An electrical machine has a rotor shaft which carries a plurality of rotor discs for rotation therewith. Each rotor disc has two pairs of rotor rims secured thereto. Each rotor rim consists of a single row of alternate magnets and pole pieces and is opposed by a series of stator cores which straddle the rotor rim. The stator cores are `c` shaped so that they receive flux from two adjacent magnets and close around two opposite rotor poles on either side of the rotor rim. The stator cores, formed by winding electrical steel around a former, reduce the losses caused by eddy currents generated when flux impinges on the side faces of the stator core.

A synchronous machine operating in accordance with transverse flux principles consists of an armature winding in the form of a circular coil co-axial with a rotor. The armature winding links the flux generated by permanent magnets mounted on the rim of the rotor by means of a series of stator cores. An advantage of this topology is that the section of the stator cores can be increased so that more flux can be carried without encroaching on the space required by the armature winding.
In previous designs of transverse flux machines the rotor rims carry two side by side rows of permanent magnets separated by an insulating spacer. Two circular stator coils are used and stator cores are incorporated on both the inside and the outside of the rotor so that useful torque is provided at both the inner and outer surfaces of the rotor.
Problems with machines of this design are that they are difficult to assemble as the stator coils are enclosed within the stator cores. The rotor rims are long and lack stiffness and the rotor is subject to deflections as it has little stiffness against radial shock. The radial force on the stator cores as the flux alternates causes radial movement of the stator casing. This zero order stator case vibration is difficult to alleviate without adding thickness to the casing.


A photoreceptor for contact charging to be used in an electrophotographic process, which includes an electrically conductive base and a photosensitive layer formed on the base so as to be charged by contact charging, and is characterized in that even when pin holes or photosensitive layer lacking portions in the form of pin holes are present on he photosensitive layer, short-circuiting is safely and positively prevented over a long period. The electrically conductive base further includes a base main body of aluminum alloy having Brinell hardness higher than 40 H.sub.B, and an alumite treatment applied over the surface of the aluminum alloy base main body.

The present invention generally relates to a photosensitive member or photoreceptor for use in an image forming apparatus of an electrophotographic system such as a copying machine, a printer, etc., and more particularly, to a photoreceptor to be electrically charged through contact by a contact type charging device and an image forming apparatus employing such photoreceptor.
Commonly, in an electrophotographic process, for example, in a copying machine, printer or the like, it has been a normal practice to electrically charge the surface of a photoreceptor which is an electrostatic latent image holding member, by a charging device, and the charged region is subjected to exposure to image light to form an electrostatic latent image thereon, which is then developed into a visible image to be transferred onto a transfer material such as a copy paper sheet or the like.
As the charging device as referred to above, besides the non-contact type charging devices represented by corona charging devices such as corotron, scorotron chargers, etc., there have been known contact type charging devices which effect charging by causing charging members to directly contact the photoreceptor surface as in brush charging devices of stationary or rotary type, and charging devices employing charging rollers. Among these charging devices, attention has been directed to the contact type charging device, since it is very small in the deterioration on the photoreceptor surface or in the generation of ozone which affect adversely to human bodies as compared with the corona charging device.
During the manufacturing process of the electrophotographic photoreceptor, pin holes or pin hole-shaped flaws or layer lacking portions are often generated in the photosensitive layer thereof. Spray coating method, dipping coating method, and blade coating method have been commonly used to form an organic photoconductor (OPC). In these methods, photosensitive liquid is obtained by dispersing or dissolving photosensitive substance such as charge-generating substance and charge-transporting substance in a binder resin. According to spray coating method, the photosensitive liquid is sprayed onto a base member such as an aluminum drum or a resin film. According to dipping coating method, the aluminum drum or the resin film is dipped in the photosensitive liquid. According to the blade coating method, the liquid is painted on the aluminum drum or the resin film with a doctor blade. The problem of these methods is that bubbles which are formed in the liquid and may cause the generation of pin holes are liable to be formed in the photoconductor. In addition, since the organic photoconductor manufactured by these methods includes a comparatively soft binder resin as its main composition, the photoreceptor is liable to be damaged in replacing the photoreceptor or in removing jammed copy paper from a printer or a copying apparatus by a user or servicing personnel, and such damaged portion may form a pin hole or photosensitive layer lacking portion.
In charging the photoreceptor by the non-contact type charger, a short circuit rarely occurs between the base portion of the photoreceptor and the charging member even in the presence of such photosensitive layer lacking portion. But when the photoreceptor is charged by the contact type charger, the charging member to which a high voltage is applied contacts the surface of the photoreceptor, with the result that a short circuit occurs between the charging member and the base portion of the photoreceptor through the defective portion of the photosensitive layer. Such a short circuit is liable to be generated particularly by a brush charger. The occurrence of the short circuit causes the charging member or a high voltage-applying power source to be damaged and in addition, the entire surface of the photoreceptor in contact with the charging member to be uncharged because the charging member has the ground electric potential. As a result, a black stripe-like image noise is generated in reversal development, while a white stripe-like image noise is produced in normal development.
The following proposals have been made to solve the above-described problem caused by the short circuit: The proposal disclosed, for example, in Japanese Patent Laid-Open Publication Tokkaisho No. 61-148468 is such that a thin film insulating layer having a volume resistivity larger than 10.sup.12 .OMEGA. cm is formed on a conductive base portion of the photoreceptor, and thereafter, a photosensitive layer is formed on said insulating layer. Another proposal described in Japanese Patent Laid-Open Publication Tokkaihei No. 2-67575 is such that a barrier layer is provided between the base portion of the photoreceptor and the photosensitive layer.
The researches made by the present inventors have revealed that even though the insulating thin film or the barrier layer is formed between the base portion of the photoreceptor and the photosensitive layer, the charging member, for example, the charging brush in particular may be brought into contact with the insulating thin film or the barrier layer through a defective portion such as a pin hole of the photosensitive layer. Therefore, the insulating thin film or the barrier layer is destroyed because the soft base portion of the photoreceptor is incapable of supporting them, and consequently, a short circuit takes place after all.

