylic acid. In the preferred embodiment a hydroxy alcohol and a base are also present.
WO 9322367 A1/EP0591488A1, assigned to Rhone Poulenc Viscosuisse SA, refers to a dual polycondensation catalyst system comprising lithium and germanium. The invention concerns a method of producing, without using antimony, a polyester from poly(ethylene terephthalate) units. Following esterification, a mixed catalyst consisting of 10 to 75 parts per million of lithium and 15 to 80 parts per million of germanium is used for polycondensation. The antimony-free polyester thus obtained is purportedly suitable for use in the manufacture of bottles, sheeting, film, fibre, filaments and molded articles.
U.S. Pat. No. 5,417,908, assigned to Rhone Poulenc Viscosuisse SA, granted May 23, 1995, describes a polyester manufactured using manganese as an esterification catalyst, de-activating the manganese with phosphoric acid and subsequently adding germanium as the primary polycondensation to form a polyethylene terephthalate polyester.
WO 99/28033, assigned to Tioxide Specialities Limited, discloses the use of an organometallic catalyst which is a reaction product of an orthoester or condensed orthoester of titanium, zirconium or aluminium, an alcohol with at least two hydroxyl groups, an organophosphorous compound and a base.
U.S. Pat. No. 6,358,578 B1, assigned to Zimmer AG, granted Mar. 19, 2002, describes a product which uses high surface area activated charcoal to promote the activity of a polycondensation catalyst such as antimony, titanium, lead, germanium, zinc and tin. | {
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Further, a drug delivery device comprising a piston rod is disclosed. The drug delivery device may be e.g. a pen-type injector.
It is an object to provide for a bearing which facilitates an improved assembly to a piston rod body. It is another object to provide for a piston rod arrangement which facilitates improved assembly of the bearing to a piston rod body. Furthermore, a novel, in particular an improved piston rod body should be provided.
This object may be achieved by a bearing for a piston rod arrangement for a drug delivery device, by a piston rod arrangement and by a piston rod body according to the independent claims. Further features, advantageous embodiments and expediencies are subject-matters of the dependent claims. | {
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Conventional postage meters have the ability to determine the weight of a mailing, calculate the postage charge by an electronic means, and print this charge on the mailing. The payment for such a charge is then either debited from a previously charged memory or paid in cash to an employee who operates the machine in a postal office. It is generally known that these devices are used for the efficient and economical stamping of postcards, letters, and packages but that they can not significantly improve the automation of the further sorting and tracking process because such mailings must go through an additional postage checking procedure. Even in the best of solutions, these mailings can be sorted only by comparatively slow scanning procedures performed by photosensitive means with a comparatively low first read rate.
Generally known devices which have the ability to print horizontally oriented clocked code on a mailing significantly improve the sorting process but demand complicated handling because such a code must be precisely printed relative to an envelope's lower edge so that both the clock and information tracks line up with their appropriate reading head. Consequently, the location of the face of a mailing is particularly important and only single-pass scanning by photosensitive transducers is possible which makes the sorting process comparatively slow and uneconomical.
Hence, it is an object of the present invention to provide a device with the ability to weigh a mailing by electronic means and, based on its destination and other data entered on an alphanumerical keyboard, automatically print any required data in the form of laser readable bar code on the mailing or on a self-adhesive label to be stuck on the mailing for the purpose of enabling a completely automatic sorting and tracking process. When using any of the bar code types which are readable by a multi-pass laser scanning means installed on both sides of a mailing driving conveyor found in sorting hubs, an extremely fast and completely automatic sorting and tracking process with an almost perfect first read rate is achievable.
Considering the fact that some countries have an alphanumeric zip code and that a combination of two letters is the most suitable form of coding, either for a country code or a special request code, an alphanumeric type bar code is preferred for use with the present invention. By printing an alphanumeric bar code on a mailing, the present invention enables faster sorting and tracking of international mail traffic because this code allows one to choose a different two-letter code for each country and for a reasonable number of special requests while occupying very little space on the mailing itself.
Another object of the present invention is to provide a device which is able to accept payment by a variety of means including by cash or check paid to an employee, or by debit cards, various types of credit cards, or IC cards. In accordance with the present invention, all of these payment means can be used, thereby giving the invention a significant advantage, particularly in countries where the postal and telephone systems are owned by the same company and where, therefore, the postage can be debited from a pay-phone debit card or be automatically charged to a customer's telephone bill. When used in corporate mail rooms, in addition to printing a bar code on the outgoing mail, the present invention can be used for printing a bar code on the internal mail so that it too can be economically and automatically sorted. | {
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Impact property modification of thermoplastic polymers by a variety of rubbers, elastomers, and rubbers combined with the thermoplastics has been known for many years. Extensive interest has been shown for at least 30 years in rubbers combined with thermoplastics in a core-shell structure, typically prepared by emulsion polymerization, as exemplified by such commercial combinations as acrylate-butadiene-styrene (ABS) or methacrylate-butadiene-styrene (MBS) impact-property modifiers for poly(vinyl chloride), acrylic/methacrylic core-shell modifiers for polycarbonate, and the like.
In the case of the amide polymers collectively known as nylons, such as nylon 6 (polycaprolactam), nylon 66 (poly(hexamethylene adipamide)), and the like, impact strength may be improved by reacting an acid or anhydride functionality on the impact-property modifier with an amine group available on the polyamide. Such functionalized modifiers include ethylene/acrylic acid copolymers (British Patent No. 998,439), metal-ion neutralized ethylene/unsaturated acid copolymers (Murch, U.S. Pat. No. 3,845,163), acrylic rubber//methyl methacrylate-co-unsaturated acid core-shell polymers as taught in Owens and Clovis, U.S. Pat. Nos. 3,66,274, 3,796,771, 3,984,497, 4,086,300 and 4,148,846. Baer (U.S. Pat. No. 4,584,344) teaches modification with a core-shell polymer consisting of a crosslinked elastomer of particle size above 300 nanometers, with a shell containing a polymer of unsaturated carboxylic acid, styrene, and optionally a lower alkyl methacrylate and/or (meth)acrylonitrile. Impact-property modifiers which adhere to nylon, of particle size 0.01 to 3 micrometers (um) and of a tensile modulus 7-138,000 kilopascals (kPa) are disclosed in Epstein, U.S. Pat. No. 4,174,358, and similar modifiers are taught in German Offenlegungschrift 3,403,576. Polyamide-toughening reactive crosslinked acrylic rubbers having an outer layer of an alkyl acrylate and a polyamide reactive graft-linking monomer are disclosed in Novak, U.S. Pat. No. 4,474,927. Blends of nylon 6 and nylon 66 toughened with an ionic copolymer of an alpha-olefin with an unsaturated carboxylic acid, the acid moeity of which is at least partially neutralized with metal basic salts, are disclosed in Roura, U.S. Pat. No. 4,478,978. Such co-reacted modifiers may also improve the processing of the nylon, allowing melt strength sufficient for blow-molding, thermoforming, and the like. The modifiers of Owens and Clovis, above, particularly related to the present invention.
