An otoscope kit has an otoscope with an attachable ear wax removal device for ear wax removal. A fluid dispensing means which is attachable to the otoscope for ejecting fluid through said ear speculum into the ear canal, the fluid dispensing means being mounted on the gripping body of the otoscope. The fluid dispensing means preferably includes a housing, a fluid supply and dispensing container, a pump, a tube connected to the fluid supply and dispensing container at one end extending and connected to a connector on a speculum cover. The fluid dispensing means is controlled by an actuator switch that is mounted in an opening of said housing wherein the actuation of the fluid dispensing means occurs without blocking the line of sight through the viewing means. The fluid dispensing means further can have a fluid recovery means having a vacuum pump, a fluid and debris recovery container and a tube for connecting the fluid recovery container to a second connector in the speculum cover. The fluid recovery means is controlled by a second actuator switch mounted in an opening of the dispensing housing. The otoscope-come ear wax removal system has the main advantage of removing ear wax under direct vision.

Cerumen or ear wax is a waxy substance produced in the ear canal. Wax buildup is due to accumulation of cerumen as well as dirt and debris. However, excess production or impaction of cerumen can press painfully against the ear drum and can also impair hearing. Ear wax buildup can also interfere with hearing aids.
There are several methods of removing excess cerumen. A common method is to syringe the ear canal with warm water flushing the cerumen out with the water. Various solutions of oils, peroxide, glycerine or detergents are also used to flush the ear canal. Cotton swabs are also commonly used, but not recommended as they generally only remove a small amount of wax and push the rest further into the ear canal.
Physically picking or scraping the earwax out with an ear pick or curette is yet another method of removing ear wax usually performed by a health professional under direct observation with magnification.
A less common method is ear candling which is the practice of lighting a specially made hollow ear candle and placing the unlit end in the patient's ear. It is claimed to create a slight vacuum that draws out debris and wax.
There are some complications or risks associated with these various types of ear wax removal such as damage to the ear drum from excess pressure or physically perforating the ear drum.
A key limitation in the removal of ear wax or cerumen is the inability to directly observe the ear canal. A device called an otoscope provides a way to see into the ear canal. The otoscope has a handle and a head with a light source and a magnifying lens with a removable ear speculum that attaches to the front. The speculum is inserted into the external ear canal allowing the examiner to look through the lens into the ear canal. Many models have a detachable sliding rear window allowing instruments to be inserted through the speculum into the ear canal that could be used for removing ear wax. The otoscope can only be used to observe the ear canal before or after flushing, but not during actual ear wax removal as a result the physician must repeatedly stop flushing to observe the progress being made.
An object of the present invention is to be able to visually observe the ear wax removal during flushing or vacuuming of the fluid and dislodged debris from the ear canal. This objective is achieved as are other features by the use of the present invention described as follows.

Otoscope with attachable ear wax removal device


This invention provides a technique for enhancing an operating frequency and improving reliability in a system using at least level sense type sequence circuits as a plurality of sequence circuits. A microcomputer includes a clock generator configured as a clock supply source, functional modules operated in sync with a clock signal, level sense type sequence circuits which are contained in the functional modules and configured as clock supply destinations, a clock supply system which propagates the clock signal to the level sense type sequence circuits, etc. The clock supply system includes a clock wiring which propagates the clock signal outputted from the clock generator to ends thereof via a plurality of branches. At least pulse generators are disposed in the midstream of the clock wiring. Each of the pulse generators varies timing provided to change the falling edge of the clock signal, which defines an endpoint of an input operating period of each level sense type sequence circuit.

The present invention relates to a semiconductor integrated circuit operated in sync with a clock signal and a technique effective when applied to a semiconductor integrated circuit having level sense type sequence circuits as a plurality of sequence circuits corresponding to clock supply destinations, for example.
When a semiconductor integrated circuit such as a microcomputer is designed, the design of a clock supply system for propagating a clock signal outputted from a clock generator configured as a clock supply source to a plurality of sequence circuits or the like corresponding to clock supply destinations is essential. The clock supply system has a clock wiring. The clock wiring is configured as a clock tree structure for propagating the clock signal to ends thereof via a plurality of branches. The clock wiring is designed so as to assume a fixed-width and fixed-length wiring for the purpose of attaining a reduction in clock skew. The clock skew refers to a shift in the phase between the clock signals at the plural clock supply destinations to which the clock supply source is common. The phase shift of the clock signal is also grasped as an arrival time difference in clock signal between the clock supply source and each of the clock supply destinations, i.e., a variation in the propagation delay time of the clock signal. As the plural sequence circuits connected to the ends of the clock wiring, may be mentioned edge trigger type sequence circuits in each of which the rising edge of the clock signal is brought to an input/output operating period, and level sense type sequence circuits in each of which a period during which the clock signal is of a high level, is brought to an input/output operating period.
A system using the edge trigger type sequence circuits is formed with a plurality of data paths including pre-stage edge trigger type sequence circuits each configured as the data transmission side, post-stage edge trigger type sequence circuits each configured as the data reception side, and combination circuits which are disposed between these edge trigger type sequence circuits and perform predetermined arithmetic processing or the like. In each of such data paths, the timing provided to allow the predetermined combination circuit to output the result of arithmetic operation might pass or go beyond the timing provided to change the rising edge of the clock signal supplied to the post-stage edge trigger type sequence circuit, i.e., the input/output operating period. In this case, the post-stage edge trigger type sequence circuit cannot fetch or take the result of arithmetic operation by the predetermined combination circuit, thus causing a MAX delay violation. As the cause of the MAX delay violation, variations in the amount of delay at each combination circuit and the like are also considered as well as the clock skew.
In order to relieve the MAX delay violation, there is considered a method for grasping the clock skew and the variations in the amount of delay at each combination circuit as design values every data path, for example at the design stage of the microcomputer and adjusting the change timing at the rising edge of the clock signal supplied to each post-stage edge trigger type sequence circuit on the basis of the design values after the manufacture of the microcomputer. However, the design values grasped at the design stage of the microcomputer are shifted from values grasped from the result of testing in a test process after its manufacture due to factors such as variations in manufacture, a drop in power supply voltage, etc., which cannot be grasped accurately at the design stage.
A non-patent document 1 (E. Takahashi, et al., "A post-silicon clock timing adjustment using genetic algorithms, "2003 Symposium on VLSI Circuits Digest of Technical Papers, pp. 13-16) discloses a technique wherein in a system using edge trigger type sequence circuits, a variable delay circuit capable of changing a propagation delay time of a clock signal is disposed in the midstream of a clock wiring configured as a clock tree structure thereby to make it possible to adjust a clock skew according to the result of testing in a test process. According to the present technique, the amount of delay of a clock signal is changed by the variable delay circuit to adjust the timing provided to change the rising edge of the clock signal, thereby relieving a MAX delay violation.

Semiconductor integrated circuit with pulse generation sections


A molded rubber recreational block locking system, wherein a molded rubber recreational surface block includes an upper surface and a resilient supporting structure below the upper surface. At least one recessed shoulder is located below the upper surface and intersects a marginal edge of the molded rubber recreational surface block. A fastening device interconnects adjacently positioned recessed shoulders in adjacent molded rubber recreational surface blocks for securing same together. Typically, at least one generally vertically directed through hole extends through each recessed shoulder and a flexible fastening device, such as a fastening strap, interconnects the through holes of adjacently positioned recessed shoulders in adjacent molded rubber recreational surface blocks. A cap covers the fastening device and recessed shoulders of adjacently positioned molded rubber recreational surface blocks.

Children love to use playground equipment; however, as can be appreciated, the exuberance of children sometimes results in a mishap causing the child to fall from the playground equipment. Sometimes also, children simply slip and fall on the playground surface itself. As disclosed in my aforementioned U.S. Pat. No. 5,713,175, safety playground surfaces prevent or minimize playground injuries. Those playground safety surfaces that are formed from resilient and shock absorbing cushion elements have been found to reduce the possibility of injury due to a child falling from various heights of playground equipment or from slipping and falling. In the construction shown in my aforementioned patent, a series of recreational surface blocks or floor segments are connected together through complementary fastener units provided on adjacent recreational surface blocks, in order to hold a series of such recreational surface blocks together as protective flooring. Such interlocked recreational surface blocks or floor segments produce a protective cushioned area for playground surfaces, except in the areas where they are connected together. In my aforementioned patent, the complementary fastener units provided on adjacent recreational surface blocks are formed as injection molded units and thus are somewhat rigid and unyielding. As a result, it is possible that a child could be injured if the child falls in the area of such rigid or unyielding fastener units that interconnect adjacent recreational surface blocks. In actuality, my previous locking system was safe in the area of the injection molded units, but as much lower fall heights than the rest of the protective surfacing.
It has been discovered that a fastening device, such as one or more flexible fastening straps, can be effectively utilized to secure adjacent recreational surface blocks together while at the same time avoiding injury to a child who might fall on or near such fastening device. A shock absorbing cap can also be used to overlie the fastening device, thus providing a further safety cushioning feature for use with the resilient shock absorbing recreational surface block. As a result, the new protective surfacing system with flexible fastening straps and the shock absorbing cap has an equivalent safety level over the entire protective surfacing. As an added advantage, a fastening device having one or more fastening straps can be used to easily assemble recreational surface blocks together without the need for tools, thus facilitating assembly while minimizing costs.
As will be appreciated from the discussion that follows, the aforementioned novel features are embodied in a number or different variations, as will become more apparent in the ensuing description.

Recreational surface block locking system


According to one example of embodiment of the invention a ceramic pre-moulding 81 of stable form is pressed from ceramic composition in powder form in a first isostatic pressing action, at least a part of its surface being formed in contact with rigid shaping surfaces 42. The pre-moulding 81 thus obtained is then--possibly after glazing-subjected to a higher pressure, in a further pressing operation on all sides and then fired in a ONCE-ONLY quick-firing method.

