In an electric brake system with at least an electric wheel brake mechanism having a pair of brake friction pads to produce a braking force based on a brake manipulated variable, and a brake friction pad thrust sensor detecting a pressure of either one of the brake friction pad pair against a disk rotor, an electric brake control unit causing a temporary movement of the brake friction pad pair into contact with the disk rotor when a predetermined time period has expired from a time when a brake pedal has been recovered to an inoperative state. In the system, a position of the brake friction pad pair, at which the pressure becomes greater than a predetermined threshold value during the temporary movement of the brake friction pad pair into contact with the disk rotor, is detected or determined as a braking initiation position.

The present invention relates to an electric brake system, and particularly to an electronically controlled brake system based on electric brake mechanisms.
In recent years, there have been proposed and developed various electric brake systems, in which an electric brake actuator is controlled in response to a control signal from an electric-brake-system electronic control unit so as to vary the magnitude of braking force. The control signal value is based on the amount of depression of a brake pedal. One such electric brake system has been disclosed in Japanese Patent Provisional Publication No. 9-137841 (hereinafter is referred to as xe2x80x9cJP9-137841xe2x80x9d). The electric brake system disclosed in JP9-137841 is comprised of an electric brake actuator that advances and retracts a friction pad toward and away from a brake disk rotor, a thrust sensor that detects the magnitude of the pressure of the friction pad against the disk rotor, a position sensor that detects the position of the friction pad, and an electronic control unit that controls the operation of the electric brake actuator. The control unit has a thrust control function that controls the operation of the electric brake actuator responsively to a thrust indicative signal from the thrust sensor, and a position control function that controls the operation of the electric brake actuator responsively to a pad-position indicative signal from the position sensor. Concretely, a friction-pad position obtained at a timing that braking operation terminates and the magnitude of thrust or pressure of the friction pad against the disk rotor becomes zero is regarded as a braking initiation position. The friction pad is moved away from the braking initiation position by a predetermined distance or a predetermined clearance, each time braking operation terminates. Thus, it is possible to keep the pad-to-rotor clearance constant depending on the degree of friction-pad wear. However, in presence of undesired deflection or uneven wear of the disk rotor, and thermal expansion or thermal contraction, such a conventional electric brake system is still inadequate from the viewpoint of more-precise detection of the braking initiation position.
FIG. 10 shows an example of a friction-pad position versus thrust characteristic diagram. As can be seen from the characteristic diagram of FIG. 10, during the initial stage of braking operation, the friction pad is shifted toward the disk rotor from a state wherein the friction pad is held away from the disk rotor by a certain pad-to-rotor clearance, i.e., an initial pad-to-rotor clearance before a braking operation, and then brought into contact with the disk rotor (see an initial contact position Po in FIG. 10). For example, when downhill braking is continuously executed for a long time period from the initial stage of braking operation, the thrust of early stages of braking rises based on an initial-braking-period friction-pad rigidity characteristic (corresponding to a gradient of the right-hand side straight line shown in FIG. 10). However, when the downhill braking operation is released, owing to thermal expansion and reduced rigidity of the friction pad, arising from a great deal of frictional heat created during braking operation of the electric brake system, the thrust never falls in accordance with the initial-braking-period friction-pad rigidity characteristic. As can be appreciated from the characteristic diagram of FIG. 10, the thrust of last stages of the braking operation tends to fall based on a last-braking-period friction-pad rigidity characteristic (corresponding to a gradient of the left-hand side straight line shown in FIG. 10) different from the initial-braking-period friction-pad rigidity characteristic. That is, owing to thermal expansion and reduced rigidity of the friction pad, there is an increased tendency for the contact position of the friction pad with the disk rotor to become offset from initial contact position Po.
Suppose that the predetermined pad-to-rotor clearance is determined based on the contact position that is affected by thermal expansion and reduced rigidity of the friction pad and that is offset from initial contact position Po. In this case, if the friction pad is cooled during the non-braking state with the brake pedal undepressed and thus the friction pad is heat-contracted, the actual pad-to-rotor clearance varies from the previously-discussed initial pad-to-rotor clearance. Additionally, a heating state of the friction pad during braking operation always varies depending on the braking time, braking energy, non-braking time, vehicle speed during the non-braking period, and the like. The pad-to-rotor clearance tends to vary every braking operation. In particular, on four-wheeled vehicles, there is an increased tendency for the pad-to-rotor clearances at four road wheels to become different from each other. This means that there is a deviation of a timing of initiation of braking action (or braking force) at one of four road wheels from a timing of initiation of braking action (or braking force) at the other wheel, thereby resulting in a poorly balanced braking action between one of four road wheels and the other wheel and thus giving the driver a poor braking feel.
Accordingly, it is an object of the invention to provide an electric brake system, which avoids the aforementioned disadvantages.
It is another object of the invention to provide an electric brake system of an automotive vehicle with an electric-brake-system electronic control unit capable of electronically controlling the magnitude of pressure of a brake friction pad (a brake friction material) against a brake disk rotor (a rotary body being rotatable together with a road wheel), which is capable of maintaining a better braking balance among four road wheels of the vehicle by keeping the pad-to-rotor clearance at each of the road wheels constant, irrespective of the degree of friction-pad wear and the presence or absence of thermal expansion and reduced rigidity of the pad.
In order to accomplish the aforementioned and other objects of the present invention, an electric brake system comprises a brake manipulated variable sensor that detects a driver""s brake manipulated variable of a brake operating device, an electric wheel brake mechanism having a pair of brake friction pads that are opposite to each other for sandwiching therebetween a disk rotor rotatable together with a road wheel and for producing a braking force resulting from braking torque application to the disk rotor, a first brake friction pad thrust sensor that detects a first pressure of a first one of the brake friction pad pair against one side wall of the disk rotor, a second brake friction pad thrust sensor that detects a second pressure of the second brake friction pad against the other side wall of the disk rotor, a control unit configured to be electronically connected to the brake manipulated variable sensor, the first and second brake friction pad thrust sensors and the electric wheel brake mechanism, for controlling the electric wheel brake mechanism responsively to the brake manipulated variable, and the first and second pressures, and the control unit causing a movement of the brake friction pad pair into contact with the disk rotor when the brake operating device is conditioned in an inoperative state, and detecting a position of the brake friction pad pair, at which the first and second pressures become greater than respective predetermined threshold values during the movement of the brake friction pad pair into contact with the disk rotor, as a braking initiation position.
According to another aspect of the invention, an electric brake system comprises a brake manipulated variable sensor that detects a driver""s brake manipulated variable of a brake operating device, an electric wheel brake mechanism having a pair of brake friction pads that are opposite to each other for sandwiching therebetween a disk rotor rotatable together with a road wheel and for producing a braking force resulting from braking torque application to the disk rotor, a brake friction pad thrust sensor that detects a pressure of either one of the brake friction pad pair against the disk rotor, a control unit configured to be electronically connected to the brake manipulated variable sensor, the brake friction pad thrust sensor and the electric wheel brake mechanism, for controlling the electric wheel brake mechanism responsively to the brake manipulated variable, and the pressure of the one brake friction pad against the disk rotor, the control unit comprising a maximum disk-rotor thickness angular position detecting section that detects an angular position of the disk rotor at which a disk rotor portion has a maximum thickness, and the control unit causing a movement of the brake friction pad pair into contact with the disk rotor when the brake operating device is conditioned in an inoperative state, and detecting a position of the brake friction pad pair, at which the pressure becomes greater than a predetermined threshold value at the angular position of the disk rotor corresponding to the disk rotor portion having the maximum thickness during the movement of the brake friction pad pair into contact with the disk rotor, as a braking initiation position.
According to a further aspect of the invention, an electric brake system comprises a brake manipulated variable sensing means for detecting a driver""s brake manipulated variable of a brake operating device, an electric wheel brake means having a pair of brake friction pads that are opposite to each other for sandwiching therebetween a disk rotor rotatable together with a road wheel and for producing a braking force resulting from braking torque application to the disk rotor, a first brake friction pad thrust sensing means for detecting a first pressure of a first one of the brake friction pad pair against one side wall of the disk rotor, a second brake friction pad thrust sensing means for detecting a second pressure of the second brake friction pad against the other side wall of the disk rotor, a brake control means configured to be electronically connected to the brake manipulated variable sensing means, the first and second brake friction pad thrust sensing means and the electric wheel brake means, for controlling the electric wheel brake means responsively to the brake manipulated variable, and the first and second pressures, and the control means causing a movement of the brake friction pad pair into contact with the disk rotor when the brake operating device is conditioned in an inoperative state, and detecting a position of the brake friction pad pair, at which the first and second pressures become greater than respective predetermined threshold values during the movement of the brake friction pad pair into contact with the disk rotor, as a braking initiation position.
According to a still further aspect of the invention, an electric brake system comprises a brake manipulated variable sensing means for detecting a driver""s brake manipulated variable of a brake operating device, an electric wheel brake means having a pair of brake friction pads that are opposite to each other for sandwiching therebetween a disk rotor rotatable together with a road wheel and for producing a braking force resulting from braking torque application to the disk rotor, a brake friction pad thrust sensing means for detecting a pressure of either one of the brake friction pad pair against the disk rotor, a control means configured to be electronically connected to the brake manipulated variable sensing means, the brake friction pad thrust sensing means and the electric wheel brake means, for controlling the electric wheel brake means responsively to the brake manipulated variable, and the pressure of the one brake friction pad against the disk rotor, the control means comprising a maximum disk-rotor thickness angular position detecting section that detects an angular position of the disk rotor at which a disk rotor portion has a maximum thickness, and the control means causing movement of the brake friction pad pair into contact with the disk rotor when the brake operating device is conditioned in an inoperative state, and detecting a position of the brake friction pad pair, at which the pressure becomes greater than a predetermined threshold value at the angular position of the disk rotor corresponding to the disk rotor portion having the maximum thickness during the movement of the brake friction pad pair into contact with the disk rotor, as a braking initiation position.
According to another aspect of the invention, a method of detecting a braking initiation position of an electric brake system with a brake manipulated variable sensor detecting a driver""s brake manipulated variable, an electric wheel brake mechanism having a pair of brake friction pads that are opposite to each other for sandwiching therebetween a disk rotor rotatable together with a road wheel and for producing a braking force resulting from braking torque application to the disk rotor and based on the brake manipulated variable, a first brake friction pad thrust sensor detecting a first pressure of a first one of the brake friction pad pair against one side wall of the disk rotor, and a second brake friction pad thrust sensor detecting a second pressure of the second brake friction pad against the other side wall of the disk rotor, the method comprises causing a primary movement of the brake friction pad pair into contact with the disk rotor when a predetermined time period has expired from a time when a brake pedal has been recovered to an inoperative state, and detecting a position of the brake friction pad pair, at which the first and second pressures become greater than respective predetermined threshold values during the primary movement of the brake friction pad pair into contact with the disk rotor, as the braking initiation position.
According to another aspect of the invention, a method of detecting a braking initiation position of an electric brake system with a brake manipulated variable sensor detecting a driver""s brake manipulated variable, an electric wheel brake mechanism having a pair of brake friction pads that are opposite to each other for sandwiching therebetween a disk rotor rotatable together with a road wheel and for producing a braking force resulting from braking torque application to the disk rotor and based on the brake manipulated variable, and a brake friction pad thrust sensor detecting a pressure of either one of the brake friction pad pair against the disk rotor, the method comprises detecting an angular position of the disk rotor at which a disk rotor portion has a maximum thickness, causing a primary movement of the brake friction pad pair into contact with the disk rotor when a predetermined time period has expired from a time when a brake pedal has been recovered to an inoperative state, and detecting a position of the brake friction pad pair, at which the pressure becomes greater than a predetermined threshold value at the angular position of the disk rotor corresponding to the disk rotor portion having the maximum thickness during the primary movement of the brake friction pad pair into contact with the disk rotor, as the braking initiation position.
The other objects and features of this invention will become understood from the following description with reference to the accompanying drawings.