General problems with incorporating impact-property modifiers into thermoplastic polymers have been (1) the difficulty of obtaining uniform dispersion of the modifier throughout the matrix polymer and (2) breaking down aggregates of the modifier to a dispersed domain within the matrix polymer having optimum size for best impact resistance, surface appearance, gloss development, absence of voids, and the like. These problems exist even when the modifier particles are quite small, as when they are made in emulsion, because the processes of isolation from emulsion and incorporation into the matrix polymer cause the particles to aggregate, and they may not be readily dispersed. Such dispersion problems are exemplified in Dunkelberger, U.S. Pat. No. 4,167,405, in which a pre-dispersion of impact-property modifier in a higher viscosity nylon is required to obtain adequate dispersion of the modifier in low molecular weight nylon.
Dunkelberger (U.S. Pat. No. 4,440,905) teaches a class of polymers effective as dispersion aids for impact-property modifiers in poly(vinyl chloride), but does not teach or suggest the compositions of the present invention, nor suggest that his technology may be used to modify nylon. Grigo, U.S. Pat. No. 4,423,186, discloses copolymers of ethylene with (meth)acrylic acid combined with crosslinked butadiene rubbers for improved low-temperature resistance. Albee et. al., U.S. Pat. No. 4,412,040, disclose that neutralized, low-molecular-weight copolymers of ethylene/unsaturated carboxylic acids act as lubricants and dispersing aids in nylon, helping disperse finely divided, dispersible, inert material. This dispersing ability as applied to nylon is not taught.
Japanese Kokai 60/60,158 discloses copolymers of aromatic vinyl monomers with unsaturated carboxylic acids microdispersed in nylon to improve mechanical properties.
Impact-property modifiers which adhere to polyesters and polycarbonates, such as zinc-neutralized ethylene/acrylate/acrylic acid terpolymers, having particle sizes from 0.01 to 3 um and tensile modulus from 7 to 138,000 kPa, are disclosed in Epstein, U.S. Pat. No. 4,172,859.
European Patent Application No. 168,652 (Campbell and Conroy) teaches improved impact-strength resistance for polyphenylene oxide when it is blended with elastomers containing highly polar groups, such as sulfonated polyethylene.
Impact-property modifiers isolated from emulsions by spray-drying or coagulation often are difficult to maintain as free-flowing powders, especially if the modifier is a core-shell polymer with high elastomer content. Several solutions to the problems of sticking to equipment walls, ready compression of the modifier under load, and poor flow in air-veying systems are taught in the literature. Ferry et al. teaches inorganic flow aids and poly(methyl methacrylate) for acrylic- and butadiene-based impact-property modifiers (U.S. Pat. Nos. 3,985,703 and 3,985,794). Grandzol et al. teaches coagulating poly(methyl methacrylate) onto a MBS modifier (U.S. Pat. No. 4,463,131). Neither teaches or suggests the additive of the present invention.
An object of the present invention is to obtain a balance of surface appearance, impact strength and tensile strength in nylon and other thermoplastic polymers which is superior to the balance obtainable with conventional impact modifiers. Another object of the invention is to improve the processing behavior of the impact-property modifiers/polymeric additive combinations with thermoplastic polymer matrices, including those with which the modifiers do and do not react. Other objects will be apparent from the following discussion of the invention. | {
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Syngas (mixtures of H2 and CO) can be readily produced from either coal or methane (natural gas) by methods well known in the art and widely commercially practiced around the world. A number of well-known industrial processes use syngas for producing various oxygenated organic chemicals.
The Fischer-Tropsch catalytic process for catalytically producing hydrocarbons from syngas was initially discovered and developed in the 1920's, and was used in South Africa for many years to produce gasoline range hydrocarbons as automotive fuels. The catalysts typically comprised iron or cobalt supported on alumina or titania, and promoters, like rhenium, zirconium, manganese, and the like were sometimes used with cobalt catalysts, to improve various aspects of catalytic performance. The products were typically gasoline-range hydrocarbon liquids having six or more carbon atoms, along with heavier hydrocarbon products.
Today lower molecular weight C1-C5 hydrocarbons (paraffins and/or olefins) are desired and can be obtained from syngas gas via Fischer-Tropsch catalytic process. There is a need to convert the paraffins and/or olefins obtained into other useful compound(s).
Accordingly, there remains a long-term market need for new and improved methods for producing useful compound(s) from syngas via intermediate low molecular weight C1-C5 hydrocarbons, such as from C2 hydrocarbons.
Accordingly, a system and a method useful for the production of polyethylene are described herein. | {
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Millboard has been used commercially for many years. It serves as thermal insulation in gaskets, linings for fire-safe cabinets, and in the glass making industry as a float roll covering material.
In the past, asbestos fibers of either the chrysotile or amphibole type have been incorporated into the starting mixture for such boards.
U.S. Pat. No. 1,594,417 (Kobbe) shows the use of a short-fibre asbestos combined with a cement binding agent and congealed sulfur to produce a high-resilient, tough, high-strength millboard.
U.S. Pat. No. 1,678,345 (Mattison) incorporates asbestos fibers into a mixture of hydraulic and calcium and aluminum carbonate to produce a millboard product.
U.S. Pat. No. 3,334,010 (Moore) utilizes both chrysotile asbestos and crocidolite (amphibole) asbestos in a millboard product.
These fibers strengthen the resulting product and provide heat resistance in high-temperature applications.
Asbestos has been shown to be a health hazard, however, and it is therefore desireable to find a suitable material for millboard use which does not contain asbestos fibers.
Asbestos-free millboard products have been developed to meet this need. One example is U.S. Pat. No. 4,308,070 (Cavicchio) which discloses a combination of a cellulosic fiber, barytes (barium sulphate), cement, and an inorganic filler such as talc, diatomaceous earth, silicates, and carbonates.