The invention relates to a method for the production of a ceramic moulded body by moulding of a ceramic moulding composition into a moulding of stable form, and subsequent firing of a moulding.
When there is mention here of ceramic moulding compositions, the term "ceramic moulding composition" is to be understood in the widest sense. It includes all fine ceramic and coarse ceramic moulding compositions, such as stoneware, crockery, vitreous china, bone china and especially porcelain, also industrial ceramic compositions, for example on the basis of silicon carbide, silicon nitride, aluminium oxide and zirconium oxide.
When there is mention here of ceramic moulding, this term too is to be understood in the widest sense independently of the shaping, but especially one has in mind thin-shelled moulded bodies such as occur as table crockery parts in the form of plates, dishes, bowls and jugs. The invention has special importance for the production of plates, dishes and bowls, which conventionally can be produced by pressing of ceramic moulding compositions in powder form, for example from granulated porcelain grain. Fundamentally the invention is applicable to the processing of all industrial dusts, even those of powder metallurgy.

Method for the production of a ceramic moulding


A heat dissipation device for electronic controllers, is provided and includes a housing that has a hollow portion into which a working fluid for heat transfer and dissipation is filled. The housing of the electronic controller is formed to have the hollow portion using the material containing the heat-conductive filler and the heat transfer working fluid is filled in the hollow portion, to improve the cooling efficiency and achieving the weight reduction. By forming the condensation unit that condenses the vaporized working fluid in the upper end portion relative to the working fluid filled in the hollow portion of the housing, the heat exchange effect of the working fluid may be maximized.

(a) Technical Field
The present disclosure relates to a heat dissipation device for electronic controllers, and more particularly, to a heat dissipation device for electronic controllers, in which a housing of an electronic controller has a hollow portion and a working fluid for heat transfer and dissipation is filled into the hollow portion.
(b) Background Art
Recently, the number of various electric and electronic parts (hereinafter, referred to as electronic controllers) mounted within vehicles has increased and the electronic controllers have also been integrated. Therefore, weight reduction and safety, especially, heat dissipation, of cooling systems for cooling the electronic controllers have emerged as a serious issue. A conventional cooling system for cooling various electronic controllers mounted within vehicles will be described in brief.
The conventional cooling system is usually of a water cooling type since an air cooling type has a lower cooling efficiency than the water cooling type and thus is not applicable to high heat-emission parts such as a battery, an inverter, and any other similar and/or suitable parts. The conventional cooling system, for example, a cooling system that cools a motor controller of a fuel-cell vehicle has a water-cooling structure that uses a heat exchanger having a closed loop, and an inverter system of an eco-friendly vehicle uses a direct liquid cooling system to cool an IGBT power module.
As illustrated in FIGS. 1A and 1B, a conventional cooling system of the water-cooling type has a heat sink for heat dissipation integrally attached to a power device of each controller, wherein a cooling tube in which a working fluid is circulated is disposed adjacent to the heat sink.
However, in the conventional cooling system of the water cooling type weight of each component of the cooling system increases, there is a difficulty in molding the cooling tube to form a cooling water circulation channel, a limitation in anti-corrosion property of metallic materials such as for the heat sink exists, and leakage of the cooling water may occur.

Heat dissipation device for electronic controllers


A remote bidding supplement for traditional-style live auctions, comprising an audio/video system for streaming instantaneous and buffer-free live audio and video data from a live auction site to one or more remote auction bidders having a bidding device for receiving the data and for transmitting instantaneously remote auction bids for each item being auctioned at the live auction site; a clerk system for controlling and accepting auction bids received at the live auction site from onsite auction bidder and from remote auction bidders for each item being auctioned at the live auction site; a marquee system for displaying instantaneously at the live auction site auction bid information, including accepted auction bids, for each item being auctioned at the live auction site; and a bid system for broadcasting instantaneously to all remote auction bidders and to the marquee system the auction bid information for each item being auctioned at the live auction site, for receiving instantaneously auction bids from each remote auction bidder for each item being auctioned at the live auction site and for transmitting instantaneously to the clerk system each remote auction bid received for each item being auctioned at the live auction, and for broadcasting instantaneously to all remote auction bidders and to the marquee system the onsite and remote auction bids that have been accepted by the clerk system.

Traditional-style auctions are ignoring a significant market—the physically remote purchasers who will purchase an item without being physically present to kick the tires, feel the smoothness of a vase, hear the roar of a diesel engine or authenticate an ancient item.
Currently, there are two types of remote auction systems. The first type of remote auction system has no "live" auctioneer and the entire bidding audience must be connected to the network or system. In this case, the network computer or server acts as the auctioneer, accepting bid values from the connected audience with associated time stamps based upon bid receipt by the server. Each bid is either accepted or rejected by the server; the bidder (sometimes the entire audience) is notified of its acceptance or rejection. All of the items for sale in this type of auction are generally available for the entire duration of the auction and each item has a specified end time after which no bids will be accepted.
The second type of remote auction system is much like the first; however, it may or may not have a "live" auctioneer. The main difference from the first type of remote auction system is that each item for sale is not available at the same time; rather, the auction moves from item to item and depending upon the bidding activity and upon either the server's or "live" auctioneer's choice, the item is sold and the event moves on to the next item on the list.
A disadvantage of remote auctioning systems is that the participating bidders are not engrained into the excitement and energy of the live auction. From the perspective of an auction company, this can have a significant impact on the success, or the earnings, of the auction company. Many books have been written about the psychology of the auction floor and the best auctioneers are talented in the science of reading a crowd and individuals, playing them off of each other, and drawing larger bids for the items being auctioned. Thus, there is a need in the art for a technique to integrate remote auctioning systems into the real life environment of the auction floor. There is also a need in the art to allow the auctioneer to extend his or her talents beyond the auction floor and "work" the crowd of remote bidders as well as the local bidders. There is also a need in the art to integrate remote bidders into a live auction setting in a manner that does not alienate or result in giving an advantage to either the local bidders or remote bidders.

This patent is subject to a terminal disclaimer.

Integrated on-line and on-site auctioning system including audio and/or video capabilities


A housing main body (20) is connectable with a mating male connector (M) and internally formed with an accommodating chamber (22) into which an auxiliary housing (30) can be accommodated. The housing main body (20) is formed with cavities (23) for accommodating female terminal fittings (40) electrically connectable with mating male terminal fittings (11), and the respective cavities (23) are arranged at positions symmetrical with respect to an axis of symmetry (L1). A lock arm (50) is disposed on the axis of symmetry (L1) of the respective cavities (23). The housing main body (20) is integrally formed with the lock arm (50) capable of holding the male connector (M) connected by the engagement with an engaging portion (16) of the male connector (M).

1. Field of the Invention
The invention relates to a divided connector.
2. Description of the Related Art
Japanese Unexamined Patent Publication No. H05-182716 and FIG. 12 herein disclose a divided connector. With reference to FIG. 12, the divided connector has a housing main body 1 and auxiliary housings 2 are accommodated in chambers 3 of the housing main body 1. The divided connector is connectable with a mating connector 4 by operating a lever 5 mounted on the housing main body 1. The lever 5 can be locked to keep the connector mated with the mating connector 4.
The lever 5 is U-shaped and crosses over the housing main body 1. Thus, the divided connector has tended to be large.
The invention was developed in view of the above problem and an object thereof is to miniaturize a divided connector.

Divided connector and connector assembly


A secure transaction method is provided for publicly-accessible transaction terminals. The method uses quantum key distribution (QKD) between a hand-portable QKD device and a complimentary QKD apparatus incorporated the transaction terminal. After the QKD device has been brought up to the transaction terminal, the QKD device and the complimentary QKD apparatus of the terminal are is used to provide the device and terminal with new secret shared random material. The new secret shared random material is then used to establish a secure classical communication channel between the device and transaction terminal for conducting a transaction. An ATM terminal and POS terminal that use quantum key distribution are also disclosed.

A known problem with current publicly-accessible card-operated transaction terminals such as ATM terminals, is that it is possible for a third party to interpose an illicit card reader in the slot intended for inserting a card into the genuine card reader of the terminal. As a result, it is possible for the third party to capture information off the card and misuse it. An attack of this type is often referred to as a "shim" attack.
Of course, most card-based transaction terminals also require the input of a PIN (personal identification number) supposedly only known to the genuine card user. however, it is possible for a third party to gain knowledge of a PIN by covert observation during PIN entry by the user at a transaction terminal, this observation being effected either by the third party in person or by use of a concealed camera.
It is an object of the present invention to enable increased security for transactions effected at a publicly-accessible transaction terminal.

Secure transaction method and transaction terminal for use in implementing such method

Hewlett-Packard Development Company, L.P.


The present invention provides a method of preparing a carbon fiber-reinforced silicon carbide composite material, wherein carbon nanotubes are formed in the composite material, and then metal silicon is melted and infiltrated into the composite material, so the amount of unreacted metal is reduced and the strength of the composite material is improved, and provides a carbon fiber-reinforced silicon carbide composite material prepared by the method.

1. Technical Field
The present invention relates to a carbon fiber-reinforced silicon carbide composite material and a method of preparing the same.
2. Description of the Related Art
A melt infiltration (MI) process is one of several methods of preparing a fiber-reinforced silicon carbide composite material, and is characterized in that a product can be very easily produced because of short process time and low production cost.
Generally, a melt infiltration (MI) process includes the steps of: 1) impregnating a fiber with a polymer to form a fiber-reinforced plastic and then curing the fiber-reinforced plastic; 2) carbonizing the cured fiber-reinforced plastic under an inert atmosphere; and 3) melting metal silicon and then infiltrating the molten metal silicon into the carbonized fiber-reinforced plastic to prepare a fiber-reinforced silicon carbide composite material.
In this case, the carbonized fiber-reinforced plastic is a porous fiber-carbon composite material, and the molten metal silicon is infiltrated into the carbonized fiber-reinforced plastic through pores by capillary force. However, when the size of pores of the carbonized fiber-reinforced plastic is large, a free metal, which cannot participate in a reaction, exists between the infiltrated molten metal silicon and the carbon contained therein, and an unreacted metal region (metal river or metal pool) is formed.
Due to such an unreacted metal region, the prepared fiber-reinforced silicon carbide composite material exhibits low strength, and particularly, the strength thereof is rapidly lowered at high temperature, thus deteriorating the high-temperature characteristics thereof.
Meanwhile, Korean Patent Registration No. 10-0689636 discloses a method of preparing a carbon fiber-reinforced silicon carbide composite by uniformly applying thermosetting resin powder and ceramic powder onto a carbon fiber and then performing a metal silicon melt-infiltration process. However, this method is problematic in that a free metal, which cannot participate in a reaction, exists between the infiltrated molten metal silicon and the carbon contained therein, thus deteriorating the strength of the carbon fiber-reinforced silicon carbide composite.