Photoreceptor for use in contact charging method and image forming apparatus employing said photoreceptor


Resorbable polylactide polymer healing membranes and methods of their applications are disclosed. In a broad embodiment, the invention features methods for inducing proper tissue healing after an open heart surgery. In one embodiment, the methods includes a step of forming a patch with a healing membrane over the open pericardium to induce proper tissue healing and placement in other open heart surgery procedures to facilitate re-entry by the surgeon.

1. Field of the Invention
The present invention relates generally to medical devices and, more particularly, to methods of applying the medical device for inducing proper healing of tissues, for example the parietal pericardium tissue, after a cardiac surgery.
2. Description of Related Art
The formation of excessive amounts of fibrotic or scar tissue (fibrosis) is a central issue in medicine. Scar tissue can block arteries, immobilize joints, damage internal organs, and can in some instances generally impede a body's ability to maintain vital functions. Every year, about 1.3 million people are hospitalized due to the damaging effects of fibrosis, yet doctors have few optimal remedies To help them control this dangerous condition. Fibrosis can follow surgery in the form of adhesions, keloid tumors or hypertrophic (very severe) scarring. Fibrotic growth can also proliferate and invade the healthy tissue that surrounds it, even after the original injury heals. Too much scar tissue may cause physiological roadblocks that disfigure, cripple or even kill.
One of the most important pathologies in which fibrosis is problematic is cardiac surgery. The number of patients undergoing cardiac surgery has been steadily increasing, and as a consequence, the number of cardiac reoperations has also increased. It has been estimated that one out of every five patients undergoing coronary artery bypass surgery will require a reoperation. Reoperative cardiac surgical procedures can be associated with an even significantly greater complication rate than that of the initial procedure. For example, the post-operative complication rate following a reoperative coronary artery bypass procedure can be double. As a consequence, cardiac reoperations can introduce increased risks of morbidity and mortality. An important contributory factor for the increased complications with cardiac reoperations is the adhesions which form secondarily from the initial entry into the pericardium. These fibrous adhesions can begin to form immediately following the surgical procedure and can consist of collagen and other extra cellular proteins.
There is a need for improved methods of inducing proper tissue healing, e.g. healing without adhesion, for tissues affected by an open heart surgery.

Methods of promoting enhanced healing of tissues after cardiac surgery


In an image forming system which has a client unit, a management unit, and a printer unit, when the client unit issues a replacement print request to the management unit, the management unit notifies the client unit of the contents of the print queue in response to the replacement print request. The client unit displays the notified contents of the print queue, and prompts the user to designate a print job to be replaced and an inserting position of a new print job into the print queue. After that, the client unit outputs, to the management unit, replacement information which includes information indicating the designated print job to be replaced, information indicating the designated inserting position, and the new print job. The management unit updates the print queue in accordance with this replacement information.