Systems for managing gaming devices in a networked environment are disclosed herein. The system includes one or more gaming device, at least one data repository, host system, and a datastore. The gaming devices have a gaming processor and a plurality of gaming components, wherein one or more parameters are associated with the gaming components. The data repository is in communication with the one or more gaming components, and the data repository stores data that includes one or more parameters from each gaming component. A host system is in communication with the gaming devices, and the host system is configured to collect data from the data repository. The host system also includes a datastore in communication with the host system, wherein the datastore stores data from the gaming devices.

Traditionally, gaming machines have been designed for gaming purposes only. In this regard, gaming machines have been constructed only to include gaming functionality. Recently, however, casino owners have become aware that by adding additional features to gaming machines, they may be able to maintain a player's attention to the gaming machines for longer periods of time. This, in turn, leads to the player wagering at the gaming machine for longer periods of time, thereby increasing casino profits. In order to maintain a player's attention, casinos need to gather as much information as possible regarding the players and the games they are playing.
Attempts to distribute gambling-related information and advertisements to players has typically required additional system components to be attached to the gaming devices separately and apart from the construction of the gaming machine itself. Such components have generally included a keypad, card reader, and display equipment, such as a 2-line LED display. As a result, the gaming machines have grown in sophistication and number of components.
While gaming machines have increased in sophistication, casino operators need to obtain a greater amount of information from gaming devices. That is, the casino operator needs to track the traditional functions of the gaming devices in addition to various qualities and/or parameters of the new components that provide expanded service and system capabilities. Obtaining the required information from each gaming machine may be a time-consuming process. Furthermore, compatibility issues may prevent a network system from obtaining the required information from each component in the gaming device. Accordingly, there remains a need for a system for managing gaming devices in a networked environment.

Gaming system for data management and collection and related methods


Disclosed is ink composition used in a recording apparatus provided with a pressure regulation valve which performs opening and closing operations to adjust a pressure in a recording head and is covered with an elastic member. The ink composition includes a slip agent and a lactone system medium. The slip agent is preferably at least one kind selected from a group consisting of a silicon system compound, a hydrocarbon system compound, a fluorine system compound, an amide system compound, and acrylic compound. In addition, the content of the slip agent is preferably not more than 1% by mass.

1. Technical Field
The present invention relates to ink composition and a recording apparatus.
2. Related Art
In the related art, image recording by applying ink composition from a recording apparatus such as an ink jet recording apparatus to a recording medium such as a paper has been known.
The ink composition is generally obtained by dissolving or dispersing colorant in a medium, and various additives are further added thereto.
As an additive to be added to the ink composition, a slip agent has been known (see JP-A-2011-213933, for example). By adding the slip agent, it is possible to improve abrasion resistance of a printed surface and prevent abrasion on the printed surface.
However, such a slip agent has a problem that an influence of the slip agent on an elastic member such as rubber in the recording apparatus (particularly, a pressure regulation valve with which the ink composition is brought into contact) is reduced and opening and closing operations of the pressure regulation valve is disturbed. More specifically, there is a problem that a sealing portion (elastic member) of the pressure regulation valve comes off and it is not possible to perform opening and closing operations of a flow path.


A combined flat bed scanner/printer machine having: a moving body; a scan module connected to the moving body to read a document; and a recording head connected to the moving body adjacent to the scan module, to print on a paper. The moving body is moved by a moving body transfer unit made up of a belt to which the moving body is secured, a guide rod to guide the moving body, and a motor to move the belt.

1. Field of the Invention
The present invention relates to an image forming apparatus, such as a photocopier, a printer, and a scanner, and more particularly, to a multi-function machine that performs functions of a printer and a scanner through a single apparatus.
2. Description of the Related Art
The term "multi-function machine" refers to an apparatus that brings together in a single unit, image forming apparatus functions of photocopying, printing, and scanning. Recently, a multi-function machine has been developed that integrates functions of a flat bed scanner, performing a scanning of a first paper, such as a document, placed on a glass plate, and an ink jet printer, printing an image on a second paper 1 fed from a paper feeding section.
One example of a combined flat bed scanner/printer machine according to the related art is shown in FIG. 1.
Referring to FIG. 1, the combined flat bed scanner/printer machine has a scan section 10, a printer section 20, a paper feeding section 30 and a paper discharging section 40.
The scan section 10 includes a scan unit 11, a scan guide rod 18, and a scan belt 16. The scan unit 11 has a scan module 12, reading a content of the first paper laid on a top surface of a glass plate 14, and a scan frame 13, supporting and moving the scan module 12. The scan belt 16 is connected to the scan frame 13, and transfers the scan unit 11 left and right. The scan belt 16 is driven by a scan motor which is not shown. The scan guide rod 18 guides the scan frame 13.
The printer section 20 includes a recording head 21, a moving belt 26, and a moving guide rod 28. The recording head 21 has a recording frame 23, which is assembled to the moving guide rod 28 and moved left and right along the moving guide rod 28 by the moving belt 26, and an ink jet head 22, which is received within the recording frame 23 and ejects ink. The moving belt 26 is connected to the recording frame 23, and is supplied with power from a moving motor (not shown), thereby moving the recording frame 23 left and right. The guide rod 28 guides the movement of the recording frame 23, so that the recording frame 23 is stably moved left and right by the moving belt 26.
The construction of the paper feeding section 30 is substantially similar to that of a paper feeding section of a common ink jet printer. The paper feeding section 30 includes a paper loading section 32, a pickup roller 34, a feed roller 36, and a paper guide 29.
The paper discharging section 40 includes a paper discharging roller 42, and a star wheel 44, in a construction substantially similar to a paper discharging section of a common ink jet printer.
The following is a description of the operation of the combined flat bed scanner/printer machine having the above construction.
When the combined machine is used as a scanner, the first paper is laid on the glass plate 14, and the scan motor (not shown) rotates and turns the scan belt 16. When the scan belt 16 is turned, the scan unit 11 reads the content of the first paper, while moving along the scan guide rod 18, along an axis (Y axis) perpendicular to a recording paper feeding axis (X axis).
When the machine is used as a printer, the second paper 1 is loaded in the paper loading section 32, and separated and fed to the feed roller 36 by the pickup roller 34. The second paper 1 transferred to the feed roller 36 is fed between the recording head 21 and the paper guide 29 at a predetermined interval by the feed roller 36. Then, the moving motor (not shown) rotates and turns the moving belt 26. When the moving belt 26 turns, the ink jet head 22 ejects ink onto the paper 1, while the recording head 21 moves along the moving guide rod 28. When the printing is complete, the second paper 1 is discharged out of the combined machine by the paper discharging roller 42 and the star wheel 44.
Thus, the combined flat bed scanner/printer machine is able to perform printing and scanning as needed.
Because such a combined flat bed scanner/printer machine is merely a combination of a flat bed scanner and an ink jet printer, it is large and needs a number of components.
In other words, the combined machine of the related art has the following disadvantages:
1) because the form of the combined machine is merely a flat bed scanner laid on an ink jet printer, the volume the machine occupies is large;
2) there are redundant mechanical elements; and
3) because there are separate motors for operating the scan unit and the ink jet head, the material costs are increased.

Combined flat bed scanner/printer machine


The usage of communication systems is improved. An IM server 4 manages presence information regarding each of IM clients and usable media and user information such that each of the IM clients can obtain these kinds of information. In order to perform text chatting, the IM server 4 manages a connection between each of the IM clients participating the chat and the IM server 4, merges text from each of the participating IM clients and distributes the result to each of the participating IM clients. In order to perform voice chatting, an AP server 5 manages a connection between each of the IM clients participating the chat and an MD server 6, mixes voice from each of the participating IM clients except for a focused IM client and distributes the result to the focused participating IM clients. This processing is performed for each of the participating IM clients.