Carbon fiber-reinforced silicon carbide composite material and method of preparing the same


A scanner which includes a motor for driving a load and circuitry for providing a position error signal responsive to the difference between a predicted position of the load and the actual position of the load, preferably a mirror scanning a scene. The motor is driven in response to the position error signal. The position error signal is provided plural times during a single scanning of the scene. The circuitry for providing a position error signal includes a closed loop filter system for filtering the error signal to provide a filtered error signal, an adaptive filter system for operating on the filtered error signal to provide an adaptively filtered error signal and summing circuitry for summing signals indicative of the predicted position, the filtered error signal and the adaptively filtered error signal. The closed loop filter system includes, in series, at least one first order lead lag filter and a double integral plus proportional filter. The adaptive filter system includes, in series, a low pass filter, a register and an integrator.

1. Field of the Invention
This invention relates to infrared (IR) scanners and, more specifically, to oscillating type IR scanners.
2. Brief Description of the Prior Art
The purpose of a scanner of the type discussed hereinbelow is to sweep in azimuth a two-dimensional infrared scene across a one-dimensional array of detectors, thus creating a two-dimensional image of the scanned scene with the infrared scanning system. This is accomplished by precisely controlling the position of a mirror which scans the scene in synchronization with the sampling of the detector. Conversely, this process may be viewed as sweeping the column of detectors across the field of view. Some scanners can also hold a static position (i.e., not scanning). An interlacer can be provided which moves in elevation in the cross-scan axis up and down one half of a detector pixel distance to scan between the prior positions of adjacent detector elements and increase the vertical resolution of the system.
The main performance attributes of an IR scanner are linearity, repeatability and efficiency. Historically, polygon scanners have had a greater advantage over the oscillating scanners in terms of linearity and repeatability performance. However, the low scan efficiency plus added power, weight and size of a polygon scanner renders it unsuitable for deployment in some systems.
Prior art galvanometer based scanners have been incapable of providing the linearity and repeatability required for focal plane array (FPA) base imaging systems.


A composition for a polarizing film including a polymer and at least one of dichroic dye, wherein the dichroic dye includes a first dichroic dye represented by Chemical Formula 1 and having a molecular weight of greater than or equal to about 500 Daltons:

1. Field
A composition for a polarizing film, a polarizing film, and a display device are disclosed.
2. Description of the Related Art
A display device such as a liquid crystal display (LCD) and an organic light emitting diode (OLED) device include a polarizing plate attached to the outside of a display panel. The polarizing plate transmits light of a specific direction only and absorbs or reflects any other light. Thus, the polarizing plate may control the direction of incident light in the display panel or light emitted from the display panel.
The polarizing plate generally includes a polarizer and a protective layer for the polarizer. The polarizer may include, for example, iodine or a dichroic dye adsorbed and arranged on polyvinyl alcohol (PVA), and the protective layer may use, for example, triacetyl cellulose (TAC).
However, the process of production of the polarizing plate including the polarizer and the protective layer is complicated and costly and high production costs. In addition, the manufacture of a thick polarizing plate leads to an increased thickness of a display device.
Accordingly, a polarizing film that does not require a protective layer has been researched. The polarizing film may include a polymer and at least one dichroic dye.
However, the dichroic dye of a polarizing film may be easily diffused into adjacent layer contacting the polarizing film at a high temperature, thereby deteriorating the optical properties of the polarizing film due to loss of a dichroic dye in the polarizing film.
Thus, there remains a need in a polarizing film capable of maintaining desired optical properties in a wide temperature range.

Composition for polarizing film, polarizing film, and display device

Abstract: wherein in Chemical Formula 1, Ar1 to Ar3, R1, R2, n, and m are the same as described in the detailed description.


This invention combines the unique antiplatelet effects of S-nitrosothiols and the antiadhesive properties of fragments of von Willebrand (vWF) in the A1 domain to provide unique molecules that exploit both of these properties. Preferred molecules comprise a fragment of A1 (Ala 444-Asn 730) in which arginine at position 545 is replaced by cysteine (the most frequent von Willebrand disease type 2b mutation) that has been discovered to impair platelet adhesion, and to inhibit an antithrombotic activity in vivo. This cysteine residue may be S-nitrosated to produce a novel molecule that has the potential for impairing platelet adhesion as well as activation/aggregation, and such molecules form the basis of a novel therapeutic method for impairing platelet responses following vascular injury or in other thrombotic disorders according to this invention.