Millboards composed of washed ceramic fiber and incorporating various fillers have also been used as roll coverings for float line rolls in the manufacture of glass. These materials contain approximately twenty percent of unfiberized material, or shot, of a size less than 100 mesh (0.0059 inches). This unfiberized material causes microscopic defects in the glass sheet as it passes over the float line rolls. Another disadvantage is that these millboard products become dusty once the binder is removed. | {
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As an integrated circuit pattern has become a very narrow pattern, forming a circuit pattern of the narrower dimension than halves of the exposure wavelengths has to study in lithography technology field, where an integrated circuit pattern formed on the mask is printed onto a semiconductor wafer with ultra violet exposure light.
For example, a reference of “Photo mask gijutu no hanashi', Kougyouchousakai K. K. pp. 236-240, 1996” discloses as follows: Optical Proximity Correction technology prevents the decline of a printing accuracy to a semiconductor wafer of an integrated circuit pattern, and accuracy of integrated circuit pattern is possible to increase by correcting of circuit pattern formed on the mask.
Japanese Patent Publication No. 2710967 invented by this inventor discloses a phase shift technology which is improved resolution of printing the integrated circuit pattern on a semiconductor wafer. This is using a dark line of light interference of transmitted light by a phase difference of light set on the mask.
Japanese Patent Publication No. 2634037 discloses an exposure technology, which is improved resolution of printing the integrated circuit pattern on a semiconductor wafer. This technique uses an off-axis illumination of exposure light limited on the mask illumination.
Japanese Patent Laid-Open No. 10-303114 discloses a liquid immersion exposure equipment which does not lead to deterioration of the image performance for fine pattern by filling the room between the reduced projection lens and wafer with liquid.
Japanese Patent Publication No. 3120474 invented by this inventor discloses a projection exposure method using a phase shift mask, which is formed by overlapping an opaque pattern substrate and a phase shifter pattern substrate.
Related Japanese Patent Documents (1) Japanese Patent Publication No. 2710967 (2) Japanese Patent Publication No. 2634037 (3) Japanese Patent Laid-Open No. 10-303114 (4) Japanese Patent Publication No. 3120474
Other References
M. Hoga et al, ‘Photo the mask gijutu no hanashi’, Kougyou Chousakai K K, pp. 235-240, Aug. 20, 1996
The subject which invention tries to solve.
A semiconductor integrated circuit device has been becoming more higher integration without stopping. Minimum pattern size of semiconductor circuit of large volume production device has become narrower than 100 nm pattern.
The reduced projection exposure method has formed circuit patterns. This exposure method cannot cope with progress of integrated circuit device any more, because shorting of exposure light wavelength and enlarging of numerical aperture of projection lens have become very difficult. The technique until now cannot be taken any more. Using the above mentioned phase shift technique, it is said to cope with pattern size to the half of exposure wavelength, but it is very difficult for narrower pattern.
The exposure technology disclosed in Japanese Patent Publication No. 3120474 had problems of both increasing printed pattern deformation and miss-matching of forming a narrow pattern. This reason is a phase shift mask fabricated by overlapping an opaque pattern and a phase shift pattern.
A liquid immersion exposure equipment disclosed in Japanese Patent Laid-Open No. 10-303114 had problems of both generating of bubbles in liquid and changing of liquid temperature during exposure. And it has practical problems of photosensitive resist material and developer material.
A reduced projection exposure equipment is repeating exposure steps after changing position between projection lens and wafer surface. Then, solid material of immersion method cannot change position between a projection lens and a wafer surface, instead of liquid material.
An object of the present invention is to provide a reduced projection exposure method, which is possible to manufacture a semiconductor integrated circuits device whose circuit pattern size is less than half of exposure wavelength.
Another objective of this invention is to provide an exposure method, which is possible to printing a very narrow pattern on a semiconductor wafer, by both increasing numerical aperture of projection lens and reducing optical phase difference between ideal wave-front and actual wave-front.
Another objective of this invention is to provide a reduced projection exposure equipment for printing circuit pattern on the mask to semiconductor wafer. And another objective of this invention is to provide a mask for a semiconductor fabrication process.
Another objective of this invention is to provide a high efficient semiconductor fabrication technology by lowering investment of both development and fabrication of a semiconductor device.
Another objective of this invention is to provide a forming method of very narrow pattern which pattern size is narrower than exposure wavelength, by overcoming surface roughness of both an insulator film and a conductor film on a semiconductor wafer.
Another objective of this invention is to provide a method of forming a circuit pattern whose pattern size is narrower than exposure wavelength, by solving problems of both micro bubbles and liquid temperature in the liquid immersion exposure.
Another objective of this invention is to provide a circuit design method of reduced cost for a new fine circuit development.
Another objective of this invention is to provide a exposure method of reduced mask fabrication cost, by using an opaque mask instead of a phase-shift mask.
The above-mentioned objects and other objects of the present invention, and new features thereof will be apparent from the description of the present specification and attached drawings. | {
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} |
There are numerous examples of catheters and other implantable medical devices that are placed into a patient's vasculature for prolonged periods of time, such as central venous catheters (“CVCs”), implantable ports (“Ports”), dialysis catheters and peripherally-inserted central catheters (“PICCs”). These devices may be used to deliver therapeutic agents and other fluids to patients over numerous weeks.
Inherent with the use of medical devices that are placed into a patient's vasculature or other blood-containing environments is the aggregation of platelets on the device surface, thus leading to a risk of thrombus formation, which can, in turn, result in catheter complications including both catheter related blood stream infection and thrombosis. Thrombus formation on catheter surfaces has been the subject of much research and product development efforts. For example, attempts to minimize thrombus formation on catheter surfaces have the incorporation of heparin, albumin and endothelial cells on the catheter surfaces. The permanent binding of biologically active moieties to catheter polymer chains or polymer surfaces has also been studied.
In U.S. Pat. No. 6,127,507, which is incorporated herein by reference for all purposes, it is proposed to use certain fluoroalkyl surface-modifying macromolecules in admixture with elastomers for the manufacture of blood-contacting medical devices. It is believed that the use of such macromolecules can result in a reduction in thrombosis formation on the medical device surfaces.
While additives such as fluoropolymers and other materials may impart beneficial properties to implantable medical devices, their addition to polymeric materials used to manufacture the medical devices may also adversely impact mechanical properties. The purity of such additives may also adversely impact these properties. As such, there is a need for additive compositional and/or purity requirements that yield advantageous anti-thrombogenic properties without compromising desired mechanical properties of medical devices made from materials that incorporate such additives. | {
"pile_set_name": "USPTO Backgrounds"
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Flexible flat cables are widely used in various electronic products, such as notebook computers, personal digital assistants, and mobile phones. A conventional flexible flat cable comprises a plurality of conductors that are each enclosed by an insulation layer and are arranged to juxtapose each other to form a flat structure. A connector or soldering is provided on the flat cable for transmission of electronic signals.
