A crush indicating device is disclosed which is designed to be attached to an object or a container for the purpose of indicating whether the object or container subsequently is subjected to excessive force, acceleration or shock. The indicator device has a contrasting agent reservoir filled with a contrasting agent, an absorbing wick and a compressible wall. The compressible wall extends between the wick and the reservoir, holding them in a fixed apart relationship while the wall is uncompressed. Application of force to the device compresses the wall and brings the wick into contact with the reservoir. The wick absorbs contrasting agent from the reservoir, resulting in a marked visible change in the wick which signifies that excessive force has been applied to the device. A base is located at one end of the wall, supporting the reservoir and providing means to attach the device to an object or container. A transparent cover sheet is located at the opposite end of the wall.

1. Field of the Invention
The present invention relates to devices for detecting when objects such as equipment, articles of manufacture, or shipping containers have been subjected to a mechanical shock.
2. Description of the Prior Art
Many items of manufacture are sensitive to excessive force or shock, and may be damaged if subject to such force or shock. For example, electronic equipment such as televisions and stereos have plastic cabinets and sensitive electronic components. Excessive shock can result in breakage of the cabinet and electronic components.
These items of manufacture are particularly vulnerable to excessive forces when being shipped. For example, when loading or unloading shipping containers, the containers may be dropped from a forklift. Also, when being shipped in a railcar, the railcar may be stopped suddenly, exposing the shipping containers loaded inside to excessive acceleration forces. There is a need for a low cost, reliable device that can be attached to a shipping container and that will provide an indication if the container has been subjected to excessive forces. With such a device, a manufacturer can accurately access fault for damage caused to its goods in transit.
The prior art has seen development of many complex electrical, mechanical and electromechanical devices which measure force applied to a container or object. These devices have tended to be expensive to manufacture, restricting the extensive use of the devices on inexpensive as well as expensive objects
A simpler force sensor device is shown in Manske, U.S. Pat. No. 4,793,717. The Manske device can register the impact of a single direct impact. However, it apparently is not sensitive to a distributed surface of pressure such as a box surface. Additionally, the threshold of force needed to activate the Manske device is fixed by its design. Some applications may require different activating forces. For example, sensor devices used on televisions may require a relatively low activating force as compared to sensor devices on more robust equipment. Thus, it is desirable to provide a sensor device that can be manufactured in different sensitivities.


A mask comprises a mask frame defining an opening; a plurality of support bars installed in the opening of the mask frame; a plurality of movable bars, each of which is installed over a corresponding one of the plurality of support bars and movable relative to the corresponding support bar, wherein the plurality of support bars and the plurality of movable bars are arranged to divide the opening into a plurality of mask holes; and a plurality of actuators installed between the plurality of movable bars and the corresponding support bars and configured to move the movable bars relative to the plurality of support bars.

(a) Field
The present disclosure relates to a variable mask in which a mask pattern may be changed.
(b) Discussion of the Related Technology
As a flat panel display, a liquid crystal display (LCD) and an organic light emitting device (OLED) are known. The flat panel display includes metal layers with particular patterns, organic emission layers with particular patterns, insulating layers, or the like.
In order to form the metal layers, the organic emission layer, the insulating layers, or the like, a deposition method or an exposure method, which uses a mask assembly, is used.
As the mask assembly, a pattern mask assembly, which has pattern openings that are formed in the same shape as the metal layers or the organic emission layers that will be deposited or exposed, is used.
However, in a case in which it is necessary to change the shape of the mask pattern of the mask assembly, the entire mask assembly needs to be replaced, and as a result, excessive costs may be incurred to replace the mask assembly.
The above information disclosed in this Background section is only for enhancement of understanding of the background of the disclosure and therefore it may contain information that does not form the prior art that is already known in this country to a person of ordinary skill in the art.


A method for management of real-time system algorithms to achieve optimal efficiency which provides for dynamically managing priorities in a complex real-time system, considering the dynamic requirements of the system. A preferred embodiment describes the management of a plurality of RRM algorithms, including algorithms for SCC escape, LM escape, SCC rate control, and F-DCA background. More specifically, one exemplary embodiment assists in deciding: when to increase algorithm priorities, how to increase/decrease algorithm priorities, how to assign priority parameters, and how to dynamically manage priorities in the system, to result in optimal system efficiency.

The following are expansions for certain acronyms used in this application:
SCCslow congestion controlF-DCAfast dynamic channel allocationLMlink maintenanceC-RNCcontrolling network controller
There is an ever-increasing need to achieve enhanced efficiency of operation in complex communication systems, and, the need is even greater in management of real time systems that use a plurality of algorithms.
In complex real-time systems, it is desirable to use priority-handling mechanisms on processes to achieve optimal efficiency. The RRM (Radio Resource Management) algorithms fall into the above category. Traditional fixed-priority handling mechanisms work well in small and stable systems. However, the wireless communication environment is very dynamic and complex. It is necessary and beneficial that the execution priority of the algorithms can be changed according to the most current system status.
Prior art offers information in patent publications that deal with operating system scheduling and packet scheduling, for example. The following are examples of US patents generally in the field of networks:
In U.S. Pat. No. 6,453,360, titled "High Performance Network Interface", a high performance network interface is provided for receiving a packet from a network and transferring it to a host computer system. A header portion of a received packet is parsed by a parser module to determine the received packet's compatibility with, or conformance to, one or more pre-selected protocols. Packets are stored in multiple queues with priorities.
U.S. Pat. No. 6,452,915, titled "IP-flow Classification in a Wireless Point To Multi-Point (PTMP) Transmission System", is directed to an IP-flow classification system used in a wireless telecommunications system. More specifically, the IP flow classification system in said U.S. patent provides for grouping IP-flows from a packet-centric wireless point to a multi-point telecommunications system. A quality of service (QoS) grouping device therein may include an optional differentiated services (Diff-Serv) device that takes into account an optional Diff-Serv field priority-marking for the IP-flow.
In U.S. Pat. 6,449,251, titled "Packet Mapper for Dynamic Data Packet Prioritization", a packet-mapper maps streams of data packets in a computer network, each data packet having a packet header containing feature values descriptive of the data packet. The packet-mapper includes a mapping table that associates application-related feature values with network-reserved feature values from a range of feature values reserved for use by selected network data packet streams. Prioritization in said US Patent is achieved by assigning a port-number for packets.
The above examples of US patent publications are, however, not directly applicable to management of and scheduling between different RRM algorithms, and do not take into account system status.
It is desirable to provide a method of dynamically managing system algorithms, e.g., RRM algorithms, so as to achieve optimal efficiency.

This patent is subject to a terminal disclaimer.

Method and apparatus for priority management of system algorithms in real time


The present invention provides a method for forming an electrode of a flat panel display device using ink for ink jet printing and an ink jet printer. The ink for ink jet printing is prepared by a method comprising the first step of contacting the vapor of a metal with the vapor of the first solvent, according to the vapor phase-evaporation technique, to thus give a dispersion of metal ultrafine particles; the second step of adding a low molecular weight polar solvent as the second solvent to the dispersion prepared in the first step to thus precipitate the metal ultrafine particles and removing the first solvent; and the third step of adding the third solvent to the precipitates thus prepared to carry out the solvent substitution and to give a dispersion of independently dispersed metal ultrafine particles, and prepared by adding a dispersant in or during the foregoing first and/or third steps, and the ink for ink jet printing consists of a dispersion excellent in ink characteristic properties. In the dispersion, metal ultrafine particles having a particle size of not more than 100 nm are independently and uniformly dispersed. The electrodes of FPD devices are formed using this ink for ink jet printing.