The present invention relates to a communication technology such as Instant Messaging (IM).
A communication technology called IM is gathering attentions. Sometimes, a matter to talk with the other party may not need a rapid response through a telephone. However, if an e-mail containing the matter is sent through an E-mail, it is not clear when the other party reads (that is, when his/her reply is obtained). IM has a time characteristic that is intermediate between the telephone and the e-mail. In IM, a current status (which may be called presence information), such as online or offline or the ability to respond, of each party is published. Thus, in response to presence information of friends using the same IM system over the Internet, a tool to be used for communication with friends, such as a chat and an e-mail, can be selected.
Presently, IM systems are released from many venders, and IM clients, each of which is application software to use a respective IM system, are distributed. However, there is no compatibility among IM systems of the respective venders. As a result, communication cannot be performed between the IM clients of the different venders. Thus, the standardization is started from a need for the interconnectivity. In Instant Messaging & Presence Protocol (IMPP) working group of Internet Engineering Task Force (IETF), the architecture, the message integration and the security (such as authentication and encryption) relating to IM are being discussed. A model is defined for Require for Comment (RFC) 2778 while a protocol requirements are defined for RFC 2779.
Conventionally, the multi-party connection (group chat) in IM is mainly used just for fun (hobby use), such as gossiping. However, recently, study for using the group chat for business has been started. Here, it is noted that the text-based group chat may be not enough for the business uses in many cases. For example, inputting Japanese language takes time. In addition, in order to express a complicated matter or a shade of meaning, which is hard to be understood from a document, the voice support is needed. In the one-to-one (Peer-to-Peer) technology, the expansion into communication using multimedia has been started. The first reference (Nikkei Communication, Nov. 5, 2001, pgs. 106 to 113) proposes such usage of multimedia that a meeting is held by using a voice chat or by exchanging files.

Communication system and communication method


Processes are provided for capturing and recycling carbonaceous fines generated during a gasification process. In particular, the recycled fines are processed into a particulate composition which is useable as a carbonaceous feedstock and is conversion into a gas stream comprising methane.

In view of numerous factors such as higher energy prices and environmental concerns, the production of value-added gaseous products from lower-fuel-value carbonaceous feedstocks, such as biomass, coal and petroleum coke, is receiving renewed attention. The catalytic gasification of such materials to produce methane and other value-added gases is disclosed, for example, in U.S. Pat. No. 3,828,474, U.S. Pat. No. 3,998,607, U.S. Pat. No. 4,057,512, U.S. Pat. No. 4,092,125, U.S. Pat. No. 4,094,650, U.S. Pat. No. 4,204,843, U.S. Pat. No. 4,468,231, U.S. Pat. No. 4,500,323, U.S. Pat. No. 4,541,841, U.S. Pat. No. 4,551,155, U.S. Pat. No. 4,558,027, U.S. Pat. No. 4,606,105, U.S. Pat. No. 4,617,027, U.S. Pat. No. 4,609,456, U.S. Pat. No. 5,017,282, U.S. Pat. No. 5,055,181, U.S. Pat. No. 6,187,465, U.S. Pat. No. 6,790,430, U.S. Pat. No. 6,894,183, U.S. Pat. No. 6,955,695, US2003/0167961A1, US2006/0265953A1, US2007/000177A1, US2007/083072A1, US2007/0277437A1 and GB 1599932.
Reaction of lower-fuel-value carbonaceous feedstocks under conditions described in the above references typically yields a crude product gas and a char. The crude product gas typically comprises an amount of entrained carbonaceous fines particles, which are removed from the gas stream. A number of prior known methods are effective for removing carbonaceous fines. Typically these fines are not directly usable, which on the industrial scale, can total to a significant amount of potentially hazardous waste and related disposal costs. Accordingly, the handling, storage and disposal operations of carbonaceous fines waste represent a significant and unproductive expense for the industry.
Thus, there is a need for improved processes and compositions that allow for recovery, recycling, and ultimate conversion of carbonaceous fines, such as entrained carbonaceous fines from the gas effluent after gasification of carbonaceous feedstock, into usable feedstock to generate product gas.


A solid-state imaging element including: a sensor substrate in which a photoelectric conversion section is arranged and formed; a circuit substrate in which a circuit for driving the photoelectric conversion section is formed, the circuit substrate being laminated to the sensor substrate; a sensor side electrode drawn out to a surface of the sensor substrate on a side of the circuit substrate and formed as one of a projection electrode and a depression electrode; and a circuit side electrode drawn out to a surface of the circuit substrate on a side of the sensor substrate, formed as one of the depression electrode and the projection electrode, and joined to the sensor side electrode in a state of the circuit side electrode and the sensor side electrode being fitted together.

The present disclosure relates to a solid-state imaging element formed by laminating a sensor substrate and a circuit substrate to each other in such a manner as to join the electrodes of the sensor substrate and the circuit substrate to each other, a method for manufacturing the solid-state imaging element, and an electronic device using the solid-state imaging element.
A three-dimensional structure in which a photoelectric conversion section and a peripheral circuit section are laminated to each other is proposed as one of structures for achieving further miniaturization of elements and higher density of pixels in a solid-state imaging element included in an electronic device such as a portable telephone, a digital camera, a camcorder, or the like.
In manufacturing a solid-state imaging element of such a three-dimensional structure, for example a sensor substrate in which a CIS (complementary metal oxide semiconductor image sensor) having a photoelectric conversion section is formed and a circuit substrate in which a peripheral circuit section is formed are laminated to each other. The lamination of these substrates is performed by arranging electrodes (bonding pads) drawn out to surfaces on one side of each of the substrates such that the electrodes (bonding pads) are opposed to each other, and performing heat treatment in this state. In order to facilitate the joining of the bonding pads to each other by the heat treatment, an insulating film surrounding bonding pads is recessed in advance (see Japanese Patent Laid-Open No. 2006-191081, for example, for the above description).
In addition, a constitution in which the sensor substrate and the circuit substrate are laminated to each other so as to cancel the internal stress of both of the substrates is proposed in order to prevent a distortion or a warp in the sensor substrate and the circuit substrate laminated as described above (see Japanese Patent Laid-Open No. 2007-234725, for example, for the above description).

Solid-state imaging element, method for manufacturing solid-state imaging element, and electronic device


A steel suitable for a fabric with or without painting and has good corrosion resistance with reproducibility, even if the steel is composed mainly of ordinary carbon steel or low alloy steel, wherein the surface of the steel is coated with rust comprising one or more selected from Ti, Nb, Ta, Zr, V and Hf in the total amount of 0.01 wt % or more. In the steel, the fraction of .alpha.-FeOOH and an amorphous rust is 35 wt % or more, and the fraction of .beta.-FeOOH is 20 wt % or less.