A flexible flat cable is characterized by reduced thickness and flexibility, and this often leads to improper and unstable insertion when the flexible flat cable is inserted into a mating connection slot. To overcome such a problem, it is often to add an insertion device at a leading end of the flexible flat cable to improve mechanical stability, as well as stability for electrical engagement for insertion. The insertion device is composed of a metal piece and a plastic piece.
To assemble, the metal piece is first fit over the flexible flat cable and then the plastic piece is positioned on a predetermined section of the flexible flat cable. The metal piece is slid forward to fit over and cover the plastic piece. Under this condition, the insertion section of the flexible flat cable may then be used to insert into an insertion slot.
Although this known structure of insertion device helps improving the engagement stability of the insertion device in an insertion operation, it is not constructed for protection against electromagnetic wave. It leads to an insufficiency of electromagnetic wave protection of the flexible flat cable at the section where the insertion device is mounted.
Further, although the known insertion device is adopted to overcome the problems of improper and unstable insertion, the known insertion device does not provide sufficient mechanical stability for the front end portion thereof. | {
"pile_set_name": "USPTO Backgrounds"
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Sequence-specific hybridization of oligonucleotide probes has long been used as a means for detecting and identifying selected nucleotide sequences, and labeling of such probes with fluorescent labels has provided a relatively sensitive, nonradioactive means for facilitating detection of probe hybridization. Recently developed detection methods employ the process of fluorescence energy transfer (FET) for detection of probe hybridization rather than direct detection of fluorescence intensity. Fluorescence energy transfer occurs between a donor fluorophore and an acceptor dye (which may or may not be a fluorophore) when the absorption spectrum of one (the acceptor) overlaps the emission spectrum of the other (the donor) and the two dyes are in close proximity. The excited-state energy of the donor fluorophore is transferred by a resonance dipole-induced dipole interaction to the neighboring acceptor. This results in quenching of donor fluorescence. In some cases, if the acceptor is also a fluorophore, the intensity of its fluorescence may be enhanced. The efficiency of energy transfer is highly dependent on the distance between the donor and acceptor, and equations predicting these relationships have been developed by Forster (1948. Ann. Phys. 2, 55-75). The distance between donor and acceptor dyes at which energy transfer efficiency is 50% is referred to as the Forster distance (R.sub.o). Other mechanisms of fluorescence quenching are also known including, for example, charge transfer and collisional quenching.
Energy transfer and other mechanisms which rely on the interaction of two dyes in close proximity to produce quenching are an attractive means for detecting or identifying nucleotide sequences, as such assays may be conducted in homogeneous formats. Homogeneous assay formats are simpler than conventional probe hybridization assays which rely on detection of the fluorescence of a single fluorophore label, as heterogenous assays generally require additional steps to separate hybridized label from free label. Typically, FET and related methods have relied upon monitoring a change in the fluorescence properties of one or both dye labels when they are brought together by the hybridization of two complementary oligonucleotides. In this format, the change in fluorescence properties may be measured as a change in the amount of energy transfer or as a change in the amount of fluorescence quenching, typically indicated as an increase in the fluorescence intensity of one of the dyes. In this way, the nucleotide sequence of interest may be detected without separation of unhybridized and hybridized oligonucleotides. The hybridization may occur between two separate complementary oligonucleotides, one of which is labeled with the donor fluorophore and one of which is labeled with the acceptor. In double-stranded form there is decreased donor fluorescence (increased quenching) and/or increased energy transfer as compared to the single-stranded oligonucleotides. Several formats for FET hybridization assays are reviewed in Nonisotopic DNA Probe Techniques (1992. Academic Press, Inc., pgs. 311-352). Alternatively, the donor and acceptor may be linked to a single oligonucleotide such that there is a detectable difference in the fluorescence properties of one or both when the oligonucleotide is unhybridized vs. when it is hybridized to its complementary sequence. In this format, donor fluorescence is typically increased and energy transfer/quenching are decreased when the oligonucleotide is hybridized. For example, a self-complementary oligonucleotide labeled at each end may form a hairpin which brings the two fluorophores (i.e., the 5' and 3' ends) into close proximity where energy transfer and quenching can occur. Hybridization of the self-complementary oligonucleotide to its complement on a second oligonucleotide disrupts the hairpin and increases the distance between the two dyes, thus reducing quenching. A disadvantage of the hairpin structure is that it is very stable and conversion to the unquenched, hybridized form is often slow and only moderately favored, resulting in generally poor performance. A "double imperfect hairpin" scheme is described by B. Bagwell, et al. (1994. Nucl. Acids Res. 22, 2424-2425; U.S. Pat. No. 5,607,834). Kramer and Tyagi (1996. Nature Biotech. 14, 303-308) describe a hairpin with the detector sequence in a loop between the arms of the hairpin.
Homogeneous methods employing energy transfer or fluorescence quenching for detection of nucleic acid amplification have also been described. R. Higuchi, et al. (1992. Biotechnology 10, 413-417) disclose methods for detecting DNA amplification in real-time by monitoring increased fluorescence for ethidium bromide as it binds to double-stranded DNA. The sensitivity of this method is limited because binding of the ethidium bromide is not target specific and background amplification products are also detected. L.G. Lee, et al. (1993. Nuc. Acids Res. 21, 3761-3766) disclose a real-time detection method in which a doubly-labeled detector probe is cleaved in a target amplification-specific manner during PCR. The detector probe is hybridized downstream of the amplification primer so that the 5'-3' exonuclease activity of Taq polymerase digests the detector probe, spearating two fluorescent dyes which form an energy transfer pair. Fluorescence intensity increases as the probe is digested. Published PCT application WO 96/21144 discloses continuous fluorometric assays in which enzyme-mediated cleavage of nucleic acids results in increased fluorescence. Fluorescence energy transfer is suggested for use in the methods, but only in the context of a method employing a single fluorescent label which is quenched by hybridization to the target. There is no specific disclosure of how a restriction endonuclease would be used in a fluorescence energy transfer system.