An image forming system in which a client terminal that generates print data and a printer that prints the generated print data are connected directly or indirectly via a server or the like is known. In the image forming system of this type, one of apparatuses which form the system sequentially registers a print job in a print job queue and manages it based on a print job request issued by the client terminal (queuing control). For example, in an arrangement in which the client terminal and printer are one-to-one connected, the client terminal performs queuing control of a print job issued by itself.
Also, an image forming system in which a client terminal, printer, and printer server are connected via a network is well known. In such image forming system, the printer server manages the execution order by the printer of print jobs issued by the client terminal using a print job queue. In general, to such network, a plurality of client terminals and a plurality of printers can be connected. Therefore, the printer server performs queuing control of print jobs issued by the plurality of client terminals, distributes the print jobs to the plurality of printers to be shared, and executes these print jobs in an appropriate order.
Also, an advanced-function printer which can execute print job queuing control processing of the printer server has been proposed. With such advanced-function printer, since the printer itself performs queuing control of print jobs requested from a plurality of client terminals, no printer server is required.
In an image forming system in which a plurality of types of printers are connected to be able to be shared by a plurality of clients, the user who issues a print job output request must recognize the characteristics of these plurality of printers and must select a printer according to the contents to be printed. For this reason, the load on the user who wants to print becomes heavier. To solve such problem, in recent years, a technique for providing a function of automatically selecting an optimal printer in correspondence with the attribute of a print job to the printer server has been proposed.
Even in an image forming system which comprises the printer server having a function of automatically selecting an optimal printer, the user often directly selects a convenient printer for him or her (e.g., a printer closest to the user) so as to print out data. Therefore, even in any of the above image forming systems, the user need designate a desired printer and set detailed information corresponding to the characteristics of the designated printer upon generation of a print job. As a result, the load on the user becomes heavier, and unwanted printing occurs despite of the intention of the user due to setting errors and the like upon setting the detailed information in the printer.
As described above, the user who issued a print job must frequently partially modify information of the print job after the print job is issued and must re-issue the print job. However, in a general image forming system, after a print request is issued (print job is enqueued), the user must request the system administrator to cancel the print job or must cancel the print job by himself or herself, and must issue an output request of the modified print job again. Hence, the operations become complicated, and the traffic on the network increases.
To solve the aforementioned problems, Japanese Patent Laid-Open No. 11-95942 allows to change setting information of a print job even after the print job is enqueued.
However, in the method described in Japanese Patent Laid-Open No. 11-95942, the execution order of replacement print jobs is not mentioned. It is sometimes desirable to place a new print job which is input in a replacement printing mode back to an original position in preference to convenience of the user, but it is sometimes desirable to postpone such job to the backmost position in preference to convenience of other users.


Techniques for handling data access conflicts are disclosed. In some embodiments, a conflict handling system detects a set of one or more objects that are currently being accessed by an application. The conflict handling system queries a database to determine whether the set of one or more objects have changes pending. Responsive to determining that an object has a change pending, the conflict handling system identifies and loads, at runtime of the application, a set of one or more application-specific rules that are defined for handling data conflicts. The conflict handling system executes the rules to generate a conflict resolution result for the object. The application may then perform an application-specific function based on the conflict resolution result.

Many computing systems allow concurrent access to stored data. For example, a multiuser database system may execute, in parallel, multiple transactions submitted by different users to modify data stored in an underlying database. When multiple users are attempting to change the same data, there is a risk of users overwriting each other's amendments without proper locking or conflict handling mechanisms. As a result, data may become corrupted and unreliable within the system.
To maintain data consistency, database systems may provide a locking mechanism to restrict simultaneous access to the same database data. For example, database sessions may be configured to lock either pessimistically or optimistically. With pessimistic locking, if a user has selected a record for an update, the record is locked to prevent other users from initiating another update operation on the record until the pending update is committed or rolled back. In contrast, optimistic locking allows multiple users to concurrently select a record for update but prevents a user from committing an update if the record has changed since the time the user selected the record for the update.
Pessimistic and optimistic locking are typically enforced at the data layer by a database system. Thus, multiple applications may initiate database transactions without having to check for potential data inconsistency. However, enforcing locks purely at the data layer limits the ability to interpret what a data conflict represents at the application layer. A locking technique may be optimal in one application context but inefficient in another context. Consequently, these enforcement mechanisms may lead to inefficient locks and resource utilization.
The approaches described in this section are approaches that could be pursued, but not necessarily approaches that have been previously conceived or pursued. Therefore, unless otherwise indicated, it should not be assumed that any of the approaches described in this section qualify as prior art merely by virtue of their inclusion in this section.