1. Field of the Invention
The present invention relates to a steel material that has high corrosion resistance and is suitable for a fabric which is difficult to maintain and is used with or without painting, for example, a bridge; and a fabric using this steel material.
2. Related Art
Hitherto, a steel material used for bridge fabrics, for example, a traffic bridge in the environment which may easily be subjected to corrosion (which may be referred to chloride environment, hereinafter) by airborne salt from the sea or deicing salt, such as an area in mountains or a seaside area, has been painted and used to improve corrosion resistance. However, the painted coating necessarily deteriorates with the passage of time. Thus, in order to maintain corrosion resistance, it is necessary to repaint the steel material in a given cycle.
Recently, as such a bridge, there has been frequently used a small number main girder bridge, which has a few main girders and includes a 2-main girder bridge as a typical example, instead of a conventional large number main girder bridge. The small number main girder bridge has the following advantages over the large number main girder bridge: the amount of used steel materials (steel weight) and the number of bridge members can be reduced and further construction efficency is good, so as to contribute to environmental protection and shortening of a construction term. For such a small number main girder bridge, it has been demanded that costs and loads for maintenance after the construction of the bridge are reduced as much as possible and the life span of the bridge itself is prolonged.
Therefore, for steel materials used for fabrics such as steel towers and buildings including the above-mentioned small number main girder bridge, it has been demanded that high corrosion resistance is maintained. For example, it has been demanded that the maintenance after the construction of the bridge is unnecessary even if the steel materials are used without any painting in the environment which may easily be subjected to chlorides, or the steel materials are used with painting and the painted coating is deteriorated or damaged in the use.
In order to improve corrosion resistance of such steel materials, improving-techniques about its parent metal, i.e., steel have been hitherto proposed. A typical example thereof is a weathering steel comprising P: 0.15% or less, Cu: 0.2-0.6%, Cr: 0.3-1.25%, and Ni: 0.65% or less. As this weathering steel, the following 2 types are standardized: types according to JIS G 3114 (Hot-Rolled Atmospheric Corrosion Resistant Steels for Weld Use) and JIS G 3125 (Superior Atmospheric Corrosion Resistant Rolled Steel). This weathering steel has such a self corrosion resisting function that rust generated on the surface of the steel in use of the steel becomes protective and this protective rust layers (weathering rust) having high atomospheric corrosion resistance by the above-mentioned elements in very small amounts. By such a property, the weathering steel is used mostly without any painting, as a maintenance-free construction material for various fabrics, for example, the above-mentioned bridge.
In the chloride environment, however, the protective rust layers, which characterize the weathering steel, are not easily formed by the influence of chloride. If the protective rust layers are not formed, the corrosion resistance of the weathering steel is remarkably lowered. This is based on the fact that the corrosion of the steel results in a drop in pH inside the rust layers in the chloride environment. That is, even if corrosion of the steel occurs slightly, the pH at the surface of the steel is lowered by the reactions of Fe.fwdarw.Fe.sup.2+ +2e.sup.- followed by Fe.sup.2+ +2H.sub.2 O.fwdarw.Fe(OH).sub.2 +2H.sup.+ so that both pH inside the rust layers and pH at the interface between the rust layers and the steel are lowered. Once these pHs are lowered, the transport number of chlorine ions in the rust layers increases to keep electrical neutralization. Thus, the concentration of chlorine ions occurs at the interface between the rust layers and the steel. As a result, a hydrochloric acid atmosphere is produced around the interface to promote the corrosion of the steel. At the same time, the solubility of iron ions increases by the drop in pH inside the rust layers to result in the phenomenon of blocking the formation of the protective rust layers, which is a main point of corrosion resistance function of low alloy corrosion resistant steels such as weathering steel. Thus, the corrosion is accelerated.
Therefore, in order to prevent the drop in pH inside the rust layers, there is proposed a technique of making the surface of the weathering steel alkali to block the acceleration of the corrosion. More specifically, Japanese Patent Application Laid-Open (JP-A) No. 58-25458, Japanese Patent No. 2572447 and the like disclose a method of dispersing an oxide (chemical species)of Be, Mg, Ca, Sr, Ba or the like for making the surface of weathering steel alkaline into the steel beforehand and acting the chemical species at the same time of the corrosion reaction of the steel to suppress the drop in pH at the steel surface.
The method of adding such an oxide to block acceleration of corrosion is indeed advantageous from the standpoint of suppression of the influence of chlorides from the external environment. However, it is difficult or restrictive in the same way as in the above-mentioned weathering steel to form the protective rust layers themselves. As a result, sufficient corrosion resistance cannot be obtained under the actual conditions. It is also feared that the oxide added to the steel has a bad influence on weldability and/or strength.
For this reason, in order to improve the corrosion resistance of steel materials, there are proposed various treatment processes for promoting protective rust formation by subjecting the steel materials to surface treatment, instead of the above-mentioned method of adjusting the components or composition of steel materials. For example, JP-A-6-93467 discloses a method of covering the surface of steel with rust comprising .alpha.-FeOOH containing 0.3 wt % or more of one or more elements selected from Cr, Cu, P and Ni, and painting an aqueous solution containing Cr, Cu, P or Ni onto the surface of the steel in order to form this rust.
JP-A-9-125224 discloses a method of covering the surface of steel with rust comprising hematite (.alpha.-Fe.sub.2 O.sub.3) of 30-200 .mu.m in thickness by heat-treating the steel.
The methods in the prior art of forming the protective rust layers themselves by surface treatment or heat treatment of steel materials are notable methods from the standpoint that attention is paid to the components or the composition of the protective rust layers. Namely, the above-mentioned weathering steel or the oxide-dispersed steel contains alloying elements in large amounts so as to exhibit inevitably lower weldability at the time of processing the steel material or lower efficiency at the time of producing the steel material by melting, rolling or the like than that of ordinary steel. Costs for producing the steel material are also high by the drop in production efficiency and the inclusion of relatively large amounts of the alloying elements. Besides, the drop in the weldability makes costs for construction using the steel material high. Accordingly, if there is a method wherein ordinary carbon steel or low alloy steel is used without using such a weathering steel to realize high corrosion resistance by adjusting the structure and/or the composition of the protective rust layers, this method has many advantages from the viewpoint of construction efficency and costs.
However, the inventors have found that when the rust comprising .alpha.-FeOOH containing 0.3 wt % of one or more selected from Cr, Cu, P and Ni, as disclosed in JP-A-6-93467, or the rust comprising hematite (.alpha.-Fe.sub.2 O.sub.3) as disclosed in JP-A-9-125224 is used without any painting in the chloride environment, or is used with painting and the painted coating is deteriorated or damaged, high corrosion resistance is not necessarily exhibited. The inventors have also found that this is caused by the facts that the rust layers cannot easily be produced and that even if chemical treatment or heat treatment is conducted for the production thereof, the reproducibility of the rust layers is not good.
Therefore, an object of the present invention is to provide a steel material that has high reproducibility and corrosion resistance and is suitable for fabrics used with or without painting even if the steel material belongs to ordinary carbon steel or low alloy steel.

Steel material excellent in corrosion resistance and fabric using the same

Kabushiki Kaisha Kobe Seiko Sho (Kobe Steel, Ltd)


An apparatus for patterning biological cells, and a method of patterning and coculturing biological cells using the apparatus. The apparatus includes a fluidic structure having an outlet and a plurality of inlets, the fluidic structure is arranged to facilitate a flow of a plurality of different cells in a cell suspension therethrough, wherein each of the plurality of inlets is arranged to facilitate a loading of the plurality of different cells from a plurality of supplies into the fluidic structure; and a flow controlling device arranged to control the flow of the plurality of different cells through the fluidic structure and/or the loading of the plurality of different cells from the plurality of supplies through the plurality of inlets; wherein the fluidic structure is further arranged to facilitate a simultaneous observation of the plurality of different cells arranged in a predetermined pattern in the fluidic structure.

Biological cells are the basic structural, functional units for all organisms. In other words, cells may be regarded as the building blocks of life. Cell communication, particularly the communication between different cell types, is important for cell regulation and for cells to process information from the environment and respond accordingly. Thus, studies on cell-cell interactions may be important in many biological and medical applications such as drug screening.
In general, the studies of cell-cell interaction may be done by in vitro cell coculture. Cell coculture is a cultivation setup involving randomly mixing two or more cell types on a Petri-dish and allowing the cells to grow thereon. The cell-cell interactions may be observed through a spontaneous cell rearrangement as a result of the differences in intercellular adhesiveness among the different cell types.

Apparatus and a method for patterning biological cells


A serial testing infrastructure includes the capability to execute a distributed test on multiple virtual processors. A test executable may be stored in a library and the test description, including the name of the test, the test library, and other test characteristics, may be stored in a separate test data file. The serial testing infrastructure initiates multiple distributed test executors that each launch an instance of the distributed test as a process that runs concurrently with other instances of the distributed test. Each distributed test executor monitors execution of it corresponding process until completion or timeout.

Large scale software applications require continual testing to ensure that the applications generate consistent results. Functional testing is typically used during development to test functions, methods, features, and/or the complete application with various inputs. Regression testing is typically used after development of the application to test correctness of the application and the quality of the output. A large number of tests may be used to test a large scale software application. Each test may include various runtime options, numerous settings, and a large volume of testing data that increases the complexity and dimension of the testing process.

Distributed testing within a serial testing infrastructure


A hand-drying device for an aircraft can be integrated into a washing stand, so that the hand washing and hand drying process can be performed within the washbasin of the washing stand. Corresponding sensors make this process contactless.

Hand washing basins, in which the passengers and flight personnel can wash their hands, are installed in aircraft cabins, in particular, in aircraft toilet modules or kitchen modules (galleys) installed therein. Tissues are provided for drying the hands, which can be taken from a dispenser located near the hand-washing basin. The used tissues are collected in a waste container.
Both the fresh tissues and used tissues must be stored. In addition, it should be ensured that enough fresh tissues are available at all times. A corresponding supply may have to be kept in stock for this purpose, and the dispensing devices for dispensing the tissues should be refilled regularly. This may be associated with the need for more space, a higher weight, and additional costs.
DE 10 2009 018 690 A1 and WO 2010/121862 A4 describe aircraft toilet modules with a hand washing basin. DE 10 2009 021 970 A1 describes an autonomous water module for aircraft, which also exhibits a hand washing basin.

Hand drying device and washing stand for an aircraft


A diorganopolysiloxane terminated only at one of the molecular chain ends with a (meth)acryloxyalkyl group bonded to the terminal silicon atom is prepared, instead of the prior art method in which a diorganopolysiloxane obtained by the anionic ring-opening living polymerization reaction of, for example, hexamethyl cyclotrisiloxane by using a lithium catalyst is subjected to a desalinating condensation reaction with a (meth)acryloxyalkyl dimethyl chlorosilane, by a novel method in which the diorganopolysiloxane obtained by the anionic ring-opening living polymerization reaction of, for example, hexamethyl cyclotrisiloxane is hydrolyzed and the thus obtained monofunctionally silanol-terminated diorganopolysiloxane is reacted with a (meth)acryloxyalkyl dimethyl dialkylamino silane to effect a deamination reaction. This method is advantageous in that the relatively narrow molecular weight distribution of the diorganopolysiloxane obtained by the anionic living polymerization is not affected and retained as such in the deamination reaction while not in the prior art method.

The present invention relates to a method for the preparation of an organopolysiloxane ethylenically polymerizable only at a single molecular chain end or, more particularly, to an efficient method for the preparation of an organopolysiloxane having a straightly linear molecular structure of a controllable molecular weight or molecular weight distribution and having an ethylenically unsaturated polymerizable linkage only at one of the molecular chain ends.
As is known, organopolysiloxanes having ethylenical polymerizability only at a single molecular chain end are widely used in the polymer industry because a copolymer of such an organopolysiloxane and (meth)acrylic acid or an ester thereof as well as other vinyl monomers is imparted with various desirable properties such as water-repellency, heat resistance, weatherability, abrasion resistance and the like.
A method for the preparation of such a polymerizable organopolysiloxane is disclosed in Japanese Patent Publication No. 59-78236, according to which a cyclic organopolysiloxane oligomer such as hexamethyl cyclotrisiloxane is subjected to a ring-opening living polymerization in the presence of an anionic polymerization initiator such as organolithium compounds, alkali metal hydroxides, alkali metal alkoxides and alkali metal silanolates and the thus obtained organopolysiloxane is subjected to a desalinating condensation reaction with an .omega.-(meth)acryloxyalkyl dichlorosilane.
In this method, however, formation of hydrogen chloride is unavoidable because the chlorosilane reactant must be used in an excess amount over stoichiometry so that the hydrogen chloride acts as a catalyst to promote the siloxane rearrangement equilibrium reaction as a consequence of scission of the siloxane linkages leading to broadening of the relatively narrow molecular weight distribution of the organopolysiloxane as obtained by the living polymerization.