Energy transfer and fluorescence quenching detection methods have also been applied to detecting a target sequence by hybridization of a specific probe. Japanese Patent No. 93015439 B discloses methods for measuring polynucleotides by hybridizing the single-stranded target to a single-stranded polynucleotide probe tagged with two labels which form an energy transfer pair. The double-stranded hybrid is cleaved by a restriction enzyme between the labels and fluorescence of one of the labels is measured. A shortcoming of this method is that the restriction site in the probe must also be present in the target sequence being detected. The patent does not describe adaptation of the probe for use in assays where the target sequence does not contain an appropriate restriction site or where cleavage of the target is not desired. S. S. Ghosh, et al. (1994. Nucl. Acids Res. 22, 3155-3159) describe restriction enzyme catalyzed cleavage reactions of fluorophore-labeled oligonucleotides which are analyzed using fluorescence resonance energy transfer. In these assays, the complementary oligonucleotides are hybridized (not amplified) to produce the double-stranded restriction site, and one of the fluorescent labels is linked to each of the two strands (i.e., they are not linked to the same strand, see FIG. 1 of Ghosh, et al.). S. P. Lee, et al. (1994. Anal. Biochem. 220, 377-383) describe fluorescence "dequenching" techniques using restriction endonucleases to cleave double-stranded DNA. However, these methods relate to assays employing only a single fluorescent label which is quenched by interaction with the DNA, not by fluorescence energy transfer from a second fluorescent label. The observed quenching effect may therefore be sequence-specific and not generally applicable. Hybridization of the labeled oligonucleotide to its complement and cleavage of the double-stranded restriction site relieved non-transfer quenching of the label and quenched fluorescence was totally recovered.
Signal primers (sometimes referred to as detector probes) which hybridize to the target sequence downstream of the hybridization site of the amplification primers have been described for use in detection of nucleic acid amplification (U.S. Pat. No. 5,547,861). The signal primer is extended by the polymerase in a manner similar to extension of the amplification primers. Extension of the amplification primer displaces the extension product of the signal primer in a target amplification-dependent manner, producing a double-stranded secondary amplification product which may be detected as an indication of target amplification. The secondary amplification products generated from signal primers may be detected by means of a variety of labels and reporter groups, restriction sites in the signal primer which are cleaved to produce fragments of a characteristic size, capture groups, and structural features such as triple helices and recognition sites for double-stranded DNA binding proteins. Examples of detection methods for use with signal primers are described in U.S. Pat. No. 5,550,025 (incorporation of lipophilic dyes and restriction sites) and U.S. Pat. No. 5,593,867 (fluorescence polarization detection). | {
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1. Field
One or more embodiments relate to a three-dimensional (3D) display device for providing an input-output interface using a dynamic magnetic field control and method thereof.
2. Description of the Related Art
In recent times, developments in display technology for generating a three-dimensional (3D) image have witnessed a great deal of progress. Accordingly, there is a need for a development in interface technology for interacting with the 3D image. | {
"pile_set_name": "USPTO Backgrounds"
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1. Field of the Invention
The present invention relates to a magnetic resonance imaging apparatus as a medical diagnostic device and a position setting support method thereof, and more particularly to a magnetic resonance imaging apparatus which is used when, e.g., reception coils should be more accurately set and stores patient information in, especially, a medical picture archiving and communication system (PACS) through a network.
2. Description of the Related Art
In recent years, when examining a patient (a test subject), imaging an imaging target region of the same patient under the same imaging conditions as before and after an operation or follow-up is often desired in a magnetic resonance imaging apparatus.
Further, in regard to a medical diagnostic imaging apparatus, for example, Jpn. Pat. Appln. KOKAI Publication No. 10-258064 discloses an apparatus that positions and fixes a head region of a test subject. Furthermore, Jpn. Pat. Appln. KOKAI Publication No. 2006-167042 discloses an apparatus that simultaneously displays a comparison image based on a recorded image acquired from a past examination and a scan image acquired from a current examination in an overlapping manner and obtains an image at a position substantially the same as that in the past examination in accordance with matching of display positions of these images.
However, in the apparatus disclosed in Jpn. Pat. Appln. KOKAI Publication No. 10-258064, since a region examined by the diagnostic imaging apparatus is not restricted to a head region, it is considered that condition matching means having higher general versatility is required. Moreover, providing such an apparatus leads to increase in cost, and there is also a concern about a burden imposed on a test subject whose head region is forcibly fixed during an examination. Additionally, since a time to fix a head region is required, an examination time may become long. Further, although a test subject is fixed by using, e.g., a fixing band, an imaging cloth, or a net, this imposes a considerable burden on the patient.
Furthermore, in the apparatus disclosed in Jpn. Pat. Appln. KOKAI Publication No. 2006-167042, there is no description about setting reception coils such as a magnetic resonance imaging apparatus.
In case of the magnetic resonance imaging apparatus, an image may become completely different depending on how reception coils are set even though imaging is carried out under the same conditions. Therefore, a method of recording, e.g., coil names or coil positional information in a previous examination is adopted.
However, even if such a method is adopted, there is no method that is suitable for recording a relative position relationship between reception coils and a test subject that is the biggest problem, and a countermeasure must be taken. | {
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1. Field of the Invention
This invention relates generally to detectors with tunable spectral responses, including for example infrared (IR) detectors.
2. Description of the Related Art
For many applications in infrared sensing, it would be desirable to use a focal plane array (hereinafter referred to as “FPA”) with a tunable spectral response that can be tuned to aid in the detection of a particular type of target or the classification of a target to one of known classes of targets. The spectral response ideally could be optimized for use under particular imaging or detection/classification scenarios or to generate multispectral or hyperspectral images, which have a spectral radiance sampled at many wavelengths at each pixel in a scene. Typically, spectral tunability is obtained using an optical or electro-optical technique.
For example, one approach to spectral tunability uses multiple and/or tunable wavelength filters located upstream of the detector elements. This approach typically is capable of implementing between approximately 3 to 15 spectral bands. Images for the different spectral bands can be collected sequentially in time, by using a single detector element (or focal plane) and switching (or spectrally tuning) the wavelength filters as a function of time. Alternately, the different spectral bands can be collected simultaneously in time by using multiple detector elements, each utilizing a different wavelength filter. However, a mechanical switching or tuning system limits the frame-rate of the device and can be cumbersome and prone to mechanical failure. On the other hand, the use of multiple focal planes typically requires complex optical systems, which also lead to bulky and expensive solutions that are limited in the total number of available spectral bands.
Because of these limitations, hyperspectral sensors with more than 100 spectral bands typically use some sort of a shearing optic, such as a grating or prism, to separate the light incident on the sensor into either spectral or interferometric paths. A first spatial dimension of the FPA is typically used to collect the spectral data and a second spatial dimension is used to collect a line image. The second spatial dimension is obtained through scanning. Other strategies instantaneously collect all of the spectral data by sacrificing spatial resolution through the subdivision of the array.