1. Field of the Invention
This invention is directed to anti-thrombotic therapy using novel anti-thrombotic agents. In particular, the anti-thrombotic agents are S-nitrosated polypeptides which bind to platelet receptor glycoprotein GPIb/IX.
2. Review of Related Art
von Willebrand Factor and Platelet Function
During the past several years significant progress has been made in understanding the molecular aspects of platelet function with regard to both their role in normal hemostasis and the development of pathological vascular occlusion. The first event in normal primary hemostasis or development of arterial thrombosis is the binding (adhesion) of platelets to the subendothelium at sites of vascular injury. This first step occurs by binding of von Willebrand factor (vWF) to the platelet receptor glycoprotein Ib/IX (GPIb/IX) following its binding to components of exposed subendothelium. Thus, vWF acts as a xe2x80x9cbridgingxe2x80x9d molecule between platelets and the vessel wall. As a consequence of vWF binding to GPIb, glycoprotein IIb/IIIa (GPIIb/IIIa) is activated through a complex signaling pathway leading to platelet aggregation mediated by fibrinogen or, under conditions of high shear stress, by vWF itself (Ruggeri, et al., 1982, Proc. Natl. Acad. Sci. USA, 79:6038-6041; Ruggeri, et al., 1983, J. Clin. Invest., 72:1-12; Ikeda, et al., 1991, J. Clin. Invest., 87:1234-1240). Furthermore, the binding of vWF to GPIb can mediate events that are associated with the effects of agonists like ADP and thrombin, such as activation of GPIIb/IIIa and support of platelet aggregation. This indicates that vWF serves as more than the xe2x80x9cgluexe2x80x9d that mediates platelet adhesion to the vessel wall but also induces and modulates other later steps of hemostasis and thrombogenesis.
vWF is a polymeric glycoprotein that circulates in plasma as a series of multimers with molecular weights ranging from 0.25xc3x97106 daltons to 20xc3x97106 daltons. In addition to its role in platelet adhesion, it carries and stabilizes factor VIII in the circulation (Sadler, 1991, J Biol. Chem., 266:22777-22780). The vWF gene, located on chromosome 12, spans 178 kb and is interrupted by 51 introns (Ginsburg, et al., 1985, Science, 228:1401; Mancuso, et al., 1989, J. Biol. Chem., 264:19514-19527.) vWF is synthesized from an 8.7 kb mRNA and is expressed in endothelial cells and megakaryocytes. Synthesis of vWF is a complex multistep process that results in the generation of a precursor protein, pre-pro-vWF (Meyer, et al., 1993, Thromb. Haemost., 70:99-104).
This large molecule comprises a 22 amino acid (aa) signal peptide, as well as prov WF, which consists of a 741 aa propeptide and a 2050 aa mature subunit. These 250 kDa subunits assemble into multimers of up to 100 subunits (Wagner, 1990, Annu. Rev. Cell Biol., 6:217-246). After dimerization by disulfide bonding at carboxyterminal domains in the endoplasmic reticulum, further multimerization takes place in the Golgi or post-Golgi compartments through disulfide linkages at amino-terminal domains.
In the blood vessel, vWF is constitutively secreted by endothelial cells. vWF is also stored within intracellular granules in both endothelial cells (Weibel-Palade bodies) and platelets (xcex1-granules). These specialized granules release vWF in response to a variety of stimuli including vascular damage. The vWF stored within these granules contains larger multimers than those which are constitutively secreted by endothelial cells. These high-molecular-weight (HMW) multimers are more effective in platelet binding than smaller sized multimers (Gralnick, et al., 1981, Blood, 58:397-397; Federici, et al., 1989, British Journal of Hematology, 73:93-99); therefore, rapid release of stored vWF into the circulation may be particularly useful in the setting of vessel injury.
The pro vWF consists of four types of repeated domains (A to D) and has two disulfide loops: one is located between cys 509 and 695 in the A1 domain and the other between cys 923 and 1109 in the A3 domain (Meyer, et al., 1993, Thromb. Haemost., 70:99-104). Progress has been made in identifying specific regions of the vWF subunit that are important for function. The A1 domain contains binding sites for GPIb, sulfatides, and heparin. Using proteolytic or recombinant fragments of vWF, the binding domain for GPIb has been located within the T116 fragments (aa 449-728) which overlaps the A1 loop (Fujimura, et al., 1986, J. Biol. Chem., 261:381-385; Cruz, et al., 1993, J. Biol. Chem., 268:21238-21245; Sugimoto, et al., 1991, Biochemistry, 30:5202-5209; Gralnick, et al., 1992, Proc. Natl. Acad. Sci. USA, 89:7880-4; Azuma, et al., 1991, J. Biol. Chem., 266:12342-12347; Pietu, et al., 1989, Biochem. Biophys. Res. Commun., 164:1339-1347; Andrews, et al., 1989, Biochemistry, 28:8326-8336).
Under its native conformation, human vWF does not spontaneously interact with GPIb. The exposure of the GPI-binding site of vWF can be regulated by a series of physiological or non-physiological events. Most of these events appear to modify the structure and/or the conformation of the A1 region. The binding of vWF to the subendothelium, which spontaneously occurs via the T116 sequence (Denis, et al., 1993, Arterioscler. Thromb., 13:398-406), is responsible for the subsequent exposure of the GPIb-binding site of vWF (Sakariassen, et al., 1979, Nature, 279:635-638). Similarly, collagen and heparin bind to vWF via sequences in the A1 loop (Mohri, et al., 1989, J. Biol. Chem., 264:17361-17367) and modulate its interaction with GPIb. Binding of vWF to collagen promotes its interaction with GPIb while binding to heparin inhibits this interaction (Fressinaud, et al., 1988, J. Lab. Clin. Med., 112(1):58-67; Sobel, et al., 1991, J. Clin. Invest., 87:1787-1793; Savage, et al., 1992, J. Biol. Chem., 267(16):11300-11306).
The interaction of vWF with non-physiologic modulators of its binding to GPIb also involves sequences close to or within the A1 loop. The immobilization of vWF on a plastic surface, for example, leads to platelet adhesion via GPIb (Berndt, et al., 1992, Biochemistry, 31:11144-11151). The interaction of vWF with ristocetin involves 474-488 and 692-708 sequences flanking the A1 loop, whereas botrocetin binds to four sequences within this loop (514-542, 539-553, 569-583 and 629-643) (Sugimoto, et al., 1991, J. Biol. Chem., 266:18172-18178; Ginsburg, et al., 1993, Thromb. Haemost., 69:177xe2x80x94184). The inhibition of vWF binding to GPIb by polyanionic compounds like aurin tricarboxylic acid (ATA) involves positively charged sequences of the A1 loop (Girma, et al., Thromb. Haemost., 68:707-13, 1992). Finally, the GPIb-binding site can be achieved by the removal of the sialic acid residues from the carbohydrate side chains of vWF (Gralnick, et al., 1985, J. Clin. Invest., 75:19-25). Since 9 of the 22 carbohydrate chains of vWF are within the T116 fragment but outside the A1 loop, the net local decrease of the negative charges may be responsible for the exposure of the GPIb-binding site.
Studies of patients with von Willebrand disease (vWD) have confirmed the role of the conformation of the A1 domain in the regulation of vWF binding to GPIb. vWF from patients with type 2B vWD is characterized by an increased capacity to bind to platelet GPIb. Mutations of this type have been identified within the 505-698 aa residues (Ginsburg, et al., Thromb. Haemost., 69:177-84, 1993). The expression of recombinant, mutated vWF has confirmed the direct role of these mutations in the increased affinity of vWF for GPIb (Randi, et al., 1992, J. Biol. Chem., 267:21187-21192; Inbal, et al., 1993, Thromb. Haemost., 70:1058-1062; Cooney, et al., 1992, Proc. Natl. Acad. Sci USA, 89:2869-2872; Kroner, et al., 1992, Blood, 79:2048-2055).
Matsushita, et al. (1995, J. Biol. Chem., 270:13406-13414) recently performed charged-to-alanine mutagenesis of the vWF A1 domain to examine the roles of specific charged residues in the interaction of vWF with platelet GPIb. By this approach, amino acid residues Glu596 and Lys599 appeared to be important in the interaction of vWF with platelet GPIb. Furthermore, alanine substitutions at Arg545, the site of the type 2b mutations studied by Inbal, et al. (1993, Thromb. Haemost., 70:1058-62), and the segments between Glu496-Arg511 and Arg687-Glu689 resulted in spontaneous binding of vWF to GPIb. The striking distribution of positive and negative charges in distinct regions of the A1 domain suggests that intramolecular electrostatic interactions among these sites play a major role in the regulation of vWF binding to GPIb. An acidic segment, Asp252 and Asp287, of the GPIb a chain was identified as a binding site for vWF (Murata, et al., 1991, J. Biol. Chem., 266:15474-15480).
Nitric Oxide and Platelet Function
An important determinant of the anti-thrombotic properties of the normal endothelium is its ability to inhibit platelet activation, adhesion, and aggregation. Two principal endothelial products account for these antiplatelet effects: prostacyclin and endothelium-derived relaxing factor (EDRF)/NO (Loscalzo, et al., 1996, in xe2x80x9cMethods in Nitric Oxide Research,xe2x80x9d M. Feelisch and J. S. Stamler, editors, John Wiley and Sons, Ltd., Chichester. U.K., pp. 584-591). These substances act synergistically to inhibit platelet function, and do so through cAMP- and cGMP-dependent mechanisms, respectively (Loscalzo, et al., 1996). Importantly, while both prostacyclin and NO inhibit platelet activation and aggregation, only NO is effective as an inhibitor of platelet adhesion (deGraaf, et al., 1992, Circ., 85:2284-2290). The importance of EDRF-mediated inhibition of platelet function in vivo is best illustrated by the observation that inhibition of NO synthesis can be accompanied by intravascular thrombosis (Shultz, et al., 1992, J. Clin. Invest., 90:1718-1725, Freedman, et al., 1996, J. Clin. Invest., 97:979-987). Inhibition of platelet function by NO can be potentiated by thiols (Loscalzo, et al., 1996), and this effect is probably a consequence of the formation of thionitrites or S-nitrosothiols (Loscalzo, et al., 1996). These NO adducts are potent platelet inhibitors that form in vivo and are probably responsible for stabilizing NO and for many of the biological effects attributed to NO directly in the vasculature (Loscalzo, et al., 1996). Previous work has shown that S-nitrosation of a protein avid for subendothelium (i.e., serum albumin) impairs platelet adhesion and smooth muscle proliferation following vascular injury (Marks, et al., 1995, J. Clin. Invest., 96:2630-2638).
It is an object of this invention to provide new antithrombotic compositions which impair platelet activation and adhesion.
It is another object of this invention to provide a compound which competes with endogenous von Willebrand""s Factor for binding to GPIb/IX but does not activate platelets upon binding to GPIb/IX.
It is another object of this invention to provide a method of treating an atherothrombotic disorder administering to patients new antithrombotic compositions which impair platelet activation and adhesion. These and other objects are met by one or more of the following embodiments.
In one embodiment, this invention provides a polypeptide which binds to platelet receptor glycoprotein Ib/IX (GPIb/IX) and competes with mature von Willebrand""s Factor for binding to GPIb/IX, but does not activate platelets upon binding to GPIb/IX. The peptide of this invention contains at least one cysteine residue which is S-nitrosated. Preferably, the polypeptide according to this invention contains at least a portion of the sequence of the A1 domain of von Willebrand""s factor. More preferably, the polypeptide according to this invention is polythiolated and a plurality of thiol groups are nitrosated.
In another embodiment, this invention provides a substantially pure polypeptide containing at least the amino acid sequence of von Willebrand""s factor from Ala at position 444 to Asn at position 730 (corresponding to Ala 1207 to Asn 1493 of SE ID NO:1), but where the amino acid residue at position 545 is Cys (corresponding to amino acid residue 1308 of SEQ ID NO:1). Preferably, the polypeptide according to this embodiment has at least one cysteine residue which is S-nitrosated. More preferably, the polypeptide according to this embodiment is polythiolated and a plurality of thiol groups are nitrosated.
In yet another embodiment. this invention provides a method of treating a patient having an atherothrombotic disorder by administering to the patient a pharmaceutical composition containing a polypeptide which binds to platelet receptor glycoprotein Ib/IX (GPIb/IX) and competes with endogenous von Willebrand""s Factor for binding to GPIb/IX, but does not activate platelets upon binding to GPIb/IX. Preferably the polypeptide used in this method contains at least one cysteine residue which is S-nitrosated. More preferably, the polypeptide according to this invention contains at least a portion of the sequence of the A1 domain of von Willebrand""s factor. Even more preferably, the polypeptide according to this invention is polythiolated and a plurality of thiol groups are nitrosated.
The inventors have combined the unique antiplatelet effects of S-nitrosothiols and the antiadhesive properties of fragments of vWF in the A1 domain, thereby providing unique molecules that exploit both of these properties. One preferred molecule comprises a fragment of A1 (Ala 444-Asn 730) in which the arginine at position 545 is replaced by cysteine (the most frequent von Willebrand disease type 2b mutation) that has been shown by the inventors to impair platelet adhesion, and to exhibit antithrombotic activity in vivo. This cysteine residue is S-nitrosated, to produce a molecule that is denoted S-NO-AR545CvWF. This unique molecule has the potential for impairing platelet adhesion as well as activation/aggregation, and as such forms the basis of a novel therapeutic strategy for impairing platelet responses following vascular injury or in other thrombotic disorders.
Antiplatelet Therapy
In both thrombosis and reclusion of coronary arteries, platelet adhesion is the initiating event. Thrombolytic therapy (streptokinase, tissue-type plasminogen activator) benefits patients who have suffered a myocardial infarction by reducing mortality and infarct size (Loscalzo, et al., 1996; Gruppo Italiano per lo Studio della Streptomachinasi nell""Infarto Miocardico, 1986, Lancet, 1:397-402; ISIS-2 (Second International Study of Infarct Survial) Collaborative Group, 1988, J. Am. Coll. Cardiol., 12:3A-13A). However, the benefit is limited by incomplete reperfusion, a delayed recanalization time, and occurrence of thrombotic reclusion in up to 15% of cases (Van de Werf, et al., 1990, British Med. J., 297:1374-1379; Colleen, 1990, Ann. Intern. Med., 112:529-538: Colleen, et al., 1991, Prig. Cardiovasc. Dis., 34:101-102). Importantly, thrombolytic therapy is also accompanied by increased platelet activation by the direct action of plasmin on the platelet, by the elaboration of thrombin through the action of plasmin in generating prothrombinase, and by the exposure of subendothelial collagen following lysis of the occlusive thrombus (Loscalzo, et al., 1995, Thromb. Haemost., 74:291-293).
Since the first event in thrombogenesis is the recognition of vessel wall-bound vWF by platelets through the GPIb receptor, it is apparent that the selective inhibition of binding of endogenous vWF to GPIb as adjunctive therapy for thrombolysis would be an appropriate early intervention, likely to result in a beneficial anti-thrombotic effect. It was previously shown that the tryptic fragment of vWF of 52/48 kDa comprising residues Val449 and Lys728 inhibits the binding of native vWF to GPIb (Fujimura, et al., 1986, J. Biol. Chem., 261:381-385). Moreover, the GPIb-binding domain of vWF expressed in E. coli has been shown to inhibit the binding of native vWF to GPIb (Sugimoto, et al., 1991, Biochemistry, 30:5202-5209), and unlike native vWF bound to GPIb, does so in the absence of any modulator. These previous studies provided the rationale for the use of a recombinant vWF fragment as an antiplatelet/anti-thrombotic agent. Indeed, recently, several fragments of vWF expressed in E. coli containing the A1 domain have been shown to bind to the platelet membrane GPIb receptor and inhibit the interaction of vWF with platelets (Gralnick, et al., 1992, Proc. Natl. Acad. Sci. USA, 89:7880-7884); Mohri, et al., 1993, Peptides, 14:125-129).
Experimental studies with VCL (Bio-Technology General, Inc.), another recombinant fragment of von Willebrand factor that spans from leu504 to lys728, showed delayed thrombus formation and reclusion in dogs (Yao, et al., 1994, Circulation, 89:2822-2828). This fragment was also shown to have local anti-thrombotic effects on nitrogen laser-induced thrombus formation in guinea pig mesenteric arteries without compromising general hemostasis and, importantly, without prolonging bleeding time (Azzam, et al., 1995, Thromb. Haemost., 73:318-323).
The inventors have discovered that recombinant mutant vWF fragment AR545C can bind to the platelet surface receptor involved in adhesion and that this mutant fragment exhibits anti-thrombotic activity in vitro. The inventors have also discovered that nitric oxide congeners, such as S-nitroso-N-acetyl-L-cysteine and S-nitroso-serum albumin, have antiplatelet effects. Nitric oxide delivered by these S-nitrosothiols inhibits platelet function by a variety of interrelated mechanisms and, importantly, is a powerful inhibitor of platelet adhesion, a property not shared by the other potent endothelial product, prostacyclin.