Method for the preparation of an organopolysiloxane polymerizable at a single molecular chain end


A replacement device for a light bulb includes a translucent shell and a base. The base supports a plurality of colored lights positioned so as to emit a light show through the shell. The base is configured to be received in a conventional light socket. The base also includes a compartment for receiving and securing a replaceable volatile active cartridge for enabling the device to emit an active ingredient from the cartridge when the cartridge is secured in the compartment. A dimmable white light source may also provided in the shell as a source of illumination. Thus, a single device is used as a replacement for a conventional light bulb and is a combination white light source/colored light show source/volatile active source.

1. Technical Field
A substitute for a conventional light bulb is disclosed which provides various combinations of features including, but not limited to, the emission of white light, colored light in the form of changing colored light shows and active ingredient vapor emission. The disclosed device screws into a conventional light socket and the active ingredient is dispensed from replaceable cartridges or bottles. The device may also serve as an adapter for receiving a conventional light bulb. The specific active ingredient emitted may be coordinated with the specific light show performed. A plurality of light shows may be programmed into the memory of the device and memory chips containing new light shows may be provided or the active ingredient cartridges may be equipped with a chip containing one or more light shows that are designed with the active ingredient in mind. The colored light may be produced by RGB LED clusters or filtered white light sources using conventional colored lenses, shrouds or covers or an LCD filter.
2. Description of the Related Art
Creating a pleasant ambience is a popular aspect of home decor. This is often achieved through various combinations of pleasant fragrances and mood lighting. Lighting can also be combined with other functions such as air sanitization, air deodorization, and the controlled release of insect repellent, insect attractant and insecticide. Conventional products such as scented candles, mood lighting devices, fragrance dispensers, and the like, are commonly used to create a pleasant environment in the home. While those conventional products help to create a pleasant living environment and ambiance, they have their drawbacks.
For example, while scented candles create soft light and fragrance, which creates a pleasant mood, candles are a potential fire hazard and often produce unwanted smoke and wax drippings. Traditional light fixtures and lamps do not provide the color effects, fragrance emission or other active emission that users often desire. While stand-alone aesthetic devices are available for providing lighting effects (such as color changing and the like), these standalone devices take up space around the home and add to the clutter that many consumers are trying to avoid. Also, because such stand-alone devices are typically placed in highly visible locations, they need to be aesthetically designed to suit the personal tastes of different categories of buyers, requiring additional design costs.
Conventional fragrance dispensers, such as plug-in diffusers, can provide pleasing aromas in a relatively inexpensive, compact package. However, such conventional fragrance dispensers generally take up outlets and are often located out of sight, causing a user to forget to adjust or refill the device. While these fragrance dispensers may also provide light, because the devices are used in existing electrical outlets, they are generally positioned too low to provide effective lighting features, other than to operate as a nightlight.
Conventional nightlights include only white light emission in combination with fragrance emission. While a single scent may be provided in the form of a decorative diffuser, colored nightlights are not generally available and there is no coordination between the light color emitted and the particular fragrance emitted. Further, sophisticated multi-colored lights that change color and that are aesthetically pleasing in combination with fragrance emission are not currently available.
Further, numerous needs exist for the combination of white light and/or colored light with other volatile active emission other than fragrances such as air sanitization, air deodorization, the controlled release of insect repellent insect attractant, insecticide, aromatherapy volatiles or other non-flagrant materials (any of which may be combined with flagrant materials if necessary to make the ambient environment more tolerable).
Therefore, multiple needs exist for devices that combine one or more of the following functions: white light emission; colored light emission; colored light shows; fragrance emission; air sanitization; air deodorization; insecticide emission; insect repellent emission; aromatherapy material emission; light emission that repels insects; light emission that attracts insects; and any combinations thereof.

This patent is subject to a terminal disclaimer.

Combination white light and colored LED light device with active ingredient emission


The invention is directed to the removal of serum gal-3 from circulation by plasmapheresis using gal-3 binding agents in either a fixed bed, or in a form easily removed, such as by being complexed with magnetic particles. This method, on its own, brings a sharp reduction and relief from the inflammation and fibroses that can be induced by circulating gal-3. The process may be combined with the administration of gal-3 binding agents, such as modified citrus pectin, to further lower unbound gal-3 levels, to the point where gal-3 in the tissues may be addressed. This method may also be combined with removal of TNF receptors to provide an effective treatment for cancer.