Application driven data change conflict handling system


An improved address re-designate circuit for a programmable microcontroller which is capable of arbitrarily selecting a peripheral circuit and re-designating an address corresponding to the selected peripheral circuit has the advantage of easily being programmed since the user can arbitrarily select a peripheral circuit disposed in the microcontroller chip according to a desired function and can re-designate an address thereof.

1. Field of the Invention
The present invention relates to a function of a microcontroller, and in particular, to an address re-designate circuit for a microcontroller which is capable of re-designating an address of a built-in peripheral circuit.
2. Description of the Prior Art
As shown in FIG. 1, a conventional microcontroller includes a memory device 102 for storing a program or data, an address decoder 103 for decoding an address and allocating it to peripheral circuits(104-1.about.104-N), and a central processing unit(CPU) 101 for executing the program stored in the memory 102 and outputting control signals(RD)(WE) to the peripheral circuits(104-1.about.104-N). These elements are interconnected with a data bus and an address bus.
The operation of a conventional address re-designate circuit will now be described in detail.
When the microcontroller is equipped in an apparatus to execute an operation, the CPU makes a chip enable signal(CE) active and the memory 102 is enabled to thereafter execute a program contained in the memory 102.
Here, the CPU 101 outputs an address for setting the peripheral circuits 104-1.about.104-N.
Then, when the address decoder 103 decodes the address (ADDR) to allocate to the peripheral circuit 104-1.about.104-N, the CPU outputs a control signal(RD,WE) so that a corresponding peripheral circuit receives data and executes a corresponding function.
The microcontroller which carries out the above-described operation can be connected to an emulator, as shown in FIG. 2.
That is, when a user inputs a key to carry out a program, a controller 111 executes the program stored in a first memory 112 and drives a microcontroller 114.
Here, the microcontroller 114 executes the program stored in the memory device 102 to generate an address, and the address decoder 103 receiving the address sequentially sets the peripheral circuits 104-1.about.104-N.
Then, the CPU outputs the control signals(RD,WE) to operate the corresponding circuit among the peripheral circuits 104-1.about.104-N, and as a result, the corresponding circuit receives data from the data bus to perform a corresponding function. Here, the data resulting from the function execution is stored in a second memory 113.
Afterward, when the user inputs a key for checking an executing state of a function while carrying out a program, the controller 111 stops the operation of the microcontroller 114.
Here, when the user inputs a key for checking the execution of an arbitrary function, the controller 111 reads out a corresponding data among the data stored in the second memory 113 to output the read data to a monitor(not illustrated).
Then, the user checks the data on the screen of the monitor(not illustrated) and judges an executing condition of the corresponding function.
However, according to the conventional art, since the address of a peripheral circuit built in the microcontroller is fixedly allocated, the user disadvantageously cannot re-designate the address arbitrarily.
That is, as shown in FIG. 2, when a microcontroller is equipped in the emulator for programming, an EVA-CHIP must be provided for supporting a new microcontroller when a program for a microcontroller having a previously unknown combination of peripheral circuits is being developed.
Therefore, to the user's disadvantage, it takes much time and high cost to fabricate the EVA-CHIP and the development of a targeted microcontroller and preparation of the software for using the microcontroller must be performed at the same time.

Address re-designate circuit for microcontroller


This invention provides a slipcover touch input apparatus and structure for displays for computing devices that converts a non-touch screen display to a touch screen display. The slipcover assembly acts as a sheath or cover for the display, and the touch screen is mounted in a window or opening of the casing of the display so that the touch screen is oriented to mimic the position of the display. This touch screen slipcover can convert any display of a computing device into a touch screen display.

1. Field of the Invention:
This invention relates to a structure suitable for converting a non-touch screen display into a touch screen display comprising a slipcover for a display for computing devices and other electronic devices that not only protects the display but also allows for conversion of a regular or non-touch screen display to a touch screen display. By allowing for easy conversion of a regular or non-touch screen display to a touch screen display, the user will realize significant cost and timesavings, adaptability, and convenience.
2. Description of Related Art:
Prior to the present invention, in order to convert a non-touch screen display to a touch screen display, the user needed to take apart and disassemble the display to install a touch screen. This touch screen installation required additional time and money for a user. In addition, due to the complexity of installation process of a touch screen to a display and the wide range of quality of different touch screens available in the marketplace, many users were not satisfied with the quality of the touch screen products and/or time required for installation.
From the preceding description, it is apparent that the devices currently being used have significant disadvantages. Thus, important aspects of the technology used in the field of invention remain amenable to useful refinement.