In fields such as colored paints and conductive paints, there have conventionally been used dispersions of metal ultrafine particles, but there has not yet been proposed any technique for forming an electrode for the FPD, which makes use of such a dispersion of metal ultrafine particles as ink and the ink jet printing system. The FPD includes a variety of display systems such as a liquid crystal display (LCD), a plasma display panel (hereunder also referred to as "PDP"), an organic EL display (EL) and a field-emission-display (FED), but the PDP will hereunder be described as a typical example thereof in the present invention.
The PDP has become of interest lately as a large-scale display for consumer products, but there has been desired the development of a technique, which permits the simplification of the production process for the PDP to achieve a considerable decrease in cost and to thus popularize the PDP worldwide. First of all, the production process thereof will be described below while taking, as an example, the production of a color PDP for 42-inch high vision. This production process comprises the steps of preparing two kinds of panels of a front panel and a back panel. The electrode for the front panel is referred to as "a scanning electrode" and ITO transparent electrodes are formed on a glass plate at a density of 2 linear electrodes per one picture element for 1024 picture elements. The resistance value of the transparent electrode in itself is too high and thus a bus electrode (metal) is in general formed on the transparent electrode. The bus electrode has a width of 50 μm and a thickness of 2 μm and it has been formed, in the conventional electrode production process, according to the screen printing method in which a bus electrode is formed as a thick layer of an Ag paste or an electrode pattern-forming technique in which a film is formed on the entire surface by the sputtering technique and then an electrode pattern is formed by the photolithography technique using a resist film. On the other hand, the electrode for the back panel is called "an address electrode" and it is directly formed on a glass plate at a density of 3 linear electrodes per one picture element for 1024 picture elements. The address electrode has a width of 50 μm and a thickness of 2 μm and it is formed according to the screen printing method or the sputtering-photolithography technique like the scanning electrode. A dielectric glass layer is formed on the both scanning and address electrodes.
Both of the front and back panels are subjected to subsequent steps commonly employed and then bonded together to thus complete a PDP panel. Among the steps required for the production of such a PDP panel, the steps for forming the electrodes are the most complicated ones and require the use of a large number of steps. This becomes a major obstacle in the reduction of the production cost.
As methods for preparing the foregoing dispersion of metal ultrafine particles, there have been known, for instance, those that comprise the steps of blending metal ultrafine particles or powder with a solvent, a resin and/or a dispersant and then dispersing the particles by, for instance, stirring the mixture, applying of ultrasonics thereto, and treating of the mixture with, for instance, a ball mill or sand mill to thus give a desired dispersion of metal ultrafine particles. The dispersions prepared according to these methods have been used in the fields of, for instance, paints and the like. For instance, there have been known those for directly preparing metal ultrafine particles in a vapor phase such as a vapor phase-evaporation method (Japanese Patent No. 2,561,537) in which a metal is evaporated in a vapor phase in the coexistence of solvent vapor, the evaporated metal is condensed into uniform ultrafine particles to disperse them in the solvent and to thus form a dispersion and those, which make use of an insoluble precipitate-forming reaction or a reducing reaction using a reducing agent. Among these methods for preparing a dispersion of metal ultrafine particles, the vapor phase-evaporation method permits the stable preparation of a dispersion in which ultrafine particles having a particle size of not more than 100 nm are uniformly dispersed and requires the use of a dispersion stabilizer or a resin component in an amount smaller than that required for the liquid phase-production methods in order to prepare such a dispersion of metal ultrafine particles having a predetermined concentration.
As has been discussed above, the dispersion of metal ultrafine particles has never been used as the ink for ink jet printer or ink jet printing (system). This is because the conventional dispersions of metal ultrafine particles did not have sufficient characteristic properties (such as viscosity and surface tension) required for making the dispersions usable in the ink for the ink jet printing. The metal ultrafine particles produced according to the conventional vapor phase-evaporation method undergo coalescence. Therefore, if they are dispersed in a solvent, they never provide any stable dispersion. For this reason, when such a dispersion of metal ultrafine particles is used as ink for the inkjet printing, a problem arises such that aggregates of metal ultrafine particles present therein would cause clogging of the nozzle for inkjet printing. Moreover, even in a dispersion comprising metal ultrafine particles independently dispersed therein, it is required for the preparation of such a dispersion to use a solvent that can satisfy the requirements for ink or possesses the required ink-characteristics, but it has been quite difficult to select such an appropriate solvent.
Moreover, in the conventional vapor phase-evaporation method, the coexisting solvent forms by-products due to the denaturation or modification thereof upon the condensation of the metal vapor and accordingly, the method sometimes suffers from such problems as those concerning the storage life, stability with time, viscosity and coloration of the resulting dispersion, depending on the amount of the by-products. In addition, as will be detailed below, it is necessary to prepare a dispersion of metal ultrafine particles in, for instance, a low boiling point solvent, water and alcoholic solvents, the use of which is difficult in the steps of the vapor phase-evaporation method, depending of the applications of the resulting dispersion.
According to the conventional method for the production of PDP, the front panel and the back panel are produced in separate steps and they are ultimately assembled to give a PDP panel.
The steps for producing the front panel will first be described below. After a test for examining acceptability of glass plates, an ITO pattern serving as scanning electrodes is formed by the sputtering and photolithography techniques. Since the ITO film in itself has a high resistance value, a metal film having a width of 50 μm and a thickness of 2 μm is formed as a bus electrode. At present, there have been known two methods for forming such a metal film, i.e., the screen printing method for forming a thick Ag paste layer and a method comprising the step of etching a Cr/Cu/Cr laminated sputter film into a pattern according to the photolithography technique. After the formation of the bus electrode, a dielectric glass layer and an MgO layer are formed on the bus electrode pattern in this order and the front panel is thus ready for the assembly with the back panel.
Next, the steps for producing the back panel will be described below. After a test for examining acceptability of glass plates, an address electrode is formed. As methods for producing the address electrode, there have been known two methods as in case of the production of the front panel, i.e., the screen printing method for forming a thick Ag paste layer and a method comprising the step of etching a Cr/Cu/Cr laminated sputter film into a pattern according to the photolithography technique. After the formation of the address electrode, a dielectric glass layer, a stripe barrier rib, and a layer of a fluorescent substance are formed on the address electrode in this order and the back panel is thus ready for the assembly with the front panel. In the assembling step, these two panels are tightly bonded together, followed by evacuation of the space between these panels, the enclosure of a gas therein and then an aging treatment to thus complete a PDP panel.
However, the screen printing method used in the foregoing electrode-forming process suffers from problems such as defects concerning the electrode-forming position due to any slippage of the screen, open defects due to insufficient patterning, which is in turn caused due to the clogging of the screen and loss of material due to the paste remaining on the screen. The sputtering-photolithography technique is a vacuum process and requires pattern-etching procedures according to the photolithography. Therefore, this technique requires the use of 6 to 7 steps such as sputtering, application of a resist, irradiation of patterned light, development, etching and resist-ashing steps and a problem also arises such that the loss in material is large since a film is formed on the whole surface of the plate.
Accordingly, an object of the present invention is to solve the foregoing problems associated with the conventional techniques and more specifically to provide a method for forming electrodes for FPD using ink for the inkjet printing, which consists of a dispersion of metal ultrafine particles independently dispersed therein and which is prepared in such a manner that the dispersion has sufficient characteristic properties required for use in the ink for the ink jet printing, and an ink jet printer.

Method for forming electrodes of flat panel display


A hand-held device (10, 10′) for contactless distance measurement measures a distance (d) between a target object (18) and at least one reference point (20) of the device (10) using an emitted modulated measurement signal (16). The device includes a housing (12, 13, 56) with a first end (34) that faces the object (18) to be measured, and a second end (35) facing away from the object (18) to be measured. The housing includes an output unit (22, 28, 29, 31) for depicting measured results. Several measured distance values are to be assigned to at least one subsection of the path between the object (18) to be measured and the opposite end (35) of the housing (12, 13, 56) via a length-measurement scale (36, 38, 54) that is displayable in the output unit (22, 28, 29, 31).

The present invention relates to a device for measuring distance, in particular for contactless distance measurement, with which a distance between a target object and at least one reference point of the device may be determined, using an emitted measurement signal. The present invention also relates to the operation of a device of this type, in particular a method for operating a digital meter rule.
In the determination of distances, a distinction in made between a direct measurement by making a direct comparison of a distance with a measurement means, e.g., a ruler, a tape-measure, or a folding rule, and by performing an indirect measurement using contactless, e.g., electro-optical distance-measuring devices. Electro-optical distance-measuring devices make it possible to determine distances using transit time or phase measurements of a measurement signal.
The indirect distance-measuring devices on the market are designed nearly exclusively as measuring devices for determining a distance value, and not as auxiliary devices for use to perform actions associated with measurement, e.g., determining and marking points or lines.
Publication EP 15 666 58 A1 makes known a hand-held device for measuring distances that emits transmission beams via optics located in a housing toward the background region of an object to be measured, and then collects the reflected beams. This device also includes a component that is connected with the housing, which may be extended beyond the housing in order to measure short distances in the direction of propagation of the transmission beams. One embodiment of this device provides a component that serves as a spacer and extends beyond the housing by a fixedly predetermined length. The fixedly predetermined length of this spacer is at least as great as the critical distance in front of the housing of the measuring device within which it is not possible to carry out optical measurements on surface areas.

Device for measuring distance and method for operating said type of device


New polymers are provided that have non-carbon tetravalent species (Si, Ti, Ge, Zr, Sn) and photoimageable compositions that contain such polymers. Preferred polymers are organic, e.g. one or more polymer repeat units comprise carbon atom(s). Particularly preferred are polymers that comprise SiO2 or TiO2 repeat units and which can be highly useful as a resin component of resists imaged at short wavelengths such as sub-300 nm and sub-200 nm.

1. Field of the Invention
The present invention relates to new polymers that have non-carbon tetravalent species (Si, Ti, Ge, Zr, Sn) and photoimageable compositions that contain such polymers. Preferred polymers are organic, e.g. one or more polymer repeat units comprise carbon atom(s). Particularly preferred are polymers that comprise SiO2 or TiO2 repeat units and which can be highly useful as a resin component of resists imaged at short wavelengths such as sub-300 nm and sub-200 nm.
2. Background
Photoresists are photosensitive films used for transfer of images to a substrate. A coating layer of a photoresist is formed on a substrate and the photoresist layer is then exposed through a photomask to a source of activating radiation. The photomask has areas that are opaque to activating radiation and other areas that are transparent to activating radiation. Exposure to activating radiation provides a photoinduced chemical transformation of the photoresist coating to thereby transfer the pattern of the photomask to the photoresist-coated substrate. Following exposure, the photoresist is developed to provide a relief image that permits selective processing of a substrate.
Photoresists are of particular interest that can be photoimaged with short wavelength radiation, including exposure radiation of about 300 nm or less, or 200 nm or less, such as wavelengths of about 248 nm (provided by KrF laser), 193 nm (provided by an ArF exposure tool), or 157 nm (provided by a F2 excimer tool). See European Published Application EP915382A2.
Use of such short exposure wavelengths can enable formation of smaller features. Accordingly, a photoresist that yields well-resolved images upon 248 nm, 193 nm or 157 nm exposure could enable formation of extremely small (e.g. sub-0.2 or 0.1 μm) features that respond to constant industry demands for smaller dimension circuit patterns, e.g. to provide greater circuit density and enhanced device performance.
In addition to using shorter wavelengths during exposure, it is also desirable to use a thinner layer of resist. However, the major drawback of using a thin layer of resist is that the variation of resist thickness over a diffusion step on a substrate and into an etched pattern increases as the pattern size becomes smaller. This variation means that the dimensions of any pattern being imaged in the resist will vary as the step geometry is traversed. Therefore, in a single layer resist system, the lack of dimensional control on the wafer can create different line widths throughout the resist which reduces the quality of the electronic package.
To attempt to improve dimensional control, bilayer (or bilevel or multilevel) resist systems have been utilized. In a typical bilevel system, a bottom resist is first applied to a substrate to planarize wafer topography. The bottom resist is cured and a second thinner imaging top resist is then applied over the bottom resist. The top resist is then soft baked, and patterned (or imaged) using conventional resist exposure and development, followed by etch transfer of the top pattern through the bottom resist using the top resist pattern as an etch mask. See Sugiyama et al., Positive Excimer Laser Resists Prepared with Aliphatic Diazoketones, Soc. Plastics Eng., Conference Proceedings, pages 51-60 (November 1988); and U.S. Pat. Nos. 4,745,169; 5,338,818; 5,619,396; 5,731,126; 6,296,985; and 6,340,734. See also WO 02/091083; U.S. Pat. Publication 2002/0090572; and U.S. Pat. No. 5,378,585.
Certain inorganic Si compositions for imaging have been reported. See Fedynyshyn et al., Encapsulated Inorganic Resist Technology, Proceedings of SPIE, vol 3999, p. 627 (2000); Y. Hu et al., Nanocomposite resists for electron beam lithography, Microelectronic Engineering 56, 289 (2001); L. Merhai et al., Nanocomposite resists systems for next generation lithography, Microelectronic Engineering 1 (2002). These reported systems are currently not practical for high performance applications.
A problem associated with the thin-layer bi-layer resist systems is to provide acceptable transparency to exposure radiation as well as good resistance to plasma etchants. This is particularly an issue for bi-layer resists that are imaged at sub-200 nm wavelengths such as 193 nm and 157 nm. See US Published Application 2003/0207205 and U.S. Pat. No. 6,593,058, where efforts at increasing etch resistance of bi-layer resists are reported..
It would be desirable to have new photoresists that could provide small images of high resolution. It would be particularly desirable to have new photoresists that could be effectively imaged with short wavelength radiation, including sub-300 nm such as 248 nm and sub-200 nm radiation such as 193 nm and 157 nm. It would be further desirable to have such photoresists that exhibited plasma etch resistance and good transparency to short exposure wavelengths such as 193 nm and 157 nm.