In another approach, the detector array consists essentially of two or three separate detector arrays stacked on top of each other, with each detector array designed to be sensitive to a different spectral band. For example, one array may be sensitive to the mid-wave infrared band and another array may be sensitive to the long-wave infrared band. These types of FPAs are typically referred to as two- or three-color cameras. The different detectors are electronically activated so that the FPA can switch between the two different wavelength bands. However, these cameras are limited to a very small number of spectral bands, typically two or three, and require a complex detector structure and read-out electronics just to achieve that. Furthermore, they are typically limited to switching between the two spectral bands, which are fixed in spectral response. They typically cannot implement continuous or fine-tuning of the spectral response. For example, the spectral response typically cannot be tuned to an arbitrary center wavelength and spectral width.
Among non-tunable IR detectors, quantum dot infrared photodetectors (QDIPs) have shown steady progress in their performance ever since their first demonstration. The design, performance characteristics, and limitations of prior art QDIPs, such as dots-in-well (DWELL) detectors, are reviewed by Raghavan et al., in Applied Physics Letters Vol. 81 Number 8, Aug. 19, 2002, which is hereby incorporated by reference. QDIPs have demonstrated normal incidence operation in the mid-wave infrared (MWIR, between approximately 3 and 5 μm), the long wave infrared (LWIR, between approximately 8–12 μm) and in the very long wave infrared (VLWIR, for wavelengths longer than approximately 14 μm). For certain forward-looking infrared applications, such a broadband response may be desirable. For multispectral/hyperspectral imaging applications, however, it is not.
Thus, there is a need for semiconductor detectors with tunable spectral responses, especially responses that can be tuned by electrical signals, including for use in the IR, typically 2–30 μm. There is also a need for detectors with tunable and narrow spectral bands suitable for use with multispectral/hyperspectral imaging. | {
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Technical Field
The present disclosure relates to a communication system, a communication apparatus, and a communication method.
Description of the Related Art
Conference systems that hold a remote conference between users at remote places through a communication network, such as the Internet, have been widely used. With the conference system, in a conference room of one of the parties of the conference, images of the conference room and audio, such as remarks thereof, are image-captured and collected using a terminal device of the remote conference system. Then, the captured data is converted to digital data and transmitted to a terminal device of the other party. In a conference room of the other party, the images are displayed on a display and the audio is output through a speaker. Thus, techniques of holding a conference between users at remote places in a state close to an actual conference are known.
In the conference system, firmware (programs and applications) are periodically updated in some cases in order to improve call security performance and operation performance. The following method has been known as a method of updating the program in the conference system. That is, update data and meta information (metadata) are acquired by accessing a server through a network so as to update the program, and a program version that depends on this program.
Japanese Patent Application Laid-open No. 2012-084118 discloses the following update method. The update method includes determining whether an update is necessary for a communication device, receiving a selection operation from a user indicating whether the update is to be executed when the update is present, and executing the update when the selection operation for executing the update is made. | {
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The present invention relates to a corrosion probe used in both polarization and weight loss measurements of corrosion rates of metallic material upon exposure to a corrodant electrolyte.
Initially, corrosion rates were determined by simply inspecting the surfaces of corroded equipment. Such a method is undesirable since the equipment is often irreparably damaged before corrosion is evident. Furthermore, it is often necessary to shut-down equipment in order to make an inspection.
Accordingly, small test specimens were developed for relatively simple insertion and removal from a representative part of a corroding system to be tested. Typically, such test specimens are integral parts of a corrosion probe assembly which additionally includes support equipment for the specimens. These probe assemblies are designed for ease of incorporation into the test system. For example, the assembly may be designed as a pipe fitting, requiring no special tools for insertion techniques.
Two types of corrosion probe assemblies commonly used are known as weight loss types and polarization resistance types. Measurement of corrosion rate by weight loss probe assemblies is performed by initially measuring and recording the test specimen's initial weight to give W.sub.i (grams). The probe assembly is installed in the corrodant system such that the specimen is subjected to the system fluid, such as cooling water. The time of installation is recorded. At the end of the test period the specimen is removed and carefully cleaned in order to remove all corrosion products without removing uncorroded specimen material. Also, the time of specimen removal is recorded. The test specimen's final weight is measured to give W.sub.f (grams). The corrosion rate is calculated from this data from: EQU Corrosion rate (mpy) = K (W.sub.i - W.sub.f)/t (1)
where t = time duration of the test (days) and K = constant factor related to the metal being tested, its density, and its surface area.
Polarization type probe assemblies make use of the electrochemical nature of corrosion. Such probes typically utilize test, reference, and auxiliary electrodes. The test electrode, in the form of a test specimen, in initially permitted to corrode freely. A small electric current is passed through the corrodant between the test and auxiliary electrodes while the polarization potential between the test and reference electrodes is measured. The current is increased until a small given change in electrode potential, usually 10 mv, is measured between the test and reference electrodes. The resulting current required to produce the change is proportional to the instantaneous corrosion rate. Accordingly, this resultant current can be read and converted into units of corrosion rate. In fact, one among the inventors, in U.S. Pat. No. 3,716,460, which is hereby incorporated by reference, discloses a device which gives direct readings of instantaneous corrosion rate from a polarization-type probe assembly.
There is a third type of corrosion probe commonly used based on a measurement of electrical resistance of a small wire preferably manufactured from the same metal as in the test system. As the wire corrodes, its resistance increases since the diameter gets smaller. Thus, the change of resistance with time is a measure of the corrosion rate of the wire. The main disadvantage is that localized corrosion (pitting, deposit corrosion, etc.) has a tendency to cause the wire to corrode in a small area. Thus, the resistance measured will be determined largely by the smaller diameter which exists at the localized corrosion site. Also, since this site corrodes much faster than the rest of the wire, there is a tendency for the wire to break off at this point. The prime advantage of this technique is its ability to measure metallic corrosion in nonelectrolyte systems.
It is a common observation among workers in this field that there is often a discrepancy between hot corrosion and scaling occurring on surfaces experiencing heat transfer (e.g., heat exchanger surfaces) and cold corrosion and scaling occurring on those not experiencing heat transfer (e.g., corrosion specimens). Accordingly, the inventors set out to develop means for accurate corrosion rate measurements either by polarization resistance or by weight loss techniques wherein heat transfer is simultaneously taking place.