Slipcover touch input apparatus for displays of computing devices


The object of the invention is to impart a suitable target slip amount depending on a state of change in an output from a driving power source to a torque converter, while simplifying control. A controller has a calculation part for calculating an engine torque change rate that is a rate of change in the output, and a target slip addition amount calculation part for calculating a negative value as an addition amount, when the engine torque change rate is less than or equal to a predetermined value that is a positive value, and for calculating a positive value as the addition amount, when the engine torque change rate is greater than the predetermined value. The controller is configured to set the target slip amount of a lockup clutch by arithmetic processing that integrates the addition amount, determined based on the calculated engine torque change rate, every control period.

Conventionally, in a device for controlling an automatic transmission configured to execute slip lockup control by which a slip amount of a lockup clutch is brought to a target slip amount, when a rate of change in a required load for an engine is greater than or equal to a predetermined threshold value, the target slip amount is increased at a predetermined rate of increase, and then the increased target slip amount is decreased at a predetermined rate of decrease. At this time, the predetermined rate of decrease is set to decrease, as the operating condition when the rate of change in the required load has reached or exceeded the predetermined threshold value approaches an operating condition in which a rate of increase in a rotational speed on the automatic-transmission side of a torque converter with respect to an increase in the required load is low. Such a slip lockup control device is well known and set forth in Patent document 1, for example.

Device for controlling automatic transmission


A method and an apparatus for producing a container packing filler are provided, which ensure that a net can be correctly and speedily rolled up into a bulk or ball shape. A stretchable tubular net (N) is fitted around a columnar support member (6). Then, a distal portion of the net is forcibly folded radially outward or inward by a plurality of roller belts (30) disposed circumferentially of the net (N), while the roller belts (30) are moved toward a net proximal side axially of the net (N), whereby the net (N) is rolled up radially outward or inward with the distal portion thereof being forcibly folded by circular rotation and axial movement of the roller belts (30) to form an annular roll portion (C).

A novel form of a packing filler to be filled in an upper space of a solid drug container and a production apparatus for the packing filler have been developed by the inventors of the present invention, and disclosed in Patent Documents 1 and 2.    Patent Document 1: JP-A-2003-40335    Patent Document 2: JP-A-2003-276754
In the production apparatus, a tubular net having one closed end is fitted around a columnar support member, and rolled up radially outward from an open end thereof into a bulk or ball shape.

Production method for container packing filler and tubular net rolling apparatus


The present invention relates to a garage light assembly having a housing with a lamp mounting surface wherein a main high intensity discharge lamp and an auxiliary circular high output fluorescent lamp are mounted. The auxiliary lamp is mounted centrally within the assembly and above the light emitting portion of the high intensity discharge lamp so that the light pattern emitted from the auxiliary lamp is symmetrical and the auxiliary lamp does not shadow the light emitted from the high intensity discharge lamp.