1. Field of the Invention
This invention pertains to treatment of disease and biological conditions mediated at least in part by one or more galectins. Galectins are a family of lectins (sugar binding proteins) that are characterized by having at least one carbohydrate recognition domain (CRD) with an affinity for beta-galactosides. These proteins were recognized as a family only recently, but are found throughout the animal kingdom, and are found in mammals, birds, amphibians, fish, sponges, nematodes and even fungi. This application focuses on galectins in mammals, and in particular, humans. Although the invention herein may be employed with both companion animals (e.g., pets such as dogs and cats) and commercial animals (such as cows, pigs and sheep) the methods and subject matter addressed herein are particularly focused on the treatment of humans.
Galectins mediate and modulate a wide variety of intracellular and extracellular functions, and thus are both expressed within the cell and frequently targeted to a specific cytosolic site, and secreted from the cell, for distribution extra-cellularly, as a component of human plasma. Among the many functions that are mediated by extracellular galectins are inflammation, fibrosis formation, cell adhesion, cell proliferation and metastatic formation (cancer) and immunosuppression.
Galectins are a family of fifteen (15) carbohydrate-binding proteins (lectins) highly conserved throughout animal species. Most galectins are widely distributed, though galectin-5, -10 and -12 show tissue-specific distribution. While galectins are variably expressed by all immune cells, they are upregulated in activated B and T cells, inflammatory macrophages, natural killer (NK) cells, and FoxP3 regulatory T cells. Galectins contain a variety of structural arrangements, but a relatively conserved carbohydrate recognition domain (CRD). The majority of galectins display a single CRD, and are biologically active as monomers (galectin-5, -7 and -10), or require homodimerization for functional activity (galectin-1, -2, -11, -13, -14 and -15). Alternatively, tandem-repeat-type galectins (galectin-4, -8, -9, and -12) contain two CRDs separated by a short linker peptide, while galectin-3 (chimeric type) has a single CRD fused to a non-lectin domain that can be complexed with other galectin-3 monomers to form an oligomeric pentamer. Of note, some galectins, such as galectin-10, bind to mannose-containing glycans. Among the family of galectins -1, -3, and -9 are particularly important as potential therapeutic targets, and -2, -4, -5, -6, -7, -8, -10, -11, -12, -13, -14, and -15 also appear implicated in a variety of biological pathways associated with morbidity and mortality.
Thus, galectin-7 has been implicated in the development of certain forms of cancer. St. Pierre et al, Front. Biosci., 1:17, 438-50 (2012) and in a variety of specific cancers, including gal-2, -4 and -8 in the context of colon and breast cancer, Barrow et al, Clin. Cancer Res. 15; 17 (22) 7035-46 (2011). Squamous cell carcinoma of the tongue, Alves et al., Pathol. Res. Pract. 15; 207 (4) 236-40 (2011) has been shown to be associated with elevated levels of gal-1, -3 and -7, while cervical squamous carcinoma has been shown linked to gal-7 levels, Zhu et al, Int. J. Cancer, (August, 2012). A number of galectins, including gal-15, gal-13 and gal-10 have been demonstrated to be linked to implantation and pregnancy concerns. See, e.g., Than et al, Eur. J. Biochem. 271(6) 1065-78 (2004), Lewis et al, Biol. Reprod. 77(6); 1027-36 (2007). A number of galectins, including gal-2, 3, 8 and others have been identified as correlating with various autoimmune disorders, such as lupus. Salwati et al, J. Infect. Dis. 1; 202(1) 117-24 (2010), Pal et al, Biochim. Biophys. Acta., 1820 (10) 1512-18 (2012) and Janko et al, Lupus 21(7):781-3 (2012). Elevated levels of a number of galectins, including gal-3, are associated with inflammation and fibroses encountered in wound healing and the like. Gal et al, Acta. Histochem. Cytochem. 26:44(5); 191-9 (2011).
Quite obviously, mediation of inflammatory and fibrotic pathways makes galectins critical elements of a wide variety of disease, injury and trauma related phenomena. In many cases, the presence of unwanted concentrations of galectins can aggravate a disease condition or trauma situation, or interfere with attempts to treat diseases, such as cancer or congestive heart failure. Among the family of galectins recognized as active intracellularly in humans, galectin-1, galectin-3 and galectin-9 are of particular interest. As indicated above, these proteins are generally referred to, and referred to herein as, gal-1, gal-3 and gal-9. A wide variety of conditions in humans, ranging from problems in conceiving to asthma to chronic heart failure to cancer to viral infection to stroke and beyond are mediated or aggravated by higher than normal concentrations of galectins. Thus, among other galectins, gal-3 is particularly prominent in fibrosis, inflammation and cell proliferation, while gal-1 also plays a role in the immunosuppression required for a successful pregnancy. Gal-1 is also thought to be involved in the differentiation of nerve cells. Gal-9 has been shown to be involved in the control of lesions arising from immunoinflammatory diseases, and is generally implicated in inflammation—gal-9 apparently plays a role in eosinophil recruitment in inflammatory sites. It also appears to mediate apoptosis in certain activated cells.
While the discussion herein is applicable to circulating active gal-1, gal-3 and gal-9, and galectins in general where elevated circulating galectin levels are associated with disease or injury conditions, more has been elucidated about the role of gal-3 in disease and trauma progression than any of the other galectins, and so it is exemplified herein. More specifically, this invention focuses on the removal of gal-3 from mammalian, particularly human, plasma. Gal-3 has been shown to be involved in a large number of biological processes, many of which are related to disease states of various kinds. Binding and blocking activity of gal-3 in the circulation, or removal of large amounts of gal-3 from circulation may therefore improve existing medical treatments, suppress and/or reduce inflammation and fibrosis resulting from others, and make it possible to intervene in various disease states not otherwise easily treated. The invention is equally applicable to the reduction in circulating levels of other galectins to address conditions mediated by those galectins.
This invention makes use of plasmapheresis, sometimes referred to as therapeutic plasma exchange, to control levels of gal-3, and more specifically biologically active galectin, in circulation. Plasma is lead through a fluid pathway and either intermixed with a gal-3 binding agent which can be separated from the plasma, or returned to the body with blocked inactivated gal-3, or lead past a solid support which binds gal-3, the plasma being subsequently returned to the body with a reduced level of gal-3.
2. Related Art
This application is related to U.S. patent application Ser. No. 13/153,648, filed Jun. 6, 2011. That application in turn claims priority benefit to U.S. patent application Ser. No. 11/485,955, filed Jul. 6, 2006. The content of both these patent applications is expressly incorporated herein-by-reference. In U.S. patent application Ser. No. 13/153,648 (U.S. Patent Publication US-2011-0294755 A1) a method of treating cell proliferation conditions, inflammation and aggravated fibroses is disclosed which involves the administration of an agent that can bind circulating gal-3, such as modified citrus pectin, or MCP, a citrus pectin which has a reduced molecular weight of twenty thousand (20,000) Daltons or less, preferably ten thousand (10,000) Daltons or so. MCP is available commercially from EcoNugenics of Santa Rosa, Calif. and is discussed in U.S. Pat. Nos. 6,274,566 and 6,462,029.
3. Background of the Technology
Gal-3 is approximately 30 kDa and, like all galectins, contains a carbohydrate-recognition-binding domain (CRD) of about one hundred thirty (130) amino acids that enable the specific binding of β-galactosides. Gal-3 is encoded by a single gene, LGALS3, located on chromosome 14, locus q21-q22. This protein has been shown to be involved in a large number of biological processes. The list set forth herein is exemplary only as new situations and roles for gal-3 are continually being revealed. Among the biological processes at the cellular level that have been shown to be mediated, at least in part, by gal-3, are cell adhesion, cell migration, cell invasion, cell activation and chemoattraction, cell growth and differentiation, cell cycle, and apoptosis.
Given gal-3's broad biological functionality, it has been demonstrated to be involved in a large number of disease states or medical implications. Studies have also shown that the expression of gal-3 is implicated in a variety of processes associated with heart failure, including myofibroblast proliferation, fibrogenesis, tissue repair, inflammation, and ventricular and tissue remodeling. Elevated levels of gal-3 in the blood have been found to be significantly associated with increased morbidity and mortality. They have also been found to be significantly associated with higher risk of death in both acute decompensated heart failure and chronic heart failure populations.
Various investigations have shown elevated levels of gal-3 to aggravate a wide variety of disease conditions associated with cell proliferation. High levels of gal-3 are linked to cancer growth and cancer progression to a metastatic stage in a stunning variety of cancers. A number of cancers have been specifically linked to or associated with elevated gal-3 levels, including liver cancer, kidney cancer, breast cancer, prostate cancer, colon cancer, thyroid cancer, cancer of the gallbladder, nasopharyngeal cancer, lymphocytic leukemia, lung cancer, melanoma, multiple myeloma, glioblastoma multiforme, uterine cancer, ovarian cancer, cervical cancer, brain cancer and others. Elevated gal-3 levels have also been shown to interfere with or suppress conventional antineoplastic regimens, such as chemotherapeutic treatments like cis-platinum, doxorubicin and related chemotherapeutics.
Inflammation is a commonly encountered body condition—a natural response of the body to a variety of diseases and trauma. As with the other conditions noted above, gal-3 levels above normal levels are implicated in a wide variety of situations where harmful inflammation is encountered. Again, the list of conditions and disease states is too extensive to exhaust every possibility, but inflammatory conditions associated with elevated gal-3 levels include aggravated inflammation associated with non-degradable pathogens, autoimmune reactions, allergies, ionizing radiation exposure, diabetes, heart disease and dysfunction, atherosclerosis, bronchial inflammation, intestinal ulcers, intestinal inflammation of the bowels, cirrhosis-associated hepatic inflammation, parasitic infection associated inflammation, inflammation associated with viral infection, inflammation associated with fungal infection, inflammation associated with arthritis, with multiple sclerosis and psoriasis. Again, while inflammation is a pathway frequently employed by the body in responding to any number of challenges, elevated levels of gal-3 have been found to aggravate the inflammation, causing damage and injury leading to morbidity or mortality in a wide variety of situations that are otherwise manageable, including inflammation due to heavy metal poisoning and similar toxins, stroke and related ischemic injuries, liver inflammation due to acetaminophen, a number of T-cell mediated responses generally involved in autoimmune diseases and the like. Gal-3 is also involved with kidney injury and kidney disease, hepatitis, pulmonary hypertension and fibrosis, diabetes, and gastrointestinal inflammatory conditions such as Ulcerative colitis, Chrone's, Celiac, and others.