While conducting this developmental work, the inventors demonstrated that an interrelationship exists between the heat transfer coefficient (U) and corrosion and scaling in a system. As deposition increases it was observed that U is reduced. Also, corrosion products can contribute to the amount of deposition. In addition, reduced flow rate of the system fluid reduces U. It thus occurred to the inventors that a determination of heat transfer coefficient (U) in a corrodant system wherein corrosion and/or deposition occurs would provide an additional important tool in evaluating the system. In U.S. Patent application Ser. No. 430,453, filed on Jan. 3, 1974, now U.S. Pat. No. 3,918,300, which is hereby incorporated by reference, a U-meter is disclosed which provides an instantaneous U reading in a heat transfer system.
The probe assembly of the present invention permits detection of the necessary corrodant system parameters and feeding of the detected parameters into the U-meter for an instantaneous read-out of U. A test electrode or a test specimen of the probe assembly is heated, preferably electrically heated. The power W (watts), can be directly converted into heat, Q (BTU/hour), from the following relation: EQU Q = 3,413 W (2)
the heat flux (Q/A) is, then, EQU flux = Q/A = 3.413 W/A (3)
where A = test material specimen surface area. If, for example, the test material surface area is 9 cm.sup.2 the flux would be as follows: EQU flux (BTU/hr - ft.sup.2) = 352.3 W (watts) (4)
If 10,000 BTU/hr - ft.sup.2 (a reasonably high amount of heat flux in any plant heat exchanger) where needed in the probe assembly, then from equation (4), 28.4 watts should be fed to the heater.
At a fixed flow rate, U is defined by the equation: EQU Q/A = U(T.sub.2 -T.sub.1) (5)
where Q, A and U have been previously described; T.sub.2 = temperature of test material surface (.degree.F); T.sub.1 = external fluid temperature (.degree.F). Thus, EQU U = (Q/A)/(T.sub.2 - T.sub.1) (6)
all that is now necessary to determine U is measurement of T.sub.2 and T.sub.1. This can be accomplished, for example, by placing a temperature probe in the fluid stream near the heat transfer surface to determine T.sub.1 and placing a temperature sensor within the test specimen to determine T.sub.2. It should be noted from equation (6) that, at constant Q/A (constant W), T.sub.2 - T.sub.1 is sufficient to completely define U. Thus, the direct measurement of T.sub.2 - T.sub.1 is sufficient to determine the heat transfer coefficient.
During their work, the inventors discovered yet another important tool in evaluating corrodant systems and the treatment thereof. By simultaneously measuring cold corrosion and hot corrosion, the effect of the heat transfer load on the corrodant system can be determined. This can be accomplished by providing the probe assembly of the present invention with both a hot test specimen and a cold test specimen.
In fact, by providing a probe assembly with plural test sepcimens, various and sundry tests can be run to evaluate a corrodant system treatment program. For example, the simultaneous effect of heat load and different metallic materials in a corrodant system could be readily examined. Also, for example, galvanic interaction between two specimens can be studied by electrically connecting them externally and measuring current flowing between them.
Accordingly, it is an object of the present invention to provide a novel corrosion probe assembly which is very versatile in evaluating a corrodant system treatment program.
It is a further object of the present invention to provide a corrosion probe assembly which facilitates measurement of corrosion rate under specified heat transfer conditions.
Yet a further object of the present invention is to provide a corrosion probe which facilitates measurement of heat transfer coefficient simultaneously with measurement of corrosion rate.
An additional object of the present invention is to provide a corrosion probe which facilitates simultaneous measurement of hot and cold corrosion . | {
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In many industries, particularly the steel, plastics, rubber and lumber industries, material is produced by high speed extrusion, rolling, drawing, casting, sawing or other similar techniques wherein the output is carried along a conveyor-type system. Such techniques preclude the use of any measuring system requiring contact with the object, and, in the case of materials such as hot rolled steel, the temperature and heat of the material is too great for a contact-based measurement system. In order to maintain the required high output rate, non-contact techniques have been proposed to calculate the dimensions of the material.
U.S. Pat. No. 3,187,185 to Milnes discloses an apparatus for determining the surface contour and thickness of an article by non-contact means. The apparatus consists of one or more light beam sources and a camera which is preferably connected to a receiver. In using this apparatus, the beam source rotates such that the beam of light travels from one side of the specimen being measured to the other. The camera records the image of the line that the beam makes as it travels across the specimen, and the distance between this line and a reference line is proportional to the thickness of the specimen.
U.S. Pat. No. 4,271,477 to Williams discloses a method and apparatus for the measurement of the width and thickness of relatively thick metal workpieces. This apparatus uses two cameras, displaced vertically and longitudinally from each other, above the workpiece to measure the apparent width of the slab. The thickness of the slab may then be calculated, knowing the apparent width of the images from the two cameras and the vertical distance of the images from the surface upon which the workpiece is supported.
Also known are devices for contact-free thickness measurement of an object in which a beam is periodically deflected onto the object and the time at which the beam strikes each of a plurality of detectors is monitored. From the differential in time at which the beam strikes the various detectors, the thickness of the object may be calculated (see U.S. Pat. Nos. 4,068,955 and 4,192,612 to Bodlaj).
In U.S. Pat. No. 4,710,808 to Hoogenboom et al., there is disclosed a system for measuring the thickness of an object in which light from two sources, which are located on opposite sides of the object, is reflected from the object and the image thus formed is monitored by a video camera and the thickness of the object is determined from the light pattern of the images.
The prior art described above has several short-comings: the beam generator is constantly moving and thus susceptible to mechanical breakdown; the system measures differential thickness in relation to a calibration standard and thus cannot easily be used to accurately measure the thickness of objects with varying thicknesses; and others. | {
"pile_set_name": "USPTO Backgrounds"
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Technical Field
The present disclosure relates to methods and systems for carbon dioxide (CO2) separation. More particularly, the present disclosure relates to methods and systems for sorbent-based CO2 separation.
Discussion of Related Art
Power generating processes that are based on combustion of carbon containing fuel typically produce CO2 as a byproduct. It may be desirable to capture or otherwise separate the CO2 from the gas mixture to prevent the release of CO2 into the environment and/or to utilize CO2 in the power generation process or in other processes.
However, typical CO2 capture processes, such as, for example, aqueous amine-based process may have limitations, for example, the process can sometimes result in sharp increases in the viscosity of the liquid absorbent, which can decrease the mass transfer of CO2 into the sorbent. To avoid this problem, the concentration of amines in the absorbent stream may be maintained at low levels (using carrier solvents), which may greatly reduce absorbing capacity, as compared to the theoretical capacity of the neat absorbent. Moreover, energy consumption in the amine process may be high, due in large part to the need for heating and evaporation of carrier solvent (for example, water). Another example of a commercial CO2 post-combustion capture process may use aqueous solutions of piperazine-promoted potassium carbonate (K2CO3) that has disadvantages similar to the amine process because of the additional solvent. Further, this process is often very energy-intensive, and may be economically inferior to the amine process.