1. Field of the Invention
This invention relates to the lighting arts, and in particular to an electronic auxiliary lighting system for a high intensity discharge lamp. More particularly, the auxiliary lighting system of the present invention uses as a light source a high output compact fluorescent lamp.
2. Description of Related Art
A high-intensity discharge (HID) lamp will extinguish when power to the HID lamp is interrupted. Momentary power interruptions, such as a lightning strike or someone inadvertently hitting the on/off switch, will cause the HID lamp to extinguish. An extinguished HID lamp will not immediately re-ignite upon the restoration of power to the HID lamp because gases within the HID lamp must be cooled before the HID lamp will re-ignite. With the power restored, restarting a hot HID lamp can take several minutes. Even when they are cool, and easy to start, HID lamps still take up to 2 minutes to come to full bright after they are ignited.
The garage building industry puts a great deal of stock in emergency lighting standards. The industry likes to see a certain minimum amount of light along path of egress in their structures during power interruptions. Accordingly, auxiliary lighting control circuitry has been used for automatically lighting an auxiliary light source, such as an incandescent lamp, following a brief power interruption of a HID lamp. It is known in the art to use quartz lamps to meet these emergency lighting requirements. Round and square garage lights having a HID lamp as a primary light source and a quartz auxiliary lamp have been used for many years. The premise is that when the HID lamp, located at the center of the fixture, is not on the quartz lamp, which is typically a smaller cylindrical incandescent lamp mounted to the side of the HID lamp, is lit to provide emergency illumination. However, there are inherent problems with these current practices of providing auxiliary light to garage lighting systems.
The quartz lamps that are typically used as auxiliary lamps are short lived and are very inefficient in converting electric power into lumens. This causes problems with continued reliability, maintenance, and the ability to meet auxiliary lighting needs. A significant problem associated with these current practices is that the quartz lamps are not located at the photometric center of the fixture. This causes the pattern of light projected from the auxiliary lamp to lack uniformity and thus portions of the lighted area are only dimly lit. Additionally, during normal operation, the quartz lamp mounted on one side of the fixture blocks or refracts light from the HID lamp located at the center of the fixture. This causes the quartz lamp, during normal operation of the HID lamp, to form a shadow on the area being lit. It has also been found that emergency incandescent lamp sources are inherently glary and consistently mounted off of the centerline of the fixture, causing the luminaire to be aesthetically unappealing.
What is needed in the garage lighting industry is an auxiliary lamp system that provides emergency light without the problems found in the current systems.

Garage light luminaire with circular compact fluorescent emergency lighting optics


The present invention provides a prodrug of propofol and crystalline forms thereof, methods of making the propofol prodrug and crystalline forms thereof, pharmaceutical compositions of the propofol prodrug and crystalline forms thereof, methods of using the propofol prodrug and crystalline forms thereof and pharmaceutical compositions thereof to treat diseases or disorders such as headache pain, post-chemotherapy or post-operative surgery nausea and vomiting, neurodegenerative disorders, and mood disorders.

The present invention provides a prodrug of propofol and crystalline forms thereof, methods of making the propofol prodrug and crystalline forms thereof, pharmaceutical compositions of the propofol prodrug and crystalline forms thereof, methods of using the propofol prodrug and crystalline forms thereof and pharmaceutical compositions thereof to treat or prevent diseases or disorders such as headache pain, post-chemotherapy or post-operative surgery nausea and vomiting neurodegenerative disorders, and mood disorders.
Propofol (2,6-diisopropylphenol), (1), is a low molecular weight phenol that is widely used as an intravenous sedative-hypnotic agent in the induction and maintenance of anesthesia and/or sedation in mammals. The advantages of propofol as an anesthetic include rapid onset of anesthesia, rapid clearance, and minimal side effects (Langley et al., Drugs 1988, 35, 334-372, which is incorporated by reference herein in its entirety). Propofol may mediate hypnotic effects through interaction with the GABAA receptor complex, a hetero-oligomeric ligand-gated chloride ion channel (Peduto et al., Anesthesiology 1991, 75, 1000-1009, which is incorporated by reference herein in its entirety).