As noted, elevated levels of circulating, active gal-3 are associated with, and apparently aggravate, a number of inflammatory conditions, including those contributing to heart, kidney, lung, and liver disease. Gal-3 is also associated with a fibrotic formation, particularly in response to organ damage. Higher levels of circulating gal-3 are found to induce pathogenic fibroses in cardiovascular disease, gastroenterological disease, cardiovascular trauma, renal tissue trauma, brain trauma, lung trauma, hepatic tissue trauma, tissue damage due to radiation therapy and diseases and conditions of connective tissue and skin such as systemic sclerosis.
Accordingly, the art is replete with observations that elevated levels of gal-3, as well as gal-1 and gal-9, can complicate or exacerbate a wide variety of disease and injury conditions. It would be of value to find a way to control inflammation and formation of fibroses, where the inflammation and fibroses are injurious, particularly in the environments described above, and notably in cardiac care and other organ tissue disease and trauma. By the same token, it would be of value to control the cellular responses mediated by gal-3 that accelerate cell proliferation and transformation, including the formation and growth of tumors, the transformation of cancer cells and metastatic spread of cancer. Another goal in the art is to avoid the problem posed by the interference in the treatment of cancer by conventional agents, like bleomycin, Adriamycin, doxorubicin, cyclophosphamide and cyclosporine. Some of the side effects caused by these agents are gal-3 mediated, and can be addressed and ameliorated by the invention. Elevated gal-3 levels also appear to interfere with pharmaceuticals used in other applications, such as the antiarrhythmic drug amiodarone, and statin drugs.
Plasmapheresis is a blood separation technology, where blood is diverted from the body through a needle or catheter to a separator which removes blood cells and returns them to the body, leaving a plasma. This type of technique has been used historically in the treatment of autoimmune diseases, where the antibodies at issue are removed by contacting the plasma with the ligands to which they bind. The plasma is then augmented as required, with anticoagulants, therapeutics and associated elements, and returned to the body.
An early form of apparatus for plasmapheresis is set forth in U.S. Pat. No. 3,625,212, which describes measures to ensure return of treated plasma, as well as the separated blood cells, to the proper donor. U.S. Pat. No. 4,531,932 addresses plasmapheresis by centrifugation, the method used to separate out the red blood cells, on a rapid and near-continuous basis. U.S. Pat. Nos. 6,245,038 and 6,627,151 each describe a variety of methods of separating out plasma contents and returning the treated plasma to the patient after first removing red blood cells, in general, to reduce blood viscosity by removal of high molecular weight protein. While the invention that is the subject of this application focuses on the reduction in galectins circulating levels, such as gal-3 levels, and not high molecular weight proteins or directly addressing viscosity, the disclosure of these four (4) patents is incorporated herein-by-reference for their disclosure of available plasmapheresis techniques and apparatus which may generally be employed in this invention.
Prior to the development of this invention, those of skill in the art had experimented with the reduction of gal-3 levels in various respects. Thus, the activity of gal-3 in aggravating or promoting cancer, as well as the ability of a cancer to metastasize, is widely commented on in the literature following 2006. These literature findings stress repeatedly the importance of binding or reducing the circulating concentration or titer of gal-3, and/or inactivating gal-3 through gal-3 binders such as PectaSol-C MCP. See, for example, Wang et al, Cell Death and Disease, 1-10 (2010) (gal-3 inhibition promotes treatment) and Yu et al, J. Biol. Chemistry, Vol. 282, 1, pp. 773-781 (2007) establishing that gal-3 interactions may enhance formation of cancer or transformation of metastatic cancer.
As disclosed and claimed in U.S. Pat. No. 6,274,566, Gal-3 binders such as Modified Citrus Pectin and other compounds can bind to circulating tumor cells (CTC's) and prevent them from creating new metastasis. These CTC's are often implicated in mutations and a more aggressive disease. Cancer stem cells that may also be circulating and get stimulated under conditions of stress and inflammation, provide gal-3 another mechanism for aggravating cancer. The method of these prior cases may be used in conjunction with the invention of this application. In particular, when there are a high number of gal-3 molecules circulating in the blood stream it makes it more difficult for the gal-3 binders to target these CTCs. In this respect, gal-3 molecules serve as decoy molecules. The decoy prevents, in this particular application of the invention, binding of the cancer cells in the circulatory or lymph system, as opposed to tissue level gal-3.
As a consequence, reports link acceleration of cancer formation and transformation to circulating gal-3 concentrations, and suggest that reducing gal-3 circulating concentrations, reducing its free expression or otherwise reducing available gal-3 or gal-3 interactions improves cancer prognosis. Zhao et al, Cancer Res, 69, 6799-6806 (2009), Zhao et al, Molecular Cancer 9, 154, 1-12 (2010) and Wang et al, Am. J. of Pathology, 174, 4, 1515-1523 (2009) wherein siRNA-induced reduction of gal-3 is shown to slow the course of prostate cancer. Similarly, high-risk bladder cancer recurrence and prognosis is related indirectly to gal-3 levels. Rodriguez et al, J. Curr. Opin. Urol. 22(5):415-20 (2012) and Raspollini et al, Appl. Immunohistochem. Mol. Morphol. (July 2012). Clearly, there is substantial literature that supports the conclusion that reducing circulating gal-3, either by blocking its expression, or by binding it, is important in controlling cancer, both in tissue and in circulation.
Circulating gal-3 is empirically implicated in a wide variety of biological conditions, however. Cardiac fibrosis is gaining significant attention as a complicating risk factor in cardiac disease, and in particular, chronic heart failure (CHF). Lok et al, Clin. Res. Cardiol, 99, 323-328 (2010). DeFillipi et al, U.S. Cardiology, 7,1, 3-6 (2010) clearly indicate that circulating gal-3 is an important factor in fibrosis of many organs and organ systems, and that reducing circulating gal-3 may have an important role in remediating cardiac injury and progression to heart failure (HF). Similarly, Psarras et al, Eur. Heart J., Apr. 26, 2011 demonstrate that reduction in gal-3 levels in the myocardium may reduce fibrosis in the heart and improve outlook. De Boer et al, Ann. Med., 43,1, 60-68 (2011) identify gal-3 as a key indicator in cardiac health. Shash et al, Eur J. Heart Fail., 12, 8, 826-32 (2011) identify gal-3 levels as a key agent in heart failure through fibrosis. De Boer et al., Eur. J. Heart Fail., 11, 9, 811-817 (2009) link an increase in gal-3 expression and presence to heightened fibrosis, and heart failure. The same article links gal-3 to inflammation. Inflammation is the hallmark of arteriosclerosis and therefore gal-3 levels also contribute to coronary artery disease, peripheral artery disease, strokes, and vascular dementia.
Fibrosis and inflammation, both mediated to some degree by gal-3 (cellular or circulating) are implicated in a variety of conditions of the mammalian body, not just cardiac injury and heart failure. The binding of gal-3 achieved by administration of low molecular weight pectins (at least, as reflected in U.S. patent application Ser. No. 11/485,955, 10,000-20,000 Daltons molecular weight such as PectaSol-C MCP) is effective in reducing trauma due to kidney injury. Kolatsi-Jannou et al, PlusOne, 6, 4, e18683 (2011). Reducing circulating gal-3 levels may be effective in reducing fibrosis in the lungs and associated asthma. Cederfur et al, Biochim. Biophys. Acta. 1820(9):1429-36 (2012). The reduction in circulating gal-3 levels is also indicated to reduce inflammation associated with type 2 diabetics, and similar metabolic diseases, as well as obesity. Weigert et al, J. Endocrinol. Metab. 95, 3,1404-1411(2010). Thus, high levels of gal-3 have been linked to thyroid cancer, Sethi et al, J. Exp. Ther. Oncol., 8, 4,341-52 (2010) and reduction of gal-3 expression and circulation may delay or reduce tumor cell transformation. Chiu et al, Am J. Pathol. 176, 5, 2067-81 (2010).
As noted, gal-3 is implicated in a wide variety of biological conditions, and a reduction in gal-3 activity, such as that which can be achieved by gal-3 binding with PectaSol-C MCP and similar low molecular weight pectins may be of value in treating gastric ulcerative conditions. Srikanta, Biochimie, 92, 2, 194-203 (2010) Kim et al, Gastroenterology, 138, 1035-45 (2010) indicate that reducing gal-3 levels may be of therapeutic value in reducing gastric cancer progression. By the same methodology, reducing gal-3 levels sensitizes gastric cancer cells to conventional chemotherapeutic agents. Cheong et al, Cancer Sci., 101, 1, 94-102 (2010). Gal-3 is implicated in a wide variety of gastrointestinal conditions. Reducing gal-3, by binding for example, may reduce inflammation in the gut mucosa, making MCP an important agent for treatment of ulcerative colitis, non-specific colitis and ileitis, Crohn's disease, Celiac disease, and gluten sensitivity. Fowler et al, Cell Microbiol., 81,1,44-54 (2006).
Biliary artesia, a liver disease, is associated with extensive fibrosis of the liver linked with elevated gal-3 levels. Honsawek et al, Eur. J. Pediatr. Surg., April, 2011. Reduction of gal-3 levels resulted in a general improvement in hepatic health, including reducing inflammation, hepatocyte injury and fibrosis. Federici et al, J. Heptal., 54, 5, 975-83 (2011). See also, Liu et al, World J. Gastroenterol. 14,48, 7386-91 (2008) which reported, following Applicant's teaching in 2005 and 2006 to administer low molecular weight MCP, that MCP inhibited liver metastases of colon cancer and reduced gal-3 concentrations. MCP, or other gal-3 binders, may be used for prevention of liver inflammation, liver fibrosis and liver cirrhosis as well as post-disease liver damage, including the various viral hepatitis diseases (A, B, C, and others) and may be used as well in the treatment of parasitic and chemical hepatitis, chemical liver damage, and others. Gal-3 levels are implicated in a wide variety of liver associated ailments. Thus, gal-3 may be important in the control of Niemann-Pick disease type C, which is a lysosomal disorder characterized by liver disease and progressive neurodegeneration. Cluzeau et al, Hum. Mol. Geent. 14; 21 (16) 3632-46 (2012). There is increasing evidence that elevated gal-3 levels are tied to acetaminophen-induced hepatotoxicity and inflammation. Radosavljeci et al, Toxicol. Sci., 127:609-19 (2012). Reduction in gal-3 levels may improve treatments. Dragomir et al, Toxicol. Sci. 127(2):609-19 (2012).
While administration of modified citrus pectin, or a similar binding agent, continues to be a promising therapy of inhibition of damage, and repair of damage, induced by gal-3, the inventor has continued to work to find other methods of providing faster or more profound relief. It has now been found that by selective use of certain gal-3 binding molecules, gal-3 and specifically biologically active gal-3 can be specifically removed from the plasma in significant amounts. Return of the plasma with a reduced titer of active gal-3 offers immediate opportunities for therapy and intervention that may be different from, or more profound than, the reduction achieved by administration of binding molecules to a mammal in need of same. By removing the circulating gal-3 molecules the invention removes these protective but potentially harmful molecules from the circulation. In addition, it allows targeted gal-3 blockers such as MCP, and possibly other oligo-saccharides and various pharmaceutical agents to be developed to better attach to the gal-3 on the cell surface and on the tissue level. As the expression of gal-3 is increased in the injured and inflamed tissue, such as remodeled cardiac muscle or cancer tissue, by removing the circulating gal-3, the gal-3 binding agent can more effectively bind to the Gal-3 in the target tissue.