Polymers and photoresists comprising same


Dynamic RAM (DRAM) cells are provided. Data can be read from a DRAM cell without draining the stored charge stored in the cell. During a read cycle, current flows between a Read Bit line and a supply voltage, and charge is not drained directly from the DRAM storage node. Each DRAM cell has a small number of transistors. The DRAM cell can be used to store configuration data on a programmable integrated circuits (IC). Pass gates are used on programmable ICs to drive signals across the chip. Data stored in DRAM cells is provided directly to the pass gates at the full supply voltage to prevent signal degradation.

The present invention relates to DRAM cells, and more particularly, to techniques for storing data in and accessing data from DRAM cells.
Arrays of dynamic random access memory (DRAM) cells have been provided as an alternative to static random access memory (SRAM) storage technology. DRAMs require far less transistors than SRAM devices to store a given quantity of data bytes.
A DRAM cell can be fabricated using standard CMOS technology or other well known types of processing technology. One type of DRAM cell includes a small storage capacitor coupled to a single access transistor. This DRAM cell is a much smaller cell than a typical SRAM cell.
DRAM cells dynamically store data on storage capacitors. Because charge leaks from the capacitors, the cells must be refreshed periodically. A typical DRAM refresh cycle includes the steps of addressing the cells, sensing their contents (i.e. logic high or logic low), and writing the information back in the cells. To refresh DRAM cells, sense circuitry performs a read operation before writing data back. The sense circuitry typically includes sense amplifiers.
When data is read from a single-transistor DRAM cell, charge is drawn directly from the storage capacitor. For example, a stored high voltage will be pulled below the high supply voltage. Because a read operation disturbs the amount of charge stored on the cell capacitor, the operation of the memory array must be synchronized to avoid reading data in the cells during a refresh cycle. This requires more circuitry and tends to limit the operating speed of the circuit.
DRAM technology has been used in many integrated circuit applications. For example, a DRAM cell can be used as the programmable element in a programmable logic device (PLD) instead of an SRAM cell.
PLDs typically require that memory cells store charge at the full value of the supply voltage. The operation of a PLD is adversely effected when charge stored in memory is degraded during read cycles.
It would therefore be desirable to provide DRAM cells that output the full value of the supply voltage. It would also be desirable to provide DRAM cells that do not drain charge away from the storage node during read cycles so that the stored charge can be maintained at the supply voltage.


A magnetic resonance blood flow imaging method employs a field-echo technique and a gapless multi-slice acquisition technique in which a selective excitation pulse with a flip angle of less than 90 degrees is utilized and a pulse repetition time is set shorter than usual. Imaging data are acquired from multiple slices of a subject under examination while the multiple slices are shifted in sequence in position. A cross-sectional image is reconstructed for each of the multiple slices. Images obtained by performing subtractions on plural images for the same slice are gathered to thereby produce an image of blood vessels of the subject under examination which contain at least two blood vessels which run substantially in parallel and are opposite to each other in the direction of blood flow therein.

1. Field of the Invention
The present invention relates to a method and apparatus for imaging blood vessels employing magnetic resonance and, more specifically, to an imaging method and apparatus which permit visualization of only arteries, only veins or both the arteries and veins.
2. Description of the Related Art
A description will be made of a conventional method of imaging blood vessels, which is generally referred to as magnetic resonance (MR) angiography. As shown in FIG. 1, let us imagine a slice P which is perpendicular to the direction in which a blood vessel V runs. A radio frequency (RF) pulse-is applied to the slice P to excite it. Then, the entire slice is excited. In this case, fresh blood which has not been subjected to the RF pulse flows into the blood vessel V in the slice P. For this reason an MR signal at a high level will be generated from the blood vessel V. Since, in this case, fresh blood flows into the vessel with each repetition of the RF pulse, a phenomenon will occur in which a high-level MR signal is produced each time an RF pulse is applied. This is generally referred to as the time-of-flight phenomenon. Also, there is a phenomenon in which the phase of the MR signal varies because of the flow of blood. This is generally referred to as the phase modulation phenomenon. There is a method which employs these phenomena to obtain MR angiograms.
Besides the above methods, there is the following method. First, in this method, a single-slice pulse sequence whose pulse repetition period Tr is short is adopted. In executing this pulse sequence a plurality of slices are excited in sequence for visualization of plural regions. During this process a saturation phenomenon due to the short repetition period and the time-of-flight phenomenon act, whereby the amount of generation of MR signals from static portions becomes small and eventually high-level MR signals are obtained selectively from flowing blood, so that MR angiograms are obtained.
Every one of the above-described conventional methods permits presentation of desirable angiograms for blood flow (blood vessels) in one direction. However, in the case where an artery and a vein are mixed, blood flow in one direction and blood flow in the other direction cannot be separated from each other. For this reason the artery and the vein are presented together. Thus, they are hardly distinguishable from each other and the blood flow is also difficult to understand properly.

Method and apparatus for imaging blood vessels employing magnetic resonance


A signal processing method includes: receiving by a terminal device, first precoding indication information, where the first precoding indication information is used for indicating related information for precoding a data signal; and processing, by the terminal device, a received data signal based on the first precoding indication information. And another signal processing method, a terminal device, a network device and a storage medium are provided.

In the current new radio (NR) technology, a linear preceding technology is commonly adopted. Even though the linear precoding technology has a low complexity, it also has a limited preceding gain, especially in a scenario of multi-user multiple-input multiple-output (MU-MIMO). Therefore, a non-linear precoding technology is widely researched as an effective means for improving the preceding gain. A vector perturbation (VP) preceding technology is one of the non-linear precoding technologies, which can provide a better downlink transmission performance, and at the same time, it is suitable for downlinks of a single-user system and a multi-user system. However the current new radio (NR) system does not support a solution of precoding a data signal based on the VP.

Signal processing method, device, and storage medium

GUANGDONG OPPO MOBILE TELECOMMUNICATIONS CORP., LTD.


An optical transmission system comprises transmission optical fibers 14 connected between an optical transmission terminal 10 and an optical receiving terminal 12 via optical amplifying repeaters 16, and equalizing fiber 18 each connected in each equalizing interval. The equalizing fiber 18 is typically located at the terminal end of each equalizing interval. Each transmission optical fiber 14 is a dispersion-shifted fiber whose wavelength dispersion is substantially zero in a specific band, for example, 1.5 .mu.m. The optical amplifying repeaters 16 include an optical amplifier, and a dispersion compensating optical element having wavelength dispersion characteristics that exhibit an inclination opposite from that of wavelength characteristics of wavelength dispersion of the transmission optical fiber 14 (more specifically, a minus inclination with respect to the wavelength). The dispersion compensating optical element compensates offset values of cumulative wavelength dispersion among different wavelengths. The dispersion compensating optical element can be made by a fiber grating technology.