Propofol is rapidly metabolized in mammals with the drug being eliminated predominantly as glucuronidated and sulfated conjugates of propofol and 4-hydroxypropofol (Langley et al., Drugs 1988, 35, 334-372). Propofol clearance exceeds liver blood flow, which indicates that extrahepatic tissues contribute to the overall metabolism of the drug. Human intestinal mucosa glucuronidates propofol in vitro and oral dosing studies in rats indicate that approximately 90% of the administered drug undergoes first pass metabolism, with extraction by the intestinal mucosa accounting for the bulk of this presystemic elimination (Raoof et al., Pharm. Res. 1996, 13, 891-895, which is incorporated by reference herein in its entirety). Because of its extensive first-pass metabolism, propofol is administered by injection or intravenous infusion and oral administration has not been considered therapeutically effective.
Propofol has a broad range of biological and medical applications, which are evident at sub-anesthetic doses and include treatment and/or prevention of intractable migraine headache pain (Krusz et al., Headache 2000, 40, 224-230; Krusz, International Publication No. WO 00/54588, each of which is incorporated by reference herein in its entirety). Propofol, when used to maintain anesthesia, causes a lower incidence of post-operative nausea and vomiting (PONV) when compared to common inhalation anesthetic agents and numerous controlled clinical studies support the anti-emetic activity of propofol (Tramer et al., Br. J. Anaesth. 1997, 78, 247-255; Brooker et al., Anaesth. Intensive Care 1998, 26, 625-629; Gan et al., Anesthesiology 1997, 87, 779-784, each of which is incorporated by reference herein in its entirety). Propofol has also been shown to have anti-emetic activity when used in conjunction with chemotherapeutic compounds (Phelps et al., Ann. Pharmacother. 1996, 30, 290-292; Borgeat et al., Oncology 1993, 50, 456-459; Borgeat et al., Can. J. Anaesth. 1994, 41, 1117-1119; Tomioka et al., Anesth. Analg. 1999, 89, 798-799, each of which is incorporated by reference herein in its entirety). Nausea, retching and/or vomiting induced by a variety of chemotherapeutic agents (e.g., cisplatin, cyclophosphamide, 5-fluorouracil, methotrexate, anthracycline drugs, etc.) has been controlled by low-dose propofol infusion in patients refractory to prophylaxis with conventional anti-emetic drugs (e.g., serotonin antagonists and corticosteroids).
Propofol has also been used to treat patients with refractory status epilepticus (Brown et al., Pharmacother. 1998, 32, 1053-1059; Kuisma et al., Epilepsia 1995, 36, 1241-1243; Walder et al., Neurology 2002, 58, 1327-1332; Sutherland et al., Anaesth. Intensive Care 1994, 22, 733-737, each of which is incorporated by reference herein in its entirety). Further, the anticonvulsant effects of propofol have also been demonstrated in rat efficacy models at sub-anesthetic doses (Holtkamp et al., Ann. Neurol. 2001, 49, 260-263; Hasan et al., Pharmacol. Toxicol. 1994, 74, 50-53, each of which is incorporated by reference herein in its entirety).
Propofol has also been used as an antioxidant (Murphy et al., Br. J. Anaesth. 1992, 68, 613-618; Sagara et al., J. Neurochem. 1999, 73, 2524-2530; Young et al., Eur. J. Anaesthesiol. 1997, 14, 320-326; Wang et al., Eur. J. Pharmacol. 2002, 452, 303-308, each of which is incorporated by reference herein in its entirety). Propofol, at doses typically used for surgical anesthesia, has observable antioxidant effects in humans (De la Cruz et al., Anesth. Analg. 1999, 89, 1050-1055, which is incorporated by reference herein in its entirety). Pathogenesis or subsequent damage pathways in various neurodegenerative diseases involve reactive oxygen species and accordingly may be treated or prevented with antioxidants (Simonian et al., Pharmacol. Toxicol. 1996, 36, 83-106, which is incorporated by reference herein in its entirety). Examples of specific neurodegenerative diseases, which may be treated or prevented with anti-oxidants include, but are not limited to, Friedrich's disease, Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Pick's disease, inflammatory diseases, and diseases caused by inflammatory mediators such as tumor necrosis factor (TNF) and IL-1.
A significant problem with the formulation and use of propofol is poor water solubility. Accordingly, propofol must be specially formulated in aqueous media using solubilizers or emulsifiers (Briggs et al., Anaesthesia 1982, 37, 1099-1101). For example, in a current commercial product (Diprivan®, Astra-Zeneca) an oil-in-water emulsion (the emulsifier is the lecithin mixture Intralipid®), is used to formulate propofol (Picard et al., Anesth. Analg. 2000, 90, 963-969). Unfortunately, the oil-in-water emulsion formulation causes discomfort and pain at the site of injection.