Nitrosated (S-NO-AR545C), or polynitrosated mutant vWF fragment, (pS-NO-AR545C), provides targeted delivery of nitric oxide to the platelet through its S-nitrosothiol functional group(s). The targeted delivery of NO, based on AR545C binding to platelet glycoprotein Ib, will impair platelet activation and aggregation directly, an effect not manifest by the vWF fragments themselves, and thereby impairs platelet adhesion by two distinct mechanisms. These mechanisms at the very least are additives, but may also be synergistic, increasing the potency of the pharmacologic effects significantly.
The novel compounds of this invention represent a potential novel class of therapeutic agents useful for the treatment of atherothrombotic disorders. AR545C manifests its anti-thrombotic properties without prolonging the bleeding time in experimental animals. With the polynitrosated derivative, the toxic/therapeutic ratio (therapeutic index) for this class of antiplatelet agents will be significantly improved over existing agents.
Compounds of this invention are generally characterized in that they compete with von Willebrand factor for binding to platelet membrane protein GP Ib/IX. Generally, the compounds of this invention will not activate platelets upon binding to GP Ib. Additionally, compounds according to this invention contain one or more nitrosated thiol groups. Usually, the base compound prior to nitrosation will not activate platelets; however, so long as the nitrosated compound fails to activate platelets, the compound may be within the contemplation of this invention. Particular preferred compounds are polypeptides derived from the amino acid sequence of the A1 domain of von Willebrand""s factor. Fragments of von Willebrand""s factor which compete for binding to receptor protein GP Ib are described above, and these fragments are suitable starting points for the compounds of this invention. Where such peptide fragments are capable of binding GPIb but do not contain cysteine residues, thiol groups for nitrosation may be added by homocysteine thiolactone dervatization of epsilon- or alpha-amino groups through ester links by the methods of Benesch and Benesch (1958, Proc. Natl. Acad. Sci. USA, 44:848-853). Alternatively, analogs of the fragments may be prepared using recombinant DNA techniques by expression of a nucleic acid sequence corresponding to a portion of the von Willebrand sequence except for point mutation of one or more codons to encode cysteine residues in the expressed polypeptide.
The practice of the present invention employs, unless otherwise indicated, conventional molecular biology, microbiology, and recombinant DNA techniques within the skill of the art. Such techniques are well known to the skilled worker and are explained fully in the literature. See, e.g., Maniatis, Fritsch and Sambrook, xe2x80x9cMolecular Cloning: A Laboratory Manualxe2x80x9d (1982): xe2x80x9cDNA Cloning: A Practical Approach,xe2x80x9d Volumes I and II (D. N. Glover, ed., 1985); xe2x80x9cOligonucleotide Synthesisxe2x80x9d (M. J. Gait, ed., 1984); xe2x80x9cNucleic Acid Hybridizationxe2x80x9d (B. D. Hames and S. J. Higgins, eds., 1985); xe2x80x9cTranscription and Translationxe2x80x9d (B. D. Hames and S. J. Higgins, eds., 1984); xe2x80x9cAnimal Cell Culturexe2x80x9d (R. I. Freshney, ed., 1986); xe2x80x9cImmobilized Cells and Enzymesxe2x80x9d (IRL Press, 1986): B. Perbal, xe2x80x9cA Practical Guide to Molecular Cloningxe2x80x9d (1984), and Sambrook, et al., xe2x80x9cMolecular Cloning: a Laboratory Manualxe2x80x9d (1989).
The polypeptide and DNA sequence of vWF is readily available to those skilled in the art, for instance in Genbank under accession No. X04385. The polypeptide sequence of vWF is shown in SEQ ID NO. 1, and the DNA sequence of vWF is shown in SEQ ID NO. 2. DNA segments or oligonucleotides having specific sequences can be synthesized chemically or isolated by one of several approaches. The basic strategies for identifying, amplifying and isolated desired DNA sequences as well as assembling them into larger DNA molecules containing the desired sequence domains in the desired order, are well known to those of ordinary skill in the art. See, e.g., Sambrook, et al., (1989); B. Perbal., (1984). Preferably, DNA segments corresponding to all or a portion of the vWF sequence may be isolated individually using the polymerase chain reaction (M. A. Innis, et al., xe2x80x9cPCR Protocols: A Guide To Methods and Applications,xe2x80x9d Academic Press, 1990). A complete sequence may be assembled from overlapping oligonucleotides prepared by standard methods and assembled into a complete coding sequence. See, e.g., Edge (1981), Nature, 292:756; Nambair, et al. (1984), Science, 223:1299 Jay et al. (1984), J. Biol. Chem., 259:6311.
The assembled sequence can be cloned into any suitable vector or replicon and maintained there in a composition which is substantially free of vectors that do not contain the assembled sequence. This provides a reservoir of the assembled sequence, and segments or the entire sequence can be extracted from the reservoir by excising from DNA in the reservoir material with restriction enzymes or by PCR amplification. Numerous cloning vectors are known to those of skill in the art, and the selection of an appropriate cloning vector is a matter of choice (see, e.g., Sambrook, et al., incorporated herein by reference). The construction of vectors containing desired DNA segments linked by appropriate DNA sequences is accomplished by techniques similar to those used to construct the segments. These vectors may be constructed to contain additional DNA segments, such as bacterial origins of replication to make shuttle vectors (for shuttling between prokaryotic hosts and mammalian hosts), etc.
Procedures for construction and expression of mutant proteins of defined sequence are well known in the art. A DNA sequence encoding a mutant form of vWF or a fragment thereof can be synthesized chemically or prepared from the wild-type sequence by one of several approaches, including primer extension, linker insertion and PCR (see, e.g., Sambrook, et at.). Mutants can be prepared by these techniques having additions, deletions and substitutions in the wild-type sequence. It is preferable to test the mutants to confirm that they are the desired sequence by sequence analysis and/or the assays described below. Mutant vWF fragments for testing may be prepared by placing the coding sequence for the polypeptide in a vector under the control of a promoter, so that the DNA sequence is transcribed into RNA and translated into protein in a host cell transformed by this (expression) vector. The mutant fragments may be produced by growing host cells transfected by an expression vector containing the coding sequence for the mutant under conditions whereby the polypeptide is expressed. The selection of the appropriate growth conditions is within the skill of the art.
Producing the Recombinant Peptide
Preferably, DNA from the selected clones should be subcloned into an expression vector, and the polypeptide expressed by cells transformed with the vector may be tested for immunoreactivity with antibodies against vWF or the polypeptide of this invention. Such subcloning is easily within the skill of the ordinary worker in the art in view of the present disclosure. The amino acid coding region of the DNA sequence for this invention may be longer or shorter than the coding region of vWF so long as the recombinant peptide expressed by the DNA sequence retains ability to bind GPIb. The preparation of selected clones which contain DNA sequences corresponding to all or part of the sequence of vWF may be accomplished by those of ordinary skill in the art using conventional molecular biology techniques along with the information provided in this specification and the vWF sequence as disclosed herein.
Where clones are selected from an expression library, selection may be accomplished by expressing the library sequences and detecting the expressed peptides immunologically. Clones are selected that express peptides which bind antibodies specific for vWF or which bind GPIb. These selection procedures are well known to those of ordinary skill in the art (see, e.g., Sambrook, et al.). Hybridization using a nucleic acid whose sequence corresponds to the sequence of vWF may be used to select clones corresponding to a portion of the vWF gene.
Cloning for Expression
Once a coding sequence for the desired polypeptide sequence has been prepared or isolated, it can be cloned into any suitable vector or replicon and thereby maintained in a composition which is substantially free of vectors that do not contain the coding sequence (e.g., free of other clones from the library). Numerous cloning vectors are known to those of skill in the art, and the selection of an appropriate cloning vector is a matter of choice (see, e.g., Sambrook, et al., incorporated herein by reference). The DNA sequences and DNA molecules of the present invention may be expressed using a wide variety of host/vector combinations. According to the present invention, the coding sequence is placed under the control of a promoter, ribosome binding site (for bacterial expression) and, optionally, an operator (collectively referred to herein as xe2x80x9ccontrolxe2x80x9d elements), so that the DNA sequence is transcribed into RNA in the host cell transformed by a vector containing this expression construct. The coding sequence may or may not contain a signal peptide or leader sequence.
Of course, not all host/expression vector combinations function with equal efficiency in expressing the DNA sequences of this invention or in producing the polypeptides of this invention. However, a particular selection of a host/expression vector combination may be made by those skilled in the art. For example, the selection should be based on a balancing of a number of factors. These include compatibility of the host and vector, toxicity of the proteins encoded by the DNA sequence to the host, ease of recovery of the desired protein, expression characteristics of the DNA sequences and the expression control sequences operatively linked to them, biosafety, costs and the folding, form or any other necessary post-expression modifications of the desired protein. Preferably, the host cell will not express proteases which degrade the recombinant polypeptide of this invention.
Depending on the expression system and host selected, the protein is produced by growing host cells transformed by an expression vector containing the coding sequence for a polypeptide cross-reactive with the hpr gene product under conditions whereby the protein is expressed. The protein is then isolated from the host cells and purified. The selection of the appropriate growth conditions and recovery methods are within the skill of the art. Suitable expression vector and host cell systems are well known to those of ordinary skill in the art, and are taught, for instance, in Sambrook, et al., 1989. The peptide may be obtained by growing the transformed cells in culture under conditions wherein the cloned DNA is expressed. Depending on the expression vector chosen, the peptide may be expressed as a fusion protein or a mature protein which is secreted or retained intracellularly, or as an inclusion protein. The desired polypeptides can be recovered from the culture by well-known procedures, such as centrifugation, filtration, extraction, and the like, with or without cell rupture, depending on how the peptide was expressed. The crude aqueous solution or suspension may be enriched for the desired peptide by protein purification techniques well known to those skilled in the art.
Purified polypeptides prepared as described herein may be readily nitrosated by S-nitroso-glutathione using standard procedures of direct nitrosation or trans-S-nitrosation (Zhang, et al., 1996, Meth. Neurosci., 31:41-46; Zhang, et al., 1996, J. Biol. Chem., 271:14271-14279). Other procedures for nitrosating thiol groups on polypeptides which are know to those skilled in the art may also be used.
The skilled worker will of course confirm that molecules prepared according to this invention have the required properties of competitive binding to the GPIb platelet receptor in a manner which competes with vWF and does not activate platelets. Suitable assays are set forth in detail in the examples below, including inhibition of ristocetin-induced platelet aggregation, inhibition of platelet aggregation induced by ADP-thrombin, and inhibition of platelet adhesion in a flow model. Further confirmatory assays may include demonstration of clot lysis in a rabbit femoral thrombosis model (see Rudd, et al., 1992, Circ. Res., 70:829-834) or radiolabeled platelet accretion model (see Marks, et al., 1995, J. Clin. Invest., 96:2630-2638).
Anti-thrombotic molecules according to this invention provide a new mode of therapy for atherothrombotic arterial diseases and venous thrombotic diseases. Atherothrombotic arterial diseases within the contemplation of this invention include coronary artery disease, such as stable angina pectoris, acute coronary syndromes, such as unstable angina pectoris and acute myocardial infarction; cerebral vascular disease, including acute stroke and transient ischemic attack; mesenteric arterial disease; mesenteric ischemia xe2x80x9cabdominal angina,xe2x80x9d and mesenteric infarction; as well as peripheral arterial disease, including acute peripheral arterial occlusion and intermittent claudication. Compounds of this invention are also useful during treatment of coronary artery disease, including anti-thrombotic therapy during coronary angioplasty, anti-thrombotic therapy during cardiopulmonary bypass, and limiting of platelet activation during ischemia reperfusion. Venous thrombotic diseases which may be treated according to this invention include deep venous thrombosis and pulmonary thromboembolism. These compounds are also useful in anti-thrombotic therapy for pulmonary hypertension.
Therapeutic compounds according to this invention are preferably formulated in pharmaceutical compositions containing the compound and a pharmaceutically acceptable carrier. The pharmaceutical composition may contain other components so long as the other components do not reduce the effectiveness of the compound according to this invention so much that the therapy is negated. Some other components may have independent therapeutic effects. Pharmaceutically acceptable carriers are well known, and one skilled in the pharmaceutical art can easily select carriers suitable for particular routes of administration (see, e.g., Remington""s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 1985). The concentrations of the active agent in pharmaceutically acceptable carriers may range from 0.01 xcexcg/ml to 500 xcexcg/ml.
The pharmaceutical compositions containing any of the compounds of this invention may be administered by parenteral (subcutaneously, intramuscularly, intravenously, intraperitoneally, intrapleurally, intravesicularly or intrathecally), topical, oral, rectal, or nasal route, as necessitated by choice of drug and disease.
Dose and duration of therapy will depend on a variety of factors, including the therapeutic index of the drugs, disease type, patient age, patient weight, and tolerance of toxicity. Dose will generally be chosen to achieve serum concentrations from about 0.1 xcexcg/ml to about 100 xcexcg/ml. Preferably, initial dose levels will be selected based on their ability to achieve ambient concentrations shown to be effective in in-vitro models, such as that used to determine therapeutic index, and in-vivo models and in clinical trials, up to maximum tolerated levels. Standard clinical procedure prefers that chemotherapy be tailored to the individual patient and the systemic concentration of the chemotherapeutic agent be monitored regularly. The dose of a particular drug and duration of therapy for a particular patient can be determined by the skilled clinician using standard pharmacological approaches in view of the above factors. The response to treatment may be monitored by analysis of blood or body fluid levels of the compound according to this invention, measurement of activity if the compound or its levels in relevant tissues or monitoring disease state in the patient. The skilled clinician will adjust the dose and duration of therapy based on the response to treatment revealed by these measurements.
These compounds may also be applied locally or topically in gels, ointments, solutions, impregnated bandages, liposomes, or biodegradable microcapsules. Compositions or dosage forms for topical application may include solutions, lotions, ointments, creams, gels, suppositories, sprays, aerosols, suspensions, dusting powder, impregnated bandages and dressings, liposomes, biodegradable polymers, and artificial skin. Typical pharmaceutical carriers which make up the foregoing compositions include alginates, carboxymethylcellulose, methylcellulose, agarose, pectins, gelatins, collagen, vegetable oils, mineral oils, stearic acid, stearyl alcohol, petrolatum, polyethylene glycol, polysorbate, polylactate, polyglycolate, polyanhydrides, phospholipids, polyvinylpyrrolidone, and the like. For example, these compounds may be used to impede restenosis by application in a hydrogel at the time of angioplasty. A preferred strategy is to administer these compounds angioscopically in a suitable formulation.
A particularly preferred formulation for compounds according to this invention is in liposomes. Liposomes containing compounds according to this invention may be prepared by any of the methods known in the art for preparation of liposomes containing inclusions. Liposomes that are particularly suited for aerosol application to the lungs are described in International Patent Publication WO 93/12756, pages 25-29, incorporated herein by reference.