1. Field of the Invention
This invention relates to an optical transmission system and an optical repeater and more particularly to a long-distance and/or wide-band optical transmission system using optical fibers and an optical repeater used in the optical transmission system.
2. Related Art
Long-distance optical transmission systems such as submarine cables, in general, use a nonreturn-to-zero (NRZ) system that transmits rectangular optical pulses or an optical soliton transmission system that transmits solitary pulses. The optical soliton transmission system transmits ultra-short optical pulses over a long distance while holding their pulse forms unchanged, by balancing the non-linearity characteristics and the wavelength dispersion (or chromatic dispersion) characteristics of optical fibers. There is a report on a successful transmission over the ultra-long distance as long as 14,000 km by ultra-high speed transmission as high as 20 gigabits/second.
In any of the transmission systems, optical fibers for transmission are designed so that their wavelength dispersion characteristics be a limited value for the signal wavelength .lambda.s, in order to prevent deterioration in transmission characteristics caused by the non-linearity of the optical fibers. However, since the wavelength dispersion has a certain value other than zero, the wave dispersion value accumulates and increases gradually according to the transmission distance, and the transmission waveform has been largely deteriorated.
Under the circumstances, there is a proposal that limits the cumulative value of wavelength dispersion within a predetermined value. This proposal uses dispersion compensating fibers (equalizing fibers) inserted among transmission optical fibers and having the opposite wavelength dispersion characteristics, such that wavelength dispersion as a whole becomes zero or quite small. FIG. 10 schematically shows a system of this type. Connected between an optical transmitter terminal 110 and an optical receiver terminal 112 are transmission optical fibers 114 (optical fibers called dispersion-shifted fibers whose wavelength dispersion becomes substantially zero in the band of 1.5 .mu.m) via optical amplifying repeaters 116. An equalizing fiber 118 is connected in each equalizing interval. For example, a single transmission optical fiber is about 40 km long, and each equalizing interval is about 500 km in NRZ transmission system and 200 km in optical soliton transmission system, although the values depend on various system designs.
FIGS. 11 and 12 show a graph of cumulative wavelength dispersion values varying with transmission distance. FIG. 11 shows the case of NRZ system, and FIG. 12 shows the case of optical soliton system, taking cumulative wavelength dispersion on vertical axes and transmission distance on horizontal axes. Typically, optical fibers used in NRZ system are designed such that their wavelength dispersion be accumulated on the minus side while those in optical soliton system are designed such that their wavelength dispersion be accumulated in the plus side.
FIG. 13 schematically shows a construction of the optical amplifier repeater 116 for the band of the wavelength 1,500 nm. An output laser beam from a pumping LD (laser diode) module 124 is introduced to an erbium-doped fiber 120 via a WDM (wavelength division multiplex) coupler 122 to excite the erbium-doped fiber 120. Located downstream of the WDM coupler 122 is an optical isolator 126 for blocking off any reflective light. Some optical soliton transmission systems further include an optical filter positioned downstream of the optical isolator 126. The optical filter is a band pass filter that permits optical signals in the band of the signal wavelength alone to pass through.
A wavelength division multiplexing system is considered useful as means for further increasing the transmission capacity. If the wavelength division multiplexing system is applied to the optical transmission line relying on wavelength dispersion compensation as shown in FIG. 10, then the following disadvantages occur. That is, since both the transmission optical fiber 114 and the equalizing fiber 118 have wavelength dispersion characteristics that exhibit a positive inclination relative to the wavelength, even if wavelength dispersion of a certain wavelength can be compensated to zero by the equalizing fiber 118, wavelength dispersion of other wavelengths cannot be reduced to zero.
FIG. 14 schematically shows wavelength characteristics of wavelength dispersion of the transmission optical fiber 114 and the equalizing fiber 118, taking wavelength dispersion on the vertical axis and wavelengths on the horizontal axis. For NRZ transmission system, the transmission optical fiber 114 is designed such that its cumulative wavelength dispersion in each equalizing interval approximately exhibits the characteristics A while the equalizing fiber 118 is designed to have the characteristics B. For optical soliton transmission system, in contrast, the transmission optical fiber 114 is designed such that its cumulative wavelength dispersion in each equalizing interval exhibits the characteristics B while the equalizing fiber 118 is designed to have the characteristics A. In the design, of course, wavelength dispersion in each unit distance is determined such that the cumulative value in each transmission distance be reduced to zero or quite a small value by addition.
It is known from FIG. 14 that, even if the wavelength dispersion of the transmission optical fiber 114 can be reduced to zero by the equalizing fiber 118 in regard of a certain wavelength .lambda.m, wavelength dispersion in regard of adjacent other wavelengths .lambda.a and .lambda.b cannot be reduced to zero. This difference is accumulated according to the transmission distance, and amounts to a non-negligible value. FIGS. 15 and 16 shows cumulative wavelength dispersion in relation to the transmission distance when three wavelengths, 1,555 nm, 1,558 nm and 1,561 nm are wavelength-division-multiplexed. FIG. 15 shows the case of NRZ system and FIG. 16 shows the case of optical soliton transmission system. Both graphs take cumulative wavelength dispersion on vertical axes and transmission distance on horizontal axes.
Preferable wavelength dispersion in every 1 km in NRZ transmission system is considered -2.0 ps/nm approximately. In a certain design employing the wavelength division multiplexing system, wavelength dispersion per 1 km is -2.0 ps/nm for the wavelength of 1,558 nm, -2.3 ps/nm for the wavelength of 1,555 nm, -1.7 ps/nm for the wavelength of 1,561 nm, and inclination of the wavelength dispersion in 1 km relative to the wavelength is 0.1 ps/nm/nm. That is, the difference of 3 nm in signal wavelength results in the difference of 0.3 ps/nm in wavelength dispersion in every 1 km. If the full length of the transmission optical fiber 114 in each equalizing interval is 500 km, and if the equalizing fiber 118 reduces cumulative wavelength dispersion for the wavelength .lambda.s=1,558 nm into zero, cumulative wavelength dispersion of a shorter wavelength deviates in the minus direction, and that of a longer wavelength deviates in the plus direction as shown in FIG. 15. That is, in regard of wavelengths other than the center wavelength .lambda.s=1,558 nm, even the equalizing fiber 118 cannot fully compensate the cumulative wavelength dispersion, and the offset value of cumulative wavelength dispersion increases with the transmission distance.
Preferable wavelength dispersion in every 1 km for optical soliton transmission system is considered 0.4 ps/nm approximately. In a certain design employing the wavelength division multiplexing system, wavelength dispersion in 1 km is 0.4 ps/nm for the wavelength of 1,558 nm, 0.19 ps/nm for the wavelength of 1,555 nm, 0.61 ps/nm for the wavelength of 1,561 nm, and inclination of the wavelength dispersion in every 1 km relative to the wavelength is 0.07 ps/nm/mn. Then, the difference of 3 nm in signal wavelength results in the difference of 0.21 ps/nm in wavelength dispersion in 1 km. If the full length of the transmission optical fiber 114 in each equalizing interval is 200 km, and if the equalizing fiber 118 reduces cumulative wavelength dispersion for the wavelength .lambda.s=1,558 nm into zero, cumulative wavelength dispersion of a shorter wave length deviates in the minus direction, and that of a longer wavelength deviates in the plus direction as shown in FIG. 16. Even in the optical soliton transmission system, in regard of wavelengths other than the center wavelength .lambda.s=1,558 nm, the equalizing fiber 118 cannot fully compensate the cumulative wavelength dispersion, and the offset value of cumulative wavelength dispersion increases with the transmission distance.

Optical transmission system and optical repeater


A position determination method for a set of new points to be surveyed, using a geodetic device and reference points whose positions in an absolute coordinate system are known. The position determination is effected by referencing the new points relative to a set of reference points and measurement of the reference points and of the new points in a relative coordinate system for referencing by the geodetic device—relative measured quantities being registered. Furthermore, the new points and the reference points are updated by successive addition in each case of the measured new points and reference points to the set of new points and set of reference points, respectively, and updating the position determination of the new points taking into account all of the respective actual reference points is effected if a specified minimum coefficient of determination for the referencing is ensured by the actual set of reference points.

The invention relates to a position determination method for points to be surveyed, comprising a geodetic device.
A multiplicity of measuring methods have been known since antiquity for recording properties of defined points in a measuring environment, in particular of data with spatial reference. The location of a measuring device in addition to any reference points present and direction, distance and angle to measuring points are recorded as standard spatial data. While in many applications the position of the geodetic measuring device is known and unknown positions are measured, there are, however, also applications in which some measuring points are known or are surveyed and hence serve as reference points but the location of the surveying device is unknown.
A generally known example of such surveying devices or geodetic devices is the theodolite or a total station. An overview of geodetic measuring apparatuses of the prior art appears in "Elektronische Entfernungs- und Richtungsmessung [Electronic distance and direction measurement]" by R. Joeckel and M. Stober, 4th edition, Verlag Konrad Wittwer, Stuttgart 1999. Such devices have angle and distance measuring functions which permit a direction and distance determination to a selected target. The angle or distance magnitudes are determined in the internal reference system of the device and, if appropriate, have to be linked to an external reference system for an absolute position determination.
In principle, the position of the geodetic device itself, i.e. the station coordinates of the measuring device, or the position of new points to be surveyed as so-called free stationing, can be derived from measurements to known, fixed measuring points as reference points. This process is also designated as referencing of the measuring device position or of the new points relative to the measured reference points of known position.
For this purpose, the position of the known reference points relative to the stand point in a local coordinate system is first calculated. With the aid of the known coordinates of these reference points, if more than the necessary number of measurements are present, matched transformation parameters are calculated, from which the sought station coordinates or the sought coordinates of the new points can then be derived. The process can be illustrated by an example: distances and directions are measured to some surrounding points and the position of these points relative to the location, i.e. in a local coordinate system, is plotted on a transparent sheet. A map of the desired coordinate system is now placed underneath this sheet. This system may be the national coordinate system or the coordinate system of a specific construction product. Measured reference points are now also to be found on this map. The sheet is rotated and shifted until the sheet points agree as well as possible with the points drawn on the map, which can be effected algorithmically by fit calculation according to the least squares method. Thereafter, the position of the geodetic measuring device and the positions of the new points measured in relative terms can be read on the map. This principle is applied not graphically but analytically, it always being necessary for the point number of a measuring point and the measured values from the geodetic device to this measuring point to be known and assigned.
The software for the calculations required for this purpose is integrated into most modern total stations or tacheometers. However, this still means that measurement of all reference points and derivation of a transformation relationship between device-related and absolute coordinate system must first be effected and only thereafter is it possible to start the measurement of new points actually to be surveyed. The minimum number of initially measured reference points which is required for such referencing is dependent on the surveying situation and on the relative measured quantities registered during the measurement, for example distance and direction from the geodetic device to the reference points. In practice, however, measurements over and above this to further known reference points are carried out where possible in order to obtain data on the reliability of the results, i.e. coefficient of determination, by agreement.
Algorithms by means of which overdetermined referencing of new points—for example referencing relative to more than two measured fixed points—is effected may be, for example, similarity transformations in combination with an averaging fit which is also referred to in the technical literature as Helmert transformation.
The erection of a total station and the determination of the actual station coordinates from known measuring points are generally tailored to the trained surveying engineer with regard to user guidance. The user must reliably identify in the field the reference points used for calculating the station coordinates and must assign to said reference points the correct point numbers which produce the linkage to the position of the reference point. After all known reference points were surveyed, the fitted relationship can then be derived and hence the absolute device position determined—i.e. the geodetic device referenced with respect to the reference points. Only thereafter is it possible to start measurement and surveying of the new points actually to be surveyed, the absolute positions of new points being determined in each case on the basis of the determined absolute device position from relative quantities of new points measured thereby.
Position determination methods of the prior art are therefore based on the surveying of known reference points whose measured values are recorded or further processed before the beginning of measurements to new points actually to be surveyed, in order to reference the subsequently measured new points relative to the reference points by derivation of a transformation relationship between device-related and absolute coordinate system. This necessary sequence with the prior stationing of the geodetic device by measurement of the known reference points, the derivation of the transformation relationship being carried out therefrom once, and the subsequent surveying of the new points proves to be complicated, slows down the method and increases the susceptibility to errors since there is a danger that reference points and new points will be confused or measured in duplicate. If, for example, a reference point and a new point have spatial directions similar from the location of the geodetic device, in position determination methods of the prior art a measurement of all reference points of the set of reference points must nevertheless first be effected, after which it is necessary to swivel back to the new point then to be surveyed.
In methods of the prior art, too, the relationship between absolute and device-related reference system is always derived once and this is then used for absolute position determination of the geodetic device and for transformation of measured values determined in all subsequent measurements of new points. If, for example in the measurement of the reference points from the set of reference points, effected for stationing of the device, a reference point is incorrectly read in or is forgotten and/or the transformation relationship is incorrectly derived, all measured values determined to the new points in the measuring process are also incorrectly transformed into the external reference system.