Thus, there is a need for efficient methods and systems for separation of CO2. Further, there is a need for efficient methods and systems for sorbent-based separation of CO2. | {
"pile_set_name": "USPTO Backgrounds"
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1. Field of the Invention
The present invention relates to a 1 bit/1 bit digital correlator with an independently adjustable integrator reference voltage.
2. Description of the Prior Art
Control loops are required in a number of circuits for demodulation, equalization and regeneration of a quadrature-amplitude-modulated digital signal. Acquisition of the setting voltage for the control elements in such conventional circuits is generally achieved by the use of a correlator which identifies the correlation of two digital bit sequences by means of an exclusive OR circuit and a following integrator stage, the setting voltage being derived from the output of the integrator stage. The performance capability of such demodulation, equalization and regeneration circuits greatly depends upon the precision of the setting voltages. In circuits having a relatively large number of correlators such as, for example, an adaptive basis equalizer, it is a problem in the art to provide a small, simple circuit which generates the setting voltage with optimally high precision, independently of signal scatter, temperature drift and aging characteristics of the components. | {
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In virtually every kitchen and similar facility in which a recessed sink or other similar facility is situated, the facility includes a countertop of some sort providing a flat working surface usually encircling and extending in either or both directions from the recessed sink. While the fabrication of countertop and sink combinations has varied substantially through the years, in general all provide a flat planar surface having a sink opening defined therein. A recessed sink often having a plurality of individual bowl portions or the like is secured to the countertop and extends beneath the sink opening. Various types of mechanical attachment mechanisms are used to secure the sink and countertop in a tight liquid seal attachment intended to simultaneously provide an attractive outer appearance.
Because of the wide differences in customer needs and customer preferences, practitioners in the art have provided many types and colors of sink and countertop materials as preferences and styles have changed. Colors alone have provided a substantial variation and numbers of combinations as countertops and sinks have transitioned from the common white or off-white utilitarian items to items having colors which provide fashion accents and eye appeal within the kitchen. The style of such facilities has also changed considerably through the years as designers attempt to brighten and lighten kitchens to provide an enjoyable work environment for the user. A number of advanced materials have also been provided which has further increased the available options to the consumers. For example, countertops are now available having been formed of high strength marbleized or epoxy type materials as well as ceramic materials or the like leading to one piece molded style countertops having a minimum of visible seams or other discontinuities.
This substantial variety of sinks and countertops available to the consumers leads to a great number of combinations available and while providing flexibility and excitement to the user greatly complicates the selection process. Dealers in such products in attempting to service consumers often select several combinations and provide kitchen mock-ups or showrooms which permit the consumer to directly view a full size example of the selected combinations. The problem, however, is that as a practical matter, the dealer cannot afford to install examples of the many combinations of product and color and style from which the consumer may select. Faced with the need to interest and please consumers together with the limitations of space for providing full size displays of such products, dealers have resorted to various sales brochures and photograph collections to be used in combination with selected full size showroom combinations.
While such photo combinations and brochures assist the consumer, the fact remains that a great number of consumers are not comfortable selecting a large size important item such as a counter and sink combination using a picture or brochure. This simple fact is the consumer has a need or at least desire in most instances to view a full size article prior to making the product choice. Thus, a dilemma arises in that purchasers find themselves traveling from store to store hoping to view the combination or combinations in which they are interested while retailers having limited showroom space are forced to watch potential customers leave their facility and travel to a competitor's facility to view the final product.
There remains, therefore, a need in the art for a simple, effective and economically practical system for permitting the dealer of countertop and sink products to permit potential customers to view a realistic example of the combination which interests them without the need of impractical expensive showroom facilities. | {
"pile_set_name": "USPTO Backgrounds"
} |
Ultrasound imaging systems are used to support examination and diagnosis of patients in a range of medical applications. Ultrasound utilizes sound waves at frequencies higher than those perceptible to the human ear. Ultrasonic images known as sonograms are generated as a result of pulsed ultrasonic energy that has been directed into tissue using a probe. The probe obtains echoed sound energy from the internal tissue and provides signal content that represents the different sound reflectivity exhibited by different tissue types. This signal content is then used to form images that visualize features of the internal tissue. Medical ultrasound, also known as diagnostic sonography or ultrasonography, is used as a diagnostic imaging technique used to help visualize features and operation of tendons, muscles, joints, vessels and internal organs of a patient.
FIG. 1 shows an exemplary portable ultrasound system 10 that use a cart/base/support, cart 12, a display/monitor 14, one or more input interface devices 16 (such as keyboard or mouse), and a generator 18. The display 14 can also be a touch screen to function as an input device. As illustrated, the ultrasound system 10 can be a mobile or portable system designed to be wheeled from one location to another.
Like other types of imaging systems, ultrasound imaging equipment requires periodic calibration. Calibration procedures, carried out by a lead operator, field technician, or other qualified person, help to provide consistent results from the ultrasound system.
To assist in calibration of the ultrasound probe and system, a number of types of ultrasound phantom have been devised. Used to evaluate the performance of diagnostic ultrasound systems, these devices are configured with surfaces that are compatible with ultrasound probes and with internal features that allow ultrasound measurement over a range of relative densities and dimensions, mimicking the acoustic properties of human tissue and providing target structures with acoustic densities in a range that is encountered in anatomical examinations. Phantoms help to detect undesirable performance changes that can occur through normal use, compensating for factors such as aging and deterioration of ultrasound system components. Routine calibration can help to reduce the number of repeat examinations, the duration of examinations, and overall maintenance down-time, as well as helping to verify the effectiveness of maintenance actions. Phantoms are routinely employed for clinical Quality Assurance (QA), Preventative Maintenance, field service testing, research and development, manufacturing, teaching, and sales and marketing use.
The calibration sequence often requires the technician to simultaneously operate system controls and the keyboard console of an ultrasound system while manually maintaining the ultrasound probe in place along a particular portion of the phantom. This arrangement can become very awkward and physically straining, particularly where calibration techniques or their results may require more in-depth image acquisition and analysis. For portable systems such as those shown in FIG. 1, the calibration technician may have to perform calibration under adverse conditions, such as where space, lighting, and accessibility are limited.
Thus, it can be seen that a need exists for flexible tools to support ultrasound image calibration procedure. | {
"pile_set_name": "USPTO Backgrounds"
} |
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