Disclosed are an apparatus and method for providing packet data service from a radio network controller (RNC) to user equipment (UE) in a mobile communication system. A radio bearer (RB) of a predetermined channel type is configured to compress and de-compress headers of packets passed between the RNC and the UE. The packet data service is provided from the RNC to the UE via the RB. When the channel type is changed, configuration information associated with an RB of the changed channel type is determined. Header compression (HC) context used in the RB of a previous channel type is acquired according to the configuration information and the RB of the changed channel type including the acquired HC context is configured. The packet data service is continuously provided via the RB of the changed channel type. Therefore, the invention reduces waste of radio resources that is due to a channel type change and delay that is due to system reset.

1. Field of the Invention
The present invention relates to a mobile communication system supporting packet data, and more particularly to an apparatus and method for establishing header compression context necessary for header compression/decompression when a channel type for data transfer has been changed.
2. Description of the Related Art
A universal mobile telecommunication service (UMTS) system is the third generation mobile communication system using (3G MCS) wideband code division multiple access (CDMA). 3G MCS system is based on a global system for mobile (GSM) communications. It serves as a European mobile communication system and is being developed into multimedia communication that transfers large-capacity data such as packet data, circuit data, etc. as well as voice service.
FIG. 1 shows the architecture of a conventional mobile communication system. Here, the structure of the UMTS system is shown. Referring to FIG. 1, the UMTS system comprises a core network (CN) 100 and a plurality of radio network subsystems (RNSs) 110 and 120. The plurality of RNSs 110 and 120 configure a UMTS terrestrial radio access network (UTRAN)
The RNSs 110 and 120 comprise radio network controllers (RNCs) 111 and 112 and a plurality of Node Bs 115, 113, 114 and 116. In more detail, the RNS 110 is constituted by the RNC 111 and the Node Bs 113 and 115, and the RNS 120 is constituted by the RNC 112 and the Node Bs 114 and 116. The RNCs 111 and 112 are classified into a serving RNC (SRNC), a drift RNC (DRNC) and a controlling RNC (CRNC) according to their roles. The SRNC manages information of user equipment (UE), and is responsible for data transfer with the CN 100. The DRNC is directly connected to the UE, and the CRNC controls radio resources for each of the Node Bs 113-116.
The RNCs 111 and 112 and the Node Bs 113 to 116 are connected to each other via interfaces called Iub. The RNCs 111 and 112 are connected to each other via an interface called Iur. The UE 130 and the UTRAN are connected to each other via a Uu interface (not shown in FIG. 1). The RNCs 111 and 112 allocate radio resources to the plurality of Node Bs 113 to 116 managed thereby, and the Node Bs 113 to 116 provide the radio resources allocated from the RNCs 111 and 112 to the UE 130. The radio resources are configured cell by cell. The radio resources provided by each Node B are radio resources associated with a specific cell covered by a corresponding Node B. The UE 130 establishes a radio channel using the radio resources associated with the specific cell covered by the Node Bs 113 to 116, such that data is transmitted and received via the established radio channel. Because the UE 130 recognizes only a physical channel configured on a cell-by-cell basis, distinction between the Node B 113-116 and the cell is meaningless. Hereinafter, the terms Node B and cell will be used interchangeably.
With the development of communication technology, packet data service provided by the mobile communication system has developed into broadcast/multicast service that provides identical data from a single data source to a plurality of UEs. The broadcast/multicast service can be divided into cell broadcast service (CBS), i.e., message-centered service, and multimedia broadcast/multicast service (MBMS) supporting a multimedia form such as real-time image and speech, still pictures, text, etc.
The MBMS is a service for sending identical multimedia data such as real-time images, speech, still pictures, text, etc. to a plurality of recipients over a radio network. Because an MBMS data stream must be sent to a plurality of cells in which the UEs are located, the UEs set up a point to point (PTP) connection or a point to multipoint (PTM) connection according to the number of UEs located in a corresponding cell that use the MBMS via the set-up connection, respectively.
The MBMS using the PTP connection is provided via a dedicated channel allocated to each UE. The MBMS using the PTM connection is provided via a common channel that all the UEs located within a corresponding cell can access. An MBMS system counts the number of UEs coupled to the MBMS cell by cell, and determines a channel type to be used for the MBMS according to a count value. When the number of UEs using a specific MBMS within an arbitrary cell varies, the UEs will newly establish a channel based on a new channel type under control of the RNC, respectively. Each UE receives configuration information necessary for using the new channel from the system in order to carry out a new channel setup operation. In case of the MBMS based on the Internet protocol (IP), the configuration information includes many parameters associated with protocol in a wireless zone and the IP.
As described above, because the MBMS provides identical data from a single data source to a plurality of UEs, the identical parameters are used in the IP irrespective of a channel type in the wireless zone. In particular, although the channel type for the MBMS in an arbitrary cell is changed from a PTM channel to a PTP channel, the UEs located in the cell still have the IP-related parameters for the MBMS. Nevertheless, the UE must re-receive a large amount of configuration information to carry out a radio channel setup operation based on a new channel type in the conventional MBMS system. For this reason, there are problems in that radio resources are unnecessarily wasted, which may cause a service delay or cutoff phenomenon.