Method for determining positions of points to be measured


A work vehicle including an engine, configured to supply power for driving a ground engaging traction device, and a hybrid power system to drive a powertrain. An engine controller is operatively coupled to the engine and is configured to generate a hybrid torque command received by a hybrid powertrain controller operatively coupled to the engine controller. The hybrid powertrain controller is configured to generate an available hybrid torque signal and a desired hybrid torque signal both of which are configured to be received by the engine controller. The engine controller generates an engine command signal configured to command the engine to operate at a commanded engine torque, in response to the available hybrid torque signal and the desired hybrid torque signal.

Agricultural equipment, such as four wheel drive loader, a tractor or a self-propelled combine-harvester, includes a prime mover which generates power to perform work, a shaft power conversion machine, and reversible energy storage. In the case of a four wheel drive loader, for instance, the prime mover is often a diesel engine that generates power from a supply of diesel fuel. The diesel engine drives a transmission which moves a ground engaging traction device, such as wheels or treads, to propel the loader, in some situation, across unimproved ground for use in construction. Such loaders include a hydraulic machine having a hydraulic pump which can be used for instance, to raise or lower a piece of equipment such as a bucket.
In the case of a tractor, the prime mover is often a diesel engine that drives a transmission which moves wheels or treads to propel the tractor across a field. In addition to providing power to wheels through a transmission, tractors often include a power takeoff (PTO) which includes a shaft coupled to the transmission and driven by the engine. The power takeoff can be used to drive a variety of work implements or accessories including pumps, plows, and harvesters.
Other work vehicles having prime movers include construction vehicles, forestry vehicles, lawn maintenance vehicles, as well as on-road vehicles such as those used to plow snow, spread salt, or vehicles with towing capability. While each of the work vehicles, including the work equipment described above, often include combustion engines as the prime mover, some vehicles have what is known as a hybrid power system. A hybrid power system integrates one or more reversible energy storage device(s) and one or more machines to convert power between the energy storage device(s) and one or more rotating shafts.
Generally, the hybrid power system delivers power and absorbs power using a reversible shaft power conversion machine. Examples of reversible shaft power conversion machines are electric motor/generator and hydraulic motors/pumps. The reversible shaft power conversion machine is configured to receive power from the hybrid energy storage device(s) and provide shaft power to assist a powertrain, and to receive power from the powertrain, such as from regenerative braking, for delivery into the hybrid energy storage device(s) When using a hybrid power system, it is still necessary to provide speed control or overall torque control, while simultaneously keeping the energy storage device within a desired stored energy level. While separate control governors can be used, one for the diesel engine which limits engine speed, and one for the reversible shaft power conversion machine, limiting motor speed, separate control governors can lead to difficulty with smooth torque control when one of the engine and hybrid power system reaches a maximum limit. In addition, optimization of the overall system is difficult. What is needed, therefore, is a control system having combined control for both the engine and the reversible shaft power conversion machine.

Combined engine and hybrid power system load control


The method for using a catheter system suitable for electrophysiology mapping and radiofrequency ablation of cardiac tissue comprises a catheter shaft having a distal end, a proximal handle, and at least one lumen extending therebetween, wherein a distal section of the shaft is either a fixed curve type or a deflectable type; and a safety means provided to maintain the integrity of the catheter, by anchoring the tip electrode in place. In one embodiment, the safety means is a tip electrode with safety anchoring pins. In another embodiment, the safety means is a long tip electrode with an extended flexible stem having at least one open slot or groove or groove on the stem.

Symptoms of abnormal heart rhythms are generally referred to as cardiac arrhythmias, with an abnormally rapid rhythm being referred to as a tachycardia. The present invention is concerned with the treatment of tachycardias, which are frequently caused by the presence of an "arrhythmogenic region" or "accessory atrioventricular pathway" close to the inner surface of the chambers of a heart. The heart includes a number of normal pathways responsible for the propagation of electrical signals from the upper to the lower chambers of the heart, which are necessary for performing normal function. The presence of arrhythmogenic region or accessory pathways can bypass or short circuit the normal pathways, potentially resulting in very rapid heart contractions, referred to here as tachycardias.
Cardiac mapping is used to locate aberrant electrical pathways and currents emanating within the heart. The aberrant pathways cause heart muscle contractions to take on abnormal and life threatening dysrhythmias. Intracardiac mapping requires careful positioning of a plurality of catheters of multiple electrodes within the heart. For example, Webster, Jr. in U.S. Pat. No. 4,960,134 shows the general use of a catheter. It is important for a catheter to move into and out of the heart chamber freely without any obstruction, or potential complications of components disengaging from the catheter shaft.
Treatment of tachycardias may be accomplished by a variety of approaches, including drugs, surgery, implantable pacemakers/defibrillators, and catheter ablation. While drugs may be the treatment of choice for many patients, they only mask the symptoms and do not cure the underlying cause. Implantable devices only correct the arrhythmia after it occurs. Surgical and catheter-based treatments, in contrast, will actually cure the problem, usually by ablating the abnormal arrhythmogenic tissue or accessory pathway responsible for the tachycardia. It is important for a clinician to be able to accurately steer the catheter to the region for ablation. Once at the region, it is important for a catheter to intimately contact the tissue site to effectively control the emission of energy to ablate the tissue within the heart.
Regardless of the type of mapping means or ablation means used, the clinician is called upon to remotely move, rotate, push, pull, and manipulate the catheters in various ways. First, a catheter is inserted into a major vein or artery, usually in the neck or groin area. It is then guided into the chambers of the heart by appropriate manipulation through the vein or artery. The distal section of a catheter must be maneuverable by a user from the proximal end of the catheter, so that the electrodes at the distal section can be positioned against the tissue at the desired location to assure that all aberrant electrical pathways are mapped and later ablated.
Development of prior catheters has focused upon the requirements of electrical continuity and interference problems. However, the mechanical and safety considerations have been overlooked. A conducting wire is soldered to the tip electrode or the band electrode. The electrode with a conducting wire is thereafter placed and secured onto the catheter shaft, mostly by adhesives. The adhering force between a tip electrode and the catheter shaft is proportional to the contact surface area. It has been reported that the tip electrode can, on occasion, disengage from the distal section of the catheter shaft. The frequency of tip electrode disengagement becomes more frequent when a longer tip electrode is used for atrial flutter applications. In an atrial flutter procedure, a tip electrode of an 8 mm length or longer is generally required. In this case, the contact area for adhesion, between the stem of the electrode and the inner surface of the catheter shaft, is not proportionally increased. The electrode is generally prone to separate from its main catheter shaft body because of inadequate contact area, and subsequently adhesive strength. If separation of the tip electrode from the catheter shaft occurred, the tip electrode could inadvertently be left behind in a patient's heart or circulation system. The prior development has overlooked the importance in providing a safe, intact catheter system having safety means, in addition to the adhesive force. It is the objective of this invention to provide the needed safety means for the electrophysiology cardiovascular catheter system having a tip electrode.