Reduction of galectin-3 levels by plasmapheresis


An ultrasonic low-noise analog beamformer for Doppler acquisition achieves high sensitivity by translating the frequency of the ultrasound echoes to an intermediate frequency, which is well above of the 1/f corner. This is accomplished by beamforming the downconverted RF signals instead of using their baseband representation. The baseband conversion, succeeding the beamformation, also incorporates the steps of clutter filtering and anti-aliasing. The invention is particularly suitable for low-voltage process technologies that support broadband applications.

1. Field of the Invention
This invention relates to coherent ultrasound imaging systems and, more particularly, to phased array ultrasound imaging systems operating in different scan formats and imaging modes. Specifically, but not limited to, the invention relates to phased array beamformer system with low-noise Doppler data acquisition.
2. Description of the Related Art
Medical ultrasound imaging systems are capable of many different modes of operation. One of these is the Doppler mode dedicated to displaying the movement of blood within a vein or an artery.
Doppler imaging can be performed using either continuous wave (CW) or pulse wave (PW) techniques. In CW Doppler acquisition, the ultrasound transmitter continuously insonifies the body, while the receiver continuously receives echoes from all objects within the receiver's area of sensitivity. In this case, information received from any specific range interval cannot be isolated. Accordingly, the observation region is the overlap portion between the transmitting and receiving transducer beam profiles. To select the desired target, the instrument's area of sensitivity is adjusted, by either physical placement of the probe, by beamforming, or both.
As a single scatterer passes the observation region, the scatterer generates a burst of oscillations that contributes to the received radio frequency (RF) signal. The frequency of this oscillation is different from the transmit frequency because of the Doppler shift, which is proportional to the component of the blood velocity along the phase gradient of the combined transmitter and receiver beams. The "sign," or relative polarity, of the frequency difference between the transmitted and received signals determines the direction of the blood flow.
In PW mode, the scanner transmits a periodic pulse wave at a certain operating frequency F0 that is directed to a particular location having blood flow. The signal reflecting from the moving blood is shifted in frequency by an amount proportional to the velocity of the blood flow. Thus, with the PW Doppler technique, the received signal has the same essential properties as for the CW. The difference is that the range gate limits the observation region along the beam to the range cell. This allows one to obtain only samples of the Doppler signal with the pulse repetition frequency, the PRF, which introduces the problem of frequency aliasing. Besides, due to limitations in the PRF rate, PW Doppler has limited ability to measure very high blood flow velocities. The rate limitations are fundamental because the transmitted pulse must reach the target and echoes are reflected back to the receiver before the next pulse can be sent.
CW Doppler, on the other hand, transmits a constant continuous wave signal toward the area to be imaged at a particular transducer operating frequency. The signal is continuously reflected by the blood flow and received by a receiver. The receiver distinguishes between the transmitted signal and the received signal by determining if there is a frequency shift between the transmitted and received signals. The movement of the blood causes this frequency shift, where its value is proportional to the velocity of the blood. The direction of the blood flow is dependent on whether the frequency of the received signal is greater or less than the frequency of the transmitted signal. Because the signal is transmitted continuously, CW Doppler can detect significantly higher frequency shifts than PW Doppler since there is no inherent sampling rate limitation.
There are two sources contributed to an RF signal received from an internal structure of human body containing a blood vessel. First, this is a strong signal from slowly moving tissue with low Doppler shifts (0 Hertz for stationary tissue). The Doppler signals from blood can be 60-100 dB weaker exhibiting larger shifts in frequency because the blood has higher velocities than the tissue. FIG. 2a illustrates these differences.
In comparison with PW Doppler, it is more difficult for CW techniques to distinguish between the transmitted signal and the reflected signal originated by moving blood. First, since the transmitted signal is continuous and relatively high in amplitude, it generates interference in the receiver. Second, the high-amplitude echoes reflected from stationary tissue, typically called "clutter," do not contain a frequency shift but occur simultaneously with the signals that represent blood flow. Further, conventional CW Doppler processors have a limited dynamic range due to the limited dynamic range of the analog-to-digital converters (ADCs). Thus, the clutter filtering that precedes the ADC must be much more complex, so that the signal that feeds the converter contains as little clutter content as possible.
There are numerous methods and techniques that have been developed to enhance quality of Doppler data acquisition. The following U.S. Patents represent typical examples of prior art, merely by way of example: U.S. Pat. Nos. 4,866,613, 4,911,171, 5,555,534, 5,562,097, 6,544,180, 6,527,722, and 6,648,826.
In general, the separate analog-processing path for a CW Doppler receiver consists of cascaded stages of mixers and filters. To support a variety of transducers, the hardware includes a number of programmable filters that are tuned to the operating frequencies of the available transducers. Such architecture requires using expensive switches and precision components. For the phased array, i.e., multi-channel ultrasound systems, it causes a substantial increase in the component count and cost that makes this approach impractical.
To address the complexity issue, Fazioly, et al., U.S. Pat. No. 6,527,722, describes a CW Doppler single channel receiver consisting of a mixer accompanied by a bandpass filter (BPF), which operates to translate the RF input signal to a constant intermediate frequency (IF) signal. Consequently, the cost of the CW Doppler processing circuitry will be reduced with respect to a conventional processing system. However, referring to a single-channel receiver, Fazioly does not disclose any aspect of CW Doppler data acquisition with a phased-array transducer.
Maslak, et al., U.S. Pat. No. 5,555,534, teaches a phased array receive beamformer that is dedicated to operate in both CW and PW Doppler modes. FIG. 1 depicts a block diagram of the beamformer comprising a plurality of receive channels 110. Each of the channels includes a low-noise amplifier (LNA), a gated quadrature mixer, and a complex rotator. In operation, the RF signal amplified by LNA 111 is mixed in a quadrature mixer with a pair of clocks being out of phase by 90° with respect to each other. The in-phase clock signal LOI, which is supplied to mixer 102, is provided in common to the in-phase mixers of all of the analog receive channels 110, as is the quadrature clock signal LOQ received by mixer 104. The outputs of the mixers 102 and 104 are in-phase and quadrature-phase components of a complex baseband signal related to respective RF echo. These outputs are coupled to a complex rotator 106, which is a baseband signal processing block, that weights, selects, and sums the in-phase and quadrature-phase components. The I/Q outputs of the rotator are programmed to represent eight possible phases of the input complex signal. The rotator in each channel has its own set of three phase control input bits.
Referring to FIG. 1 again, the in-phase (I) signals 108 of all of the individual Doppler receive beamformer channels 110 are summed in four groups. At first, the per-group signals 108 are applied to respective summers 112 having a low-pass pole 114, which filters out the RF products of the mixing process without affecting the baseband component. Then, the partial sums 118 are combined by a summer 116 to generate a beamformed in-phase signal 120 from all channels. It will be understood that the quadrature signals are combined in the same manner.
The outputs of the I/Q summers are coupled to a downstream processor 140. The processor comprises in-phase and quadrature sections but since they are identical, only the in-phase section is shown. It includes an integrator 122 to integrate (PW) or to smooth (CW) the beamformed signals, a track-and-hold circuit 124, a high-pass filter 126 to remove clutter signals, an anti-aliasing filter 128, and an ADC 130 to convert the relatively clutter-free signals to digital format.
As known in the art, there are indisputable advantages of the baseband representation of composite RF signals similar to those shown in FIG. 2a. However, since blood flow originates a Doppler shift in the audible range, the spectrum of the baseband I/Q components occupies the same frequencies as flicker or 1/f noise. For reasons, which will become apparent, the overlapping of spectra as shown in FIG. 2b may substantially reduce the dynamic range of D-mode acquisition.
There are two main sources of the 1/f noise in the '534 beamformer:
First, the per-cannel quadrature mixers, 102 and 104, comprise two transistor pairs switching at the LO frequency. While switching, the gates (bases) of the pair exhibits charge fluctuations. Having a spectral density proportional to 1/f, these fluctuations are transferred to the output by multiplication with a time-varying transconductance of the switching pair. Since transconductance of the pair is varied at the 2×LO frequency, it contains only even-order harmonics of the LO. This means that flicker noise from the switching pair will directly appear at the output around DC, i.e., in baseband. (Sometimes this noise is referred as the phase noise.) For an N-channel beamformer, the resulting 1/f noise from switching is increased for a factor of N1/2 as compared with a single channel. However, since the beamformer signal gain is equal to N, the signal-to-noise ratio (SNR) is improved by a factor of N1/2.
Another source of flicker noise is subsequent summing inherently associated with the process of beamforming. Referring to '534 in particular, the complex rotator 106 sums the weighted baseband outputs of the mixers 102 and 104. It is followed by the combining of all of the per-channel I/Q output signals represented in the baseband. The noise-referred details of the summing operation are discussed below.
It will be evident to those skilled in the art that the LNA/mixer combination needs to provide a gain, which is sufficient to prevent substantial degradation of the SNR by the noise introduced by subsequent summing means. However, a weak signal representing blood flow is situated on a top of a high-amplitude clutter, which may be in the range of 500 millivolts peak-to-peak. Consequently, the entire signal-processing chain needs to be relatively high-voltage in order to avoid signal clipping.
By contrast, the latest integration technology is based on low-voltage MOS processes with signal swing of 1.8 Volts or less. Thus, developing an integrated MOS receiver for D-mode, the LNA/mixer gain may not exceed 12 dB. For a given gain G, the expected SNR degradation due to 1/f noise can be found as follows:
Let fC denote flicker noise corner frequency, i.e., the frequency at which 1/f noise exceeds thermal noise. Depending on the operating conditions of the fabrication process, MOS devices manifest a corner frequency, which varies as the reciprocal of the channel length. Typically, fC has a range of 100 kHz to 1 MHz.
If SF and ST are the power spectral densities of 1/f noise and thermal noise, respectively, their densities can be equated at a corner frequency of fC, i.e., SF (fC)=ST. By definition, the power spectral density of 1/f noise is SF=K/f. Resolving this formula for f=fC yields K=ST·fC. It allows to express flicker noise spectrum as SF=ST·fC/f.
In addition to the phase noise, noise contribution from the LNA/mixer section is primarily related to translating LNA noise from the RF range (2 to 8 MHz, typically) to the baseband. Since the above RF range is well above the 1/f noise corner, the corresponding noise is representative of thermal noise. This noise manifests a noise floor for a subsequent stage, i.e., the summer 112. The noise-floor spectrum introduces by the LNA/mixer section is relatively flat with power spectral density of G2·ST. Because noise contributions from the switching pair and said noise floor are mutually independent, their influence can be considered separately.
At the summing node of 112, the resulting noise exhibits a linear combination of the above-mentioned noise floor and the input referred noise produced by the summer itself. If we consider the input referred noise to be originated by thermal and flicker sources, the total noise power can be expressed as the sum of three definite integrals, each related to respective noise source. To determine the limits of integration, it can be taken into account that the clutter filter removes any Doppler along with noise components occurring at or near 0 Hertz. Let fMIN denote a minimal frequency of a signal passing the clutter filter. On the other end, the highest Doppler shift determines a cut-off frequency of the processing, fMAX. Typically, fMAX=100 kHz. Thus, the total noise power, VN2, yields:
      V    N    2    =                    ∫                  f          MIN                          f          MAX                                            S          T                                                                    ⅆ          f                      +                  G        2            ×                        ∫                      f            MIN                                f            MAX                                                        S            T                                                                                ⅆ                          +                                                ∫                                      f                    MIN                                                        f                    MAX                                                                                S                    F                                                                                ⅆ                    f                                                                                Evaluating the integrals,
      V    N    2    =            S      T                  [                                    (                          1              +                              G                2                                      )                    ·                      (                                          f                MAX                            -                              f                MIN                                      )                          +                                            f              C                        ·            ln                                                                                f              MAX                                      f              MIN                                          ]      In the absence of flicker noise, the total noise power would be VNT2, where:VNT2=ST·(1+G2)·(fMAX−fMIN)Taking the ratio of VN to VNT, the SNR degradation due to 1/f noise of the summer can be expressed as:
  γ  =                    V        N        2                    V        NT        2              =          1      +                                                  f              C                                                      (                                                      f                    MAX                                    -                                      f                    MIN                                                  )                                                          (                                  1                  +                                      G                    2                                                  )                                              ·          ln                                                                                f            MAX                                f            MIN
TABLE I sets forth the amount of SNR degradation, γ, for fMIN=1, 10, 100, and 1000 Hz with G=4 and fC=1 MHz.
TABLE Ifmin (Hz)1101001000γ(dB)8.9068.0747.0445.692It can be seen that flicker noise associated with subsequent summing stages increases the system noise floor by a factor of 7-8 dB that substantially degrades the performance of beamforming provided in the baseband.
As mentioned, the influence of 1/f noise can be minimized by increasing the LNA/mixer gain. However, in a low-voltage system this approach is practically inapplicable since clutter would desensitize the beamformer before the signals from blood flow become sufficiently large. Therefore, there is a need for a wide-dynamic-range phased array Doppler beamformer adapted to operate using sub-micron technology.

Low-noise ultrasound method and beamformer system for doppler processing