Apparatus and method for establishing header compression context according to channel type change in packet data service


In a merchandise order receiving system, an order controlling server receives an order of a merchandise from a user terminal; a charging and settlement server performs the charging and the settlement of the merchandise; an order receiving server receives an order of the delivery of a merchandise; a print-out apparatus prints image data from an image storing server to generate printed material such a as hologram or holographic stereogram; and a merchandise assembling apparatus generates an assembled merchandise by incorporating the printed matter in the merchandise and supplies the assembled merchandise to a shipping terminal.

1. Field of the Invention
The present invention relates to a merchandise order receiving system, i.e., a system for receiving an order for merchandise, a product, goods, commodities or the like, and a merchandise order receiving method, both for receiving order for merchandise/goods/commodities through network.
2. Description of the Related Art
Recently, systems for selling merchandise through a network such as the Internet have been established. In such systems, a customer accesses so-called a Website managed by an business operator by the use of a communication terminal to select a desired merchandise and input prescribed information to perform a process of receiving an order of the merchandise. In such a system, it is not necessary for a customer/client to actually visit a store in person in order to purchase the merchandise. Accordingly, the customer can spend more time to select merchandise among a variety of choices.

Merchandise order receiving system and merchandise order receiving method


An apparatus for overhead submerged arc welding has a hopper containing flux being pivotally mounted on a suspension for rotation about the suspension axis, the hopper having a bowl provided in the top part thereof, a welding head with a nozzle for supplying a consumable electrode, and means for supplying flux and pressing it against work.. The apparatus also has a forming means mounted for swinging in its longitudinal and transverse planes and for a vertical adjustment with respect to the work being welded. The forming means is in the form of a U-shaped body having its open top part facing towards the work being welded and legs having on the side of the nozzle a pair of diverging wedge-shaped projections, an adjusting bar being provided inside the body to extend length-wise of the joint being welded. Copying members in the form of four wheels are provided outside the body on either side of the legs thereof.. This construction of the forming means ensures maintenance of preset flux pressures at various points along the joint being welded.

1. Field of the Invention
The invention relates to the equipment for arc welding, in particular, and it deals with an apparatus for overhead submerged arc welding.
2. Description of the Related Art
A large volume of operations in the manufacture of welded structures is carried out in welding rotatable annular joints of hollow structures with a restricted access to joints being welded on the inner side of the structure. Such joints include annular joints of closed vessels, annular joints of pipelines, tanks, casings, field welds and shell plating seams of ship hulls; longitudinal joints of large-area products which cannot be positioned to facilitate welding. They also include joints of difficult-to-position webs, segments, three-dimensional and planar sections, and the like.
A submerged arc overhead welding method is characterized in that a consumble electrode and a welding bath are turned at 180.degree. in comparison with downhand welding. Flux an electrode are fed to the work from bottom up, i.e. as though towards a ceiling, the electrode being supplied through a compacted flux.
This welding method is referred to hereinbelow as overhead submerged arc welding.
This welding method is referred to as the overhead submerged arc welding also because the arc is in the body of metal.
So called overhead welds are produced as a result of such welding.
Overhead welds may be of different types, e.g. penetration overhead welds, sealing overhead welds. There may be one-pass overhead welds and other types of overhead welds.
The penetration overhead welds are welds which are first to be produced in welding a joint and which are located in the top part of sections being welded on the joint side opposite with respect to the electrode supply. Further welding of the joint, i.e. producing the necessary subsequent welds is carried out by any appropriate known method, the electrode being supplied on the same side as is the case with welding of the overhead penetration weld, e.g. the inner penetration welds of rotatable annular joints of vessels, tanks, joints between bottom sections of shell plating of ships and other structures.
The overhead penetration weld arc welding allows, to a large extent, the operation of welding from the interior of a vessel to be dispensed with in welding rotatable annular welds, and welding in confined spaces in producing straight welds of structures with a restricted access on the side of a ceiling can also be eliminated.
The sealing overhead welds are welds which are first to be produced in welding a joint and which are located in the bottom part of sections being welded on the electrode supply side of the joint. Further welding is carried out by any appropriate known method with the electrode supply on the side of the joint being welded opposite to that used in the overhead welding.
In practice, the penetration overhead welds are produced in welding annular and longitudinal joints of structures with a restricted access to joints being welded from the inside, the sealing welds being produced in welding longitudinal joints of difficult-to-position products, e.g. plate structures made out of segments, and other products.
One-pass overhead welds include welds produced in welding joints of a limited thickness arranged over the whole welded section. No further welding of the joint on any side thereof will be required.
Welding of sealing and one-pass welds poses many problems concerned with the formation of the surface of a finished weld.
During the overhead welding, the welding bath metal formed during arcing by fusion of the metal being welded, electrode material and flux is retained by a crust of partly melted flux and also by means of forming members. The forming members may be of various shapes and size and may be made, e.g. in the form of plates, backings, bars, sliders and other members and structures.
Flux is pressed against the welding zone positively from bottom up and, as flux is being consumed, its stock is continually replenished. For forming the top part of a weld, flux may be supplied both on the bottom side, through the gap between the edges of a product being welded, and from top by any appropriate known method by which a filled layer of flux is formed. Special forming backings or flux holding means may also be used.
Numerous problems arise especially in welding hard to get at joints of large-size products of cylindrical or like configuration such as ship hulls and boiler units where especially high quality of welds is required and where the products must be rotated about their axis during welding operations, as well as in welding large-area planar products which it is very difficult to place in a position facilitating the welding.
Known in the art is an apparatus for overhead submerged arc welding (SU, A, 469554), comprising a hopper containing flux and a bowl for supplying flux thereto and for pressing flux against the work. The bowl has an outlet port facing towards the joint being welded and an inlet port for supplying flux to the bowl and for creating a desired pressure of flux in the bowl. Flux is supplied by a pipe communicating with the inlet port of the bowl. The pipe has a flux supply means in the form of an auger.
A welding nozzle through which the consumable electrode is supplied is provided in the bowl adjacent to the inlet port and a pivotally mounted adjusting plate located downstream of the welding nozzle is provided on the side of the bowl opposite to the inlet port.
For varying the angle of inclination with respect to the outlet port of the bowl, the adjusting plate has an adjusting screw.
This apparatus provided with the adjusting plate allows preset flux pressure to be controlled during welding at different points along the joint being welded.
During welding by means of this apparatus, the operator keep an eye on the joint being welded and, if parameters of the joint, e.g. the amount of clearance between the edges of the structure deviate from preset values, the operator can correct the situation by acting upon the screw to vary the angle of inclination of the plate so as to maintain the desired flux pressure since it is very important that preset flux pressure values for high-quality overhead welding be maintained with maximum possible accuracy at various points along the joint being welded because otherwise the weld would be of poor quality.
The abovedescribed apparatus cannot, however, ensure an automatic maintenance of preset flux pressure values at various points along the joint being welded without operator's interference. During welding with this apparatus, it is necessary to continually vary position of the adjusting plate so that the operator must be continually involved and must pay a special attention during welding, the operator having to be very skillful. Consequently, quality of weld in welding with the aid of this apparatus depends on the operator's skill and experience which may not unfrequently result in low-quality welds.
In addition, the experience of operation of such an apparatus showed that it is suitable for welding joints having minimum deviations of parameters of their assembly before welding (e.g. misalignment of the plate edges, gap, V-section, etc.) and cannot be used for welding elongated products or annular joints, especially of large-diameter structures.
Known in the art is an apparatus for overhead arc welding (FR, B, 2568808), comprising a hopper containing flux and accommodating a bowl having an inlet port and an outlet port, the inlet port communicating with a flux supply pipe. A welding nozzle for supplying a consumable electrode is provided in the bowl. The bowl cooperates with a forming means having an adjusting bar for providing different pressures of flux at various points along the joint being welded, a part of the forming means being located directly in the bowl, adjacent to the consumable electrode.
The hopper supports a means for supplying the electrode to the welding nozzle, and the hopper is mounted on a suspension by means of a pivot pin for rotation about this pivot pin and has a point-like contact copying member which is located substantially in line with the adjusting bar. The adjusting bar also has a pair of copying members and is mounted for longitudinal and transverse swinging movements.
In addition, the hopper is provided with a means for pressing the hopper proper and the copying member against the work being welded.
This apparatus for overhead welding can substantially automatically maintain the stability of flux pressures necessary for carrying out high-quality welding at various points along the joint being welded. Participation of the operator in controlling welding process is substantially dispensed with, especially in welding elongated products of a regular geometry (and more especially, of cylindrical and straight products), deviations from joint assembly parameters before welding being compensated for.
This apparatus makes it possible to implement the method of overhead submerged arc welding in which different present flux pressure values are automatically maintained at various points along the joint being welded during welding so as to produce high-quality penetration overhead welds.
This construction of the apparatus ensures a reliable retention of a welding bath during welding at the level of the joint being welded and the formation of high-quality welds with the desired formation of reinforcement on the inner side of the weld (on the side opposite to the ceiling), i.e. in producing penetration overhead welds.
However, the welds produced in this manner have deviations of shape of the outer side of the finished weld admissible for the penetration weld, in the form of irregularities, undercuts, local weld width fluctuations and other defects on the outer side of the weld which will require further rewelding to provide a next layer.
These defects in forming the outer side of the weld can be explained by inadequate conditions provided by this apparatus for jamming and retaining flux at various points before the formation of welding bath and in the welding zone. In addition, this apparatus does not allow high-grade copying of the surface of the welded joint to be carried out directly adjacent to the point of welding which is necessary to producing sealing overhead welds, and especially one-pass overhead welds.
Moreover, this apparatus cannot provide maximum favorable conditions for copying position of the working surface of the bar with respect to the surface of the joint being welded in cases of a substantial deviation of its surface from regular geometry. This is due to the relative position of the copying members and their position with respect to the welding bath which is not quite optimum as it is necessary for producing sealing and one-pass overhead welds. Investigations have shown that the copying members should be located as close as possible to the welding bath (welding zone).