Catheter system having safety means and methods thereof


A high-Cr and high-Ni alloy of the invention comprises the following chemical composition and has excellent corrosion resistance to hydrogen sulfide in an environment where a partial pressure of hydrogen sulfide is about 1 atm., or below and the temperature is about 150.degree. C. The alloy is free of any expensive Mo and W and is thus inexpensive, with the attendant feature that mass production is possible: Si: 0.05-1.0%, Mn: 0.1-1.5%, Cr: 20-30%, Ni: 20-40%, sol. Al: 0.01-0.3%, Cu: 0.5-5.0%, REM: 0-0.10%, Y: 0-0.20%, Mg: 0-0.10%, Ca: 0-0.10%, and balance: Fe and incidental impurities, provided that C, P and S in the incidental impurity are, respectively, 0.05% or below, 0.03% or below and 0.01% or below. As set out above, each of REM, Y, Mg and Ca do not have to be added at all. If these elements are used, one or more of REM, Y, Mg and Ca are added. Preferable ranges of the contents of these elements when added are such that REM: 0.001-0.10%, Y: 0.001-0.20%, Mg: 0.001-0.10%, and Ca: 0.001-0.10%.

Hydrogen sulfide contained in liquids, such as petroleum, is highly corrosive against alloys. Accordingly, the alloys used in liquids containing hydrogen sulfide should have a good corrosion resistance to hydrogen sulfide. The examples of alloys which are employed in environments where they are in contact with hydrogen sulfide-containing liquids include drill pipes, pipes for flow lines from oil wells, oil country tubular goods for oil and natural gas wells, plate members for natural steam power stations, plate members for installation for desulfurization from exhaust gases, and the like. Especially, drilling of oil wells, exploitation and production of natural gas involve corrosive environments which are severe. For an index indicating the corrosive environment of hydrogen sulfide, the usual practice is to use a partial pressure of hydrogen sulfide in a gas phase. This is because the concentration of hydrogen sulfide in an aqueous solution is substantially proportional to the partial pressure of hydrogen sulfide in a gas phase, thus enabling one to simply express the degree of influence on alloys. With production pipes for oil wells, it has been frequently experienced that alloys are exposed to severe environmental conditions such as a partial pressure of hydrogen sulfide of about 10 atm., and a temperature of about 200.degree. C.
The corrosion of an alloy ascribed to the hydrogen sulfide in such an environment as mentioned above results mainly in the cracking of the alloy under stress (stress corrosion cracking). Accordingly, alloys which are to be employed in an environment containing hydrogen sulfide should have a good resistance to stress corrosion cracking.
Known alloys which are used in an environment such as of a hydrogen sulfide-containing oil well wherein a partial pressure of hydrogen sulfide is as high as approximately 10 atm., include Ni--Cr--Mo--Fe Ni-based alloys which contain Ni in amounts as great as 30-50% (Japanese Laid-open Patent Application Nos. 57-131340, 57-134544 and 57-134545).
For instance, Japanese Laid-open Patent Application No. 57-131340 proposes an alloy which comprises, aside from Ni, Cr, Mo and W, Cu and Co, if necessary, in order to improve the resistance to stress corrosion cracking.
These alloys for oil wells are so designed as to improve the corrosion resistance to hydrogen sulfide including a resistance to stress corrosion cracking. More particularly, the corrosion resistance to hydrogen sulfide is greatly influenced by the content of hydrogen sulfide present in raw oil and the temperature of the raw oil. Accordingly, when used in such an environment of hydrogen sulfide as having set out above, the alloy is so designed that a corrosion-resistant film is formed on the surfaces of the alloy. The corrosion-resistant film should have a two-layer structure including an outer layer consisting of a Ni sulfide film and an inner layer consisting of a Cr oxide film. In order to facilitate the growth of the inner layer of the Cr oxide film, at least one of Mo and W is incorporated in the alloy. The reason why the corrosion-resistant film is designed to have a double-layer structure is so that hydrogen sulfide is prevented from entering into the inner layer by means of the outer layer of the Ni sulfide film thereby preventing the breakage of the Cr oxide inner film with the hydrogen sulfide. The Cr oxide inner film is able to suppress the dissolution of the alloy and thus, acts to improve the corrosion resistance, ensuring a good corrosion resistance to hydrogen sulfide.
However, it has been confirmed that in an environment where the partial pressure of hydrogen sulfide is relatively low at a level of about 1 atm., or below and the temperature is about 150.degree. C., conventional alloys of the type set out above are not satisfactorily resistant to corrosion. The reason for this has now been found as follows: the Ni sulfide film serving as the outer layer which has the corrosion resistance to hydrogen sulfide is unlikely to grow under conditions where a partial pressure of hydrogen sulfide gas is low.
Moreover, since the known alloys contain both or either of Mo and W which are expensive, the resultant alloys become undesirably high in cost.
Accordingly, there is a strong demand for the development of high-Cr and high-Ni alloys which are excellent in corrosion resistance to hydrogen sulfide including a resistance to stress corrosion cracking when placed in an environment where the partial pressure of hydrogen sulfide is as low as about 1 atm., or below and the temperature is about 150.degree. C., and which are available inexpensively.
The invention has for its object the provision of a high-Cr and high-Ni alloy which overcomes the problems involved in the prior art, which is imparted with good corrosion resistance to hydrogen sulfide under environmental conditions of a partial pressure of hydrogen sulfide of 1 atm., or below and a temperature of about 150.degree. C., and which is low in cost.

Hydrogen sulfide corrosion resistant high-Cr and high-Ni alloys


A portable information device capable of supporting a display is described. The portable information device includes a first chassis member and a second chassis member connected mutually rotatable, a first support plate that supports a display on the side of the first chassis member, a second support plate that supports the display on the side of the second chassis member, a first locking member including a first fixing portion to be fixed to the rear face of the first support plate with adhesive, and a first locking piece projecting from one end face of the first support plate, the first locking piece being configured to come in contact with and separate from the rear face of the second support plate. The first support plate includes a first contact face with which the first locking member comes in contact and a first adhesive face that fixes the first locking member with the adhesive. The first adhesive face is recessed from the first contact face by a thickness of the adhesive.

Portable information devices, such as tablet PCs and smart phones, which include a touch-panel liquid crystal display and do not have a physical keyboard have rapidly gain popularity. The display of this type of portable information device is intended to be large when being in use, but compact when being carried. To this end, a portable information device including a flexible display, such as an organic Electro Luminescence (EL), has been proposed, which includes not only the chassis but also the display that can be folded.
In addition, a portable information device may include two support plates that support the display on the inner face side of the two chassis members. These support plates have comb-teeth like locking pieces for locking between the support plates in order to suppress a level difference between the plates. Each of the locking pieces may be fixed to the corresponding support plate with an adhesive. In that case, the locking piece is displaced in the height direction from the surface of the support plate by the thickness of the adhesive, and as a result, a small gap is generated between the engaged support plates and a level difference may occur between the adjacent ends of the two support plates. This may cause waviness or bending of the display that is supported by these support plates.
Consequently, it would be desirable to provide a portable information device capable of supporting the display in a stable manner.


Disclosed are methods for preparing 2-alkynyladenosine derivatives of formula A:

Adenosine is known to modulate a number of physiological functions. At the cardiovascular system level, adenosine is strong vasodilator and cardiac depressor. In the central nervous system, adenosine induces sedative, anxiolytic and antiepileptic effects. At the kidney level, it exerts a diphasic action, inducing vasoconstriction at low concentrations and vasodilation at high doses. Adenosine acts as a lipolysis inhibitor on fat cells and as an anti-aggregant on platelets (Stone T. W., Purine Receptors and their Pharmacological Roles, Advances in Drug Research, Academic Press Limited, 1989, 18, 291-429; Progress Cardiovasc. Dis. 1989, 32, 73-97).
A number of studies have shown that adenosine actions are mediated by two subtypes of receptors that are located on the cell membrane: one of high-affinity, inhibiting the activity of the enzyme adenylate cyclase (A1 receptor), and another of low-affinity, stimulating the activity of the same enzyme (A2 receptor). (J. Med. Chem. 1982, 25, 197-207; Physiol. Rev. 1990, 70(3), 761-845; J. Med. Chem. 1992, 35, 407-422). Both receptors are widely spread in the different systems of the organism. In some tissues, however, only one of said receptors is mainly present. For example, the A1 receptor is more prevalent than the A2 receptor at the cardiac level, whereas the A2 receptor is more prevalent than the A1 receptor at the vascular level and on platelets.
Compounds capable of interacting selectively with either the A1 or A2 receptor could have an interesting pharmacological pattern. Furthermore, the vasodilating activity, together with the anti-aggregating action, of the compounds that interact with the A2 receptors may lead to useful therapeutic applications in the treatment of severe cardiovascular pathologies, such as ischemic cardiopathy, hypertension and atherosclerosis. Moreover, due to the actions on central nervous system, the use of A2 selective medicaments can be envisaged in the treatment of cerebrovascular ischemia, epilepsy and various emotional disorders, such as anxiety and psychosis.
Previously, adenosine-5′-N-ethyluronamide or NECA (Mol. Pharmacol., 1986, 25, 331-336) was the only known compound, other than adenosine, having agonist activity at the A2 receptor. Unfortunately, NECA is also active on the A1 receptor and thus lacks specificity for the A2 receptors alone. Because it was the only available compound having A2 affinity, NECA was used for pharmacological tests for the receptor binding.
More recently, however, certain NECA derivatives having A2 receptor selectivity have been developed. These compounds are NECA derivatives that are substituted at the C2-position with phenylamino groups. For example, the compound 2-(p-(carboxyethyl)phenylethylamino)-5′-N-ethyluronamide, named CGS 21680 (J. Pharmacol Exp. Ther., 1989, 251, 888-893), has become the reference compound for the pharmacological studies on A2 receptor.
Other purine derivatives having selective A2 agonist activity are disclosed, for example, in GB-A-2203149; EP-A-0309112; EP-A-0267878; EP-A-0277917; and EP-A-0323807. Substitution at the 2-position of the purine group has been considered promising to give the desired selectivity (J. Med. Chem. 1992, 35, 407-422). 2-Alkynylpurine derivatives have been disclosed in EP-A-0219876 and U.S. Pat. No. 4,956,345.
U.S. Pat. No. 5,593,975 discloses 2-alkynyl adenosine derivatives substituted at the ethyne position with aryl, heterocyclic or hydroxyalkyl groups and in which the riboside residue is substituted by the N-alkyl- (or cycloalkyl)-uronamido. It is reported that these compounds exhibit strong A2 agonist selectivity and, therefore, are useful for the treatment of cardiovascular pathologies, such as cardiac ischemia, hypertension and atherosclerosis and of diseases of the central nervous system, such as cerebrovascular ischemia, epilepsy and emotional disorders (anxiety and psychosis).
The 2-alkynyl adenosine derivatives of U.S. Pat. No. 5,593,975 have the following general formula:

wherein R is hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, phenyl C1-C3 alkyl;
wherein R1 has one of the following meanings:    (a) phenyl or naphthyl optionally substituted with one to three halogen atoms (chlorine, fluorine or bromine), C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C2-C6 alkoxycarbonyl, C2-C6 alkoxyalkyl, C1-C6 alkylthio, thio, CHO, cyanomethyl, nitro, cyano, hydroxy, carboxy, C2-C6 acyl, amino, C1-C3 monoalkylamino, C2-C6 dialkylamino, methylenedioxy; or aminocarbonyl;    (b) a group of the formula —(CH2)m-Het wherein m is 0 or an integer from 1 to 3 and Het is 5 or 6 membered heterocyclic aromatic or non aromatic ring, optionally benzocondensed, containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulphur, linked through a carbon atom or through a nitrogen atom;    (c) C3-C7 cycloalkyl optionally containing unsaturations or C2-C4 alkenyl;    (d) moieties of the following formula:
                where R2 is hydrogen, methyl or phenyl;                    R4 is OH, NH2, dialkylamino, halogen, or cyano;            R5 is hydrogen, C1-C6 linear or branched alkyl, C5-C6 cycloalkyl or C3-C7 cycloalkenyl, phenyl-C1-C2-alkyl            or R2 and R5, taken together, form a 5 or 6-membered carbocyclic ring or R3 is hydrogen and R2 and R4, taken together, form an oxo group or a corresponding acetalic derivative;            when R is different from hydrogen and/or R3 is different from ethyl, R1 can also be C1-C6 linear or branched alkyl; and            n is 0 or 1 to 4; and                        wherein R3 is C1-C6 alkyl, C3-C7-cycloalkyl, phenyl or benzyl; provided that when R is different that hydrogen or when R is hydrogen and R3 is cyclopentyl, phenyl or benzyl, R1 can also be C1-C6 linear or branched alkyl.
The 2-alkynyl adenosine compounds of U.S. Pat. No. 5,593,975 are prepared by the general synthetic schemes shown below.

In schemes I and II, R′ and R′1 have the same meanings as R and R1, respectively, or they are groups which can be converted into R and R1, respectively, for example, by removing any protecting groups which can be present in R′ and R′1 compatible with the reaction conditions; Y is Br or I and X is chlorine, bromine or iodine.
The reactions shown in schemes I and II are carried out in the presence of catalysts (for example: bis(triphenylphosphine) palladium dichloride and a cuprous halide) and a suitable acid-binding agent, such as an organic base (for example: triethylamine, diisopropylethylamine or pyridine).
As the solvent, a substituted amide (such as dimethylformamide), an ether (such as dioxane or tetrahydrofuran), acetonitrile or optionally a mixture of two or more of said solvents, are preferably used.
The compounds of formula II, in which Y is iodine and R′ is hydrogen, can be prepared from 2-iodoadenosine (Nair et al., Synthesis, 1982, 670-672) according to the following Scheme III:

Compounds of formula VIII in which Y is iodine and R′ is different from hydrogen can be prepared according to the following Scheme IV:

In the above Scheme IV, R, R1 and R3 are as above defined.
The compounds of formula V are prepared by reaction of compounds of formula II with an acetylene derivative, for example, 1-trimethylsilylacetylene, under the conditions reported for the reaction between compounds II and III. Compounds III and IV are known or they can be prepared according to well-known methods.
U.S. Pat. No. 6,322,771 discloses compounds of formula IX:

wherein                (a) each R is individually hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, phenyl or phenyl(C1-C3)-alkyl;        (b) X is —CH2OH, —CO2R2, —OC(O)R2, —CH2OC(O)R2 or —C(O)NR3R4;        (c) each of R2, R3 and R4 is individually H, C1-C6-alkyl; C1-C6-alkyl substituted with 1-3 C1-C6 alkoxy, C3-7cycloalkyl, C1-C6-alkylthio, halogen, hydroxy, amino, mono(C1-C6-alkyl)amino, di(C1-C6-alkyl)amino, or C6-C10-aryl, wherein aryl may be substituted with 1-3 halogen, C1-C6-alkyl, hydroxy, amino, mono(C1-C6-alkyl)amino, or di(C1-C6-alkyl)amino; C6-C10-aryl; or C6-C10-aryl substituted with 1-3 halogen, hydroxy, amino, mono(C1-C6-alkyl)amino, di(C1-C6-alkyl)amino, or C1-C6-alkyl; and        (d) R1 is (X—(Z)—)n[(C3-C10)cycloalkyl]-(Z′)— wherein Z and Z′ are individually (C1-C10)alkyl, optionally interrupted by 1-3 S or nonperoxide O, or is absent, and n is 1-3.It is disclosed that the compounds of Formula IX may be prepared by the synthetic methods disclosed in U.S. Pat. Nos. 5,278,150; 5,140,015; 5,877,180; 5,593,975; and 4,956,345.
U.S. Pat. No. 6,322,771 discloses preferred compounds of Formula IX, wherein each R is H, X is ethylaminocarbonyl and R1 is 4-carboxycyclohexylmethyl (DWH-146a), R1 is 4-methoxycarbonylcyclohexylmethyl (DWH-146e) or R1 is 4-acetoxymethyl-cyclohexylmethyl (JMR-193):

According to U.S. Pat. No. 6,322,771, the synthesis of the methyl 4[3-(6-amino-9(5-[(ethylamino)carbonyl]-3,4-dihydroxytetrahydro-Z-furanyl-9H-2-purinyl)-2-propynyl]-1-cyclohexanecarboxylate (DWH-146e) was accomplished by the cross coupling of an iodo-adenosine derivative (N-ethyl-1′-deoxy-1′-(amino-2-iodo-9H-purin-9-yl)-β-D-ribofuranuoramide) with methyl 4-(2-propynyl)-1-cyclohexanecarboxylate by utilization of a Pd(II) catalyst.
The iodo-adenosine derivative was first prepared from guanosine by treating it with acetic anhydride, which acetylates the sugar hydroxyls. The resulting compound was then chlorinated at position 6 with tetramethyl ammonium chloride and phosphorous oxychloride. Iodination of position 2 was accomplished via a modified Sandmeyer reaction, followed by displacement of the 6-Cl and sugar acetates with ammonia. The 2′ and 3′ hydroxyls were protected as the acetonide and the 5′ hydroxyl was oxidized to the acid with potassium permanganate. Deprotection of the 2′ and 3′ acetonide, Fisher esterification of the 5′ acid with ethanol and conversion of the resulting ethyl ester to the ethyl amide with ethylamine gave N-ethyl-1′-deoxy-1′-(amino-2-iodo-9H-purin-9-yl)-β-D-ribofuranuoramide.
The acetylene [methyl 4-(2-propynyl)-1-cyclohexanecarboxylate] was synthesized starting from trans-1,4-cyclohexanedimethanol. Initially, the trans-diol was monotosylated followed by displacement of the tosylate with an acetylene anion. The hydroxyl of the resulting hydroxyl acetylene species was oxidized to the acid via Jones reagent followed by methylation with (trimethylsilyl)diazomethane to give methyl 4-(2-propynyl)-1-cyclohexanecarboxylate.
A cross-coupling reaction of N-ethyl-1′-deoxy-1′-(amino-2-iodo-9H-purin-9-yl)-β-D-ribofuranuoramide and methyl 4-(2-propynyl)-1-cyclohexanecarboxylate was then performed. To a solution of N,N-dimethylformamide (0.5 mL), acetonitrile (1 mL), triethylamine (0.25 mL), and N-ethyl-1′-deoxy-1′-(amino-2-iodo-9H-purin-9-yl)-β-D-ribofuranuroamide (25 mg, 0.06 mmol) was added bis(triphenylphosphine)palladium dichloride (1 mg, 2 mol %) and copper(I) iodide (0.06 mg, 0.5 mol %). To the resulting mixture was added methyl 4-(2-propynyl)-1-cyclohexanecarboxylate (54 mg, 0.3 mmol) and the reaction was stirred under nitrogen atmosphere for 16 hours. The solvent was removed under vacuum and the resulting residue was flash chromatographed in 20% methanol in chloroform (Rf=0.45) to give 19 mg (off-white solid, mp 125° C. (decomposed)) of 4[3-(6-amino-9(5-[(ethylamino)carbonyl]-3,4-dihydroxytetrahydro-Z-furanyl)-9H-2-purinyl)-2-propynyl]-1-cyclohexanecarboxylate (DWH-146e).
These above-described synthetic methods for producing 2-alkynyladenosine derivatives, including DWH-146e, provide lower yields than desired, require prolonged reaction times and require extensive chromatographic purification. For example in U.S. Pat. No. 5,593,975, the acetonide protection (first step of Scheme III above) requires purification by column chromatography. Furthermore, the oxidation procedure (second step of Scheme III above) requires prolonged reaction times and has been noted to be troublesome due to competing oxidation at the 2-iodo position. Homma et al., J. Med. Chem., 1992, 35, 2881-2890. In U.S. Pat. No. 6,322,771, the first step of the synthesis of the cyclohexane-containing acetylene requires purification by column chromatography to separate the desired mono-tosyl product from the starting diol and bis-tosyl products. In the second step of the synthesis of the cyclohexane-containing acetylene, prolonged reaction times, a large excess of the acetylene anion and purification by column chromatography are required. Furthermore, the cross-coupling reaction between the cyclohexane-containing acetylene and 2-iodoNECA proceeds with poor yield after chromatography.
Thus, there is a need for improved synthetic methods for producing 2-alkynyladenosine derivatives that provide higher yields and require less purification than prior art methods. Using alternative reagents and steps, we have discovered an improved method for producing 2-alkynyladenosine derivatives at higher yields with less chromatographic purification required.

Methods for preparing 2-alkynyladenosine derivatives

Abstract: or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate or isomorphic crystalline form thereof, the method comprising the step of:        contacting 2-iodoadenosine-5′-N-ethyluronamide with a compound of formula B:

Abstract: wherein Z is —C(═O)OR or —CH2C(═O)R, where R is a C1 to C5 alkyl, preferably

Abstract: The methods are useful for preparing 2-alkynyladenosine derivatives that are, in certain embodiments, adenosine receptor agonists.


A system and method is provided for content presentation. In one or more implementations, at least one processor is operatively coupled to processor readable storage media. Further, at least one database provided with the processor readable storage media includes multimedia content. A first segment of the multimedia content is provided for presentation. At least a second segment and a third segment of the multimedia content are associated with the first segment of the multimedia content. User input is detected while the first segment of the multimedia is being presented, and the input is determined to be associated with the second segment of the multimedia content. The first segment ends, and the second segment is provided. Moreover, additional user input is detected while the second segment of the multimedia is being presented, and which is determined to be associated with the third segment of the multimedia content. The second segment is ended and the third segment of the multimedia content is provided for presentation.

Multimedia content, such as video, audio, graphical or the like, is often provided in various computing devices. For example, multimedia content is stored on a computing device and presented in a player application that runs on the computing device. Examples of such player applications include WINDOWS MEDIA PLAYER, QUICKTIME, AMAROK, AUDACIOUS, BANSHEE, MPLAYER, RHYTHMBOX, TOTEM, VLC, AND XINE. Many multimedia player applications are configured with controls that enable the user to interact with the multimedia content. Typical controls provided with such player applications include buttons, sliders and/or switches for commands such as play, pause, stop, rewind or the like.
Although most multimedia player applications include one or more controls for interactivity, realistic multimedia content is being created that may cause users to desire greater interactivity with various forms of multimedia content, such as relating to games and adult entertainment. This desire is fueled, at least in part, by increased interactive functionality supported by many mobile computing devices, such as provided by an IPAD, IPHONE, personal digital assistant, and smart phones, such as running the ANDROID operating system.
Unfortunately, the current state of the interactive experience for many users, particularly with regard to sophisticated multimedia content (e.g., high DEF video content) is not satisfactory due to limitations on the presentation of the content, particularly in response to one or more forms of user input.

System and method for controlling the progression of multmedia assets on a computing device


Liposomes containing therapeutic genes are conjugated to multiple targeting agents to provide transport of the encapsulated gene across the blood-retinal barrier and the plasma membrane of ocular cells. Once across the blood-retinal barrier and ocular cell membrane, the encapsulated gene expresses the encoded therapeutic agent within the ocular cells to provide diagnosis and/or treatment of disease.

1. Field of the Invention
The present invention relates generally to the delivery of gene medicines to the brain and the eye. More particularly the present invention involves the combination of liposome technology, blood-brain barrier (BBB)/blood-retinal barrier (BRB) receptor technology, pegylation technology, and therapeutic gene technology to provide formulations which are useful in the non-invasive delivery of genes to the brain and the eye.
2. Description of Related Art
The publications and other reference materials referred to herein to describe the background of the invention and to provide additional detail regarding its practice are hereby incorporated by reference. For convenience, the reference materials are numerically referenced and grouped in the appended bibliography.
The expression of exogenously administering genes in brain has previously been achieved in vivo with either viral vectors or cationic liposomes (1–4). However, in either case, highly invasive routes of administration are required. Such invasive techniques are needed because of the failure of either viruses or cationic liposomes to cross the brain capillary wall, which forms the blood-brain barrier (BBB) in vivo. The existence of the BBB necessitates the administration of the exogenous gene either intracerebrally via craniotomy (1), or by the intra-carotid arterial infusion of noxious agents that cause BBB disruption and transient opening of the BBB (4).
Human gene therapy of the brain will likely require repeated administration of the gene medicine. Therefore, it would be advantageous to administer the gene by a route that is no more invasive than a simple intravenous injection. With this approach, the gene therapeutic is delivered through the BBB by targeting the gene medicine to the brain via endogenous BBB transport systems (5). Carrier-mediated transport (CMT) systems exist for the transport of nutrients across the BBB (5). Similarly, receptor-mediated transcytosis (RMT) systems operate to transport circulating peptides across the BBB, such as insulin, transferrin, or insulin-like growth factors (5). These endogenous peptides can act as "transporting peptides," or "molecular Trojan horses," to ferry drugs across the BBB. In this approach, called the chimeric peptide technology, the drug that is normally not transported across the BBB is conjugated to a "transportable peptide, and the drug/transportable peptide conjugate undergoes RMT through the BBB (U.S. Pat. No. 4,801,575).
Peptidomimetic monoclonal antibodies (MAb) that bind endogenous transport systems within the BBB, such as the transferrin receptor (TfR) or insulin receptor, have been used in previous studies for targeting neuropeptides or antisense agents through the BBB in vivo (5). The ability of certain receptor-binding MAbs to mimic the action of the endogenous peptide that binds the same receptor is well known in the literature (31–33). In addition, the ability of such peptidomimetic MAbs, such as anti-TfR MAbs, to transport drugs into cells via these receptor-mediated endocytosis is also well known (34).
The expression in the brain of a therapeutic gene requires that the gene formulation that is injected into the blood is transported not only across the BBB by RMT, but also across the brain cell membrane (BCM) by receptor-mediated endocytosis (RME) into the target cell in brain. In addition, using endogenous BBB transport systems to target gene medicines non-invasively to the brain also requires the development of a suitable formulation of the gene therapeutic that is stable in the bloodstream. Cationic liposome/DNA complexes have been used for in vivo gene expression, but these formulations aggregate extensively in saline solution (6–11). This aggregation results in selective gene expression in the lung with little expression in peripheral tissues (12–14), and no expression in brain following intravenous administration of the cationic liposome/DNA complex (12). The DNA plasmid could be conjugated to the peptidomimetic MAb via a cationic polylysine bridge (15–17). However, electrostatic interactions between DNA and polycations may not be stable in blood, and highly polycationic proteins such as histone or polylysine exert toxic effects at the BBB and cause generalized BBB permeability changes in vivo (18).
Human blindness is a surprisingly common disorder that afflicts a large number of individuals (46). Approximately 10% of the population over 60 years of age suffers from macular degeneration, and approximately 1 in 3,000 births results in a mutation in a gene that plays an important role in vision (35). These inherited forms of blindness are collectively referred to as retinitis pigmentosa (RP). There are over 100,000 individuals in the U.S. alone that suffer from RP. The various RP genetic disorders can be traced to mutations in over 100 different genes with mutations in the rhodopsin gene comprising about 10% of RP (36).
In most cases, the mutated gene that causes RP is known, and the gene has been cloned. Therefore, gene discovery is no longer the rate-limiting issue in the gene therapy of RP. Rather, the rate-limiting problem is how to target the therapeutic gene throughout the entire retina. Present day forms of gene therapy to the retina involves packaging a therapeutic gene in a viral vector, such as adenovirus, herpes simplex virus (HSV), or adeno-associated virus (AAV). Next, the virus carrying the therapeutic gene is injected directly into each eye as either an intra-vitreal injection, or more commonly as a sub-retinal injection. The area of the retina that is tranduced with the virus is only at the tip of the injection needle. Areas of retina that are only 100 μm, which is thickness of human hair, away from the injection needle are not transduced with the exogenous gene (35).
There are at least two problems with the existing forms of gene therapy of retinal diseases. First, viral vectors are used. Virtually all humans have a preexisting immunity to either adenovirus or HSV, and the injection of these viruses into the central nervous system causes severe inflammation, which essentially aborts the therapeutic effect of the gene (36–45 and 25). More recently, AAV has been used as the viral vector because humans are less likely to have a preexisting immunity to this virus. However, single injection of AAV into the eye of a primate results in the development of high-tier neutralizing anti-AAV antibodies in the bloodstream (35). The development of these anti-viral neutralizing antibodies sets the stage for inhibiting the therapeutic effect of the subsequent gene treatments, and may also cause local inflammation within the eye.
The second problem with the existing forms of retinal gene therapy relates to the fact that the virus does not cross the blood-retinal barrier (BRB). Therefore, the virus cannot access the retina following non-invasive (intravenous, subcutaneous) forms of administration. Consequently, the viral vector carrying the exogenous gene must be administered to the retina or other structures of the eye by direct injection into the eye. This only allows for viral transduction within cells at the tip of the injection needle, which in turn would create a "pin-hole" visual field for the patient. Therefore, to have a wider distribution of the exogenous gene in the retina, it would be necessary to make multiple injections in both eyes. This would be an invasive procedure that may not be widely adapted to hundreds of thousands of patients with RP, and would also create an aberrant 'multiple pin-hole' field of vision for the patient. As is apparent, there is a present need to provide a non-viral non-invasive targeting technology for delivering therapeutic genes and other pharmaceutical agents to the entire retina.

Non-invasive gene targeting to ocular cells

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