Apparatus for overhead submerged arc welding


A camshaft phaser includes a housing having a housing bore extending along an axis and a plurality of lobes extending radially inward. The camshaft phaser also includes a stroke limiter having a central hub with a plurality of vanes extending radially outward such that the vanes are interspersed with lobes. The camshaft phaser also includes a harmonic gear drive unit disposed operationally between the housing and the stroke limiter, the harmonic gear drive unit being connected to a rotational actuator for imparting rotation on the harmonic gear drive unit such that rotation of the harmonic gear drive unit by the rotational actuator causes relative rotation between the housing and the stroke limiter. The amount of relative rotation between the housing and the stroke limiter is limited by at least one of the plurality of lobes and at least one of the plurality of vanes.

Camshaft phasers for varying the timing of combustion valves in internal combustion engines are well known. A first element, known generally as a sprocket element, is driven by a chain, belt, or gearing from the crankshaft of the internal combustion engine. A second element, known generally as a camshaft plate, is mounted to the end of a camshaft of the internal combustion engine. A common type of camshaft phaser used by motor vehicle manufactures is known as a vane-type camshaft phaser. U.S. Pat. No. 7,421,989 shows a typical vane-type camshaft phaser which generally comprises a plurality of outwardly-extending vanes on a rotor interspersed with a plurality of inwardly-extending lobes on a stator, forming alternating advance and retard chambers between the vanes and lobes. Engine oil is supplied via a multiport oil control valve, in accordance with an engine control module, to either the advance or retard chambers, to change the angular position of the rotor relative to the stator, and consequently the angular position of the camshaft relative to the crankshaft, as required to meet current or anticipated engine operating conditions.
While vane-type camshaft phasers are effective and relatively inexpensive, they do suffer from drawbacks such as slow operation at low engine speeds due to low oil pressure, slow operation at low engine temperatures due to high oil viscosity, increased oil pump capacity requirement for the oil pump used to lubricate the internal combustion because the same pump is used to actuate the vane-type camshaft phaser, and the total amount of phase authority provided by vane-type camshaft phasers is limited by the amount of space between adjacent vanes and lobes and may not be sufficient to provide the desired amount of phase authority. For at least these reasons, the automotive industry is developing electrically driven camshaft phasers.
One type of electrically driven camshaft phaser being developed uses a harmonic gear drive unit, actuated by an electric motor, to change the angular position of the camshaft relative to the crankshaft. One example of such a camshaft phaser is shown in U.S. Pat. No. 8,322,318 to David et al., the disclosure of which is incorporated herein by reference in its entirety. The camshaft phaser of David et al. includes stop members which limit the phase authority of the camshaft phaser, i.e. the extent to which the camshaft phaser is able to advance and retard the camshaft relative to the crankshaft. While the camshaft phaser of David et al. may be effective, other options may be desirable to offer design flexibility and meet requirements in different vehicle applications.
What is needed is an electrically driven camshaft phaser which minimizes or eliminates one of more of the shortcomings as set forth above.


An ultrasonic transmitting/receiving device that effectively suppresses ringing during emission of ultrasonic waves and improves time resolution when measuring a sonic velocity includes a pair of ultrasonic transducers. Each of the ultrasonic transducers has a piezoelectric vibrator including a first electrode and a second electrode that are separated by a piezoelectric body and a backing disposed in contact with the first electrode and composed of the same material as a material of the piezoelectric body. The ultrasonic transducers are connected by a support so as to face each other and have a substantially rectangular U-shape as a whole when viewed from the side.

1. Field of the Invention
The present invention relates to an ultrasonic transmitting/receiving device and a method for fabricating the same.
2. Description of the Related Art
A typical known ultrasonic transmitting/receiving device has two ultrasonic transducers that face each other with a predetermined gap therebetween. Each of the ultrasonic transducers includes a piezoelectric vibrator having two electrodes which are separated by a piezoelectric body composed of polarized ceramic material such as lead zirconate titanate (PZT). The surface of one electrode is covered by a backing composed of rubber such as silicone rubber (see Japanese Unexamined Patent Application Publication Nos. 2000-14672, 11-155859, and 6-90950).
In the ultrasonic transducer, application of an electrical signal between the two electrodes excites the piezoelectric vibrator, which then emits ultrasonic waves, whereas reception of ultrasonic waves between the two electrodes vibrates the piezoelectric vibrator, which then converts the vibration into an electrical signal and outputs the signal. The backing absorbs and attenuates the ultrasonic waves emitted through the back surface of the piezoelectric vibrator during vibration.
In measuring the sonic velocity in a liquid medium using the ultrasonic transmitting/receiving device having a pair of ultrasonic transducers, ultrasonic waves are transmitted from one ultrasonic transducer through the liquid medium to the other ultrasonic transducer and the gap transit time, i.e., the time required for the ultrasonic waves to travel from one ultrasonic transducer to the other ultrasonic transducer is measured. The sonic velocity is calculated based on the gap transit time and the distance between the two ultrasonic transducers (see Japanese Unexamined Patent Application Publication Nos. 6-288993 and 6-288990).
When the sonic velocity of a small amount of liquid medium is measured with the ultrasonic transmitting/receiving device having two ultrasonic transducers facing each other, the ultrasonic transducers must be placed at a small distance from each other, resulting in a short gap transit time.
When a backing is provided on the piezoelectric vibrator, the backing attenuates the ultrasonic waves emitted through the back surface of the piezoelectric vibrator. Unfortunately, the acoustic characteristic impedance of the piezoelectric body that defines the piezoelectric vibrator and that of the backing are significantly different. For example, the acoustic characteristic impedance of the piezoelectric body is 30×106 kg/m2·s, whereas that of the backing is 5-7.5×106 kg/m2·s. This great difference in the acoustic characteristic impedance causes ringing. Ringing is a phenomenon in which sonic waves are reflected at the interface between the piezoelectric vibrator and the backing during vibration of the piezoelectric vibrator, generating resonance in the piezoelectric body. Due to this resonance, the piezoelectric vibrator does not stop vibrating in a short period of time but continues vibrating.
If ringing occurs in an ultrasonic transmitting/receiving device having ultrasonic transducers disposed with a small gap, vibration attributed to the ringing may be included in the electrical signal outputted from the receiving ultrasonic transducer. This increases measurement error, thereby deteriorating the accuracy of the time resolution. Specifically, when the sonic velocity of a liquid medium is measured by consecutively emitting ultrasonic waves a number of times at certain intervals and calculating the mean of the obtained times, the ringing influences the accuracy of the measurement.
As described above, when the ultrasonic transmitting/receiving device has a pair of ultrasonic transducers, it is difficult to effectively suppress the ringing during emission of ultrasonic waves. Thus, this type of ultrasonic transmitting/receiving device is unable to maximize time resolution in measuring the sonic velocity.

Ultrasonic transmitting/receiving device and method for fabricating the same


The invention relates to a plug-in connector (1) and a plug-in module system having a first contact casing (10) with a first receptacle (14) and a second contact casing (7) with a second receptacle (8), the first receptacle (14) being designed to receive a socket contact (12) and the second receptacle (8) being designed to receive a plug contact (13), the first receptacle (14) and the second receptacle (8) being formed identically.

The invention relates to a plug-in connector and a plug-in module system having a first contact casing with a first receptacle and a second contact casing with a second receptacle, the first receptacle being designed to receive a socket contact and the second receptacle being designed to receive a plug contact.
A plug-in connector is known from U.S. Pat. No. 3,686,619 which comprises a first contact casing with a receptacle for a plug contact and a second contact casing with a second receptacle for a socket contact. Therein, the first contact casing is designed to engage around the second contact casing in parts, with the plug contact penetrating into the socket contact upon pushing the first contact casing on to the second contact casing. The first receptacle in this case is configured such that it offers the plug contact optimum holding in the first contact casing. Likewise, the second receptacle is adapted to the socket contact.

Plug-in connector and a plug-in module system