One potential solution to the poor water solubility of propofol, which avoids the use of additives, solubilizers or emulsifiers and the attendant injection site pain, is a water-soluble, stable propofol prodrug that is converted to propofol in vivo. (Hendler et al., International Publication No. WO 99/58555; Morimoto et al., International Publication No. WO 00/48572; Hendler et al., U.S. Pat. No. 6,254,853; Stella et al., United States Patent Application No. US2001/0025035; Hendler, U.S. Pat. No. 6,362,234; Hendler, International Publication No. WO 02/13810; Sagara et al., J. Neurochem. 1999, 73, 2524-2530; Banaszczyk et al., Anesth. Analg. 2002, 95, 1285-1292; Trapani et al., Int. J. Pharm. 1998, 175, 195-204; Trapani et al., J. Med. Chem. 1998, 41, 1846-1854; Anderson et al., J. Med. Chem. 2001, 44, 3582-3591; and Pop et al., Med. Chem. Res. 1992, 2, 16-21). Propofol prodrugs that are sufficiently labile under physiological conditions to provide therapeutically effective concentrations of propofol, particularly when the prodrug is orally administered, have been described (Gallop et al., U.S. patent application Ser. No. 10/766,990, which is incorporated by reference herein in its entirety).
In general, crystalline forms of drugs are preferred over amorphous forms of drugs, in part, because of their superior stability. For example, in many situations, an amorphous drug converts to a crystalline drug form upon storage. Because amorphous and crystalline forms of a drug typically have differing physical/chemical properties, potencies and/or bioavailabilities, such interconversion is undesirable for safety reasons in pharmaceutical administration. A key characteristic of any crystalline drug substance is the polymorphic behavior of such a material. Polymorphs are crystals of the same molecule, which have different physical properties because the crystal lattice contains a different arrangement of molecules. The different physical properties exhibited by polymorphs affect important pharmaceutical parameters such as storage, stability, compressibility, density (important in formulation and product manufacturing) and dissolution rates (important in determining bioavailability). Stability differences may result from changes in chemical reactivity (e.g., differential hydrolysis or oxidation, such that a dosage form discolors more rapidly when comprised of one polymorph than when comprised of another polymorph), mechanical changes (e.g., tablets crumble on storage as a kinetically favored crystalline form converts to thermodynamically more stable crystalline form) or both (e.g., tablets of one polymorph are more susceptible to breakdown at high humidity). Solubility differences between polymorphs may, in extreme situations, result in transitions to crystalline forms that lack potency or are toxic. In addition, the physical properties of the crystalline form may be important in pharmaceutical processing. For example, a particular crystalline form may form solvates more readily or may be more difficult to filter and wash free of impurities than other forms (i.e., particle shape and size distribution might be different between one crystalline form relative to other forms).
room Agencies such as the United States Food and Drug Administration can require that the polymorphic content of a drug product be monitored and controlled if the most thermodynamically stable polymorphic form of the drug is not used and/or different polymorphic forms of the drug can affect the quality, safety, and/or efficacy of the drug product. Thus medical and commercial reasons favor synthesizing and marketing solid drugs as the thermodynamically stable polymorph, substantially free of kinetically favored polymorphs.
Accordingly, a need exists for a new propofol prodrug and crystalline forms thereof. The crystalline forms thereof can exhibit have superior physicochemical properties that may be used advantageously in pharmaceutical processing and pharmaceutical compositions. These prodrug and crystalline forms thereof should be sufficiently labile under physiological conditions to provide therapeutically effective concentrations of propofol, particularly when the prodrug is orally administered.
The propofol prodrug 2-amino-3-(2,6-diisopropylphenoxycarbonyloxy)-propanoic acid or pharmaceutically acceptable salts, or solvates thereof and crystalline forms thereof are provided that satisfies these and other needs. Further provided are pharmaceutical compositions of 2-amino-3-(2,6-diisopropylphenoxycarbonyloxy)-propanoic acid or pharmaceutically acceptable salts, or solvates thereof and crystalline forms thereof, methods of using crystalline forms of 2-amino-3-(2,6-diisopropylphenoxycarbonyloxy)-propanoic acid or pharmaceutically acceptable salts, or solvates thereof (including pharmaceutical compositions thereof) to treat or prevent various diseases, and methods of making crystalline forms of 2-amino-3-(2,6-diisopropylphenoxy-carbonyloxy)-propanoic acid or pharmaceutically acceptable salts, or solvates thereof.
In one aspect, the propofol prodrug 2-amino-3-(2,6-diisopropylphenoxycarbonyloxy)-propanoic acid or a pharmaceutically acceptable salt thereof, or a solvate of any of the foregoing is provided.
In another aspect, crystalline forms of 2-amino-3-(2,6-diisopropylphenoxycarbonyloxy)-propanoic acid hydrochloride are provided. In some embodiments, a crystalline form of the hydrochloride salt of (S)-2-amino-3-(2,6-diisopropylphenoxycarbonyloxy)-propanoic acid having characteristic peaks (2θ) at 5.1°±0.2°, 9.7°±0.2°, 11.0°±0.2°, 14.1°±0.2°, 15.1°±0.2°, 15.8°±0.2°, 17.9°±0.2°, 18.5°±0.2°, 19.4°±0.2°, 20.1°±0.2°, 21.3°±0.2°, 21.7°±0.2°, 22.5°±0.2°, 23.5°±0.2°, 24.4°±0.2°, 25.1°±0.2°, 26.8°±0.2°, 27.3°±0.2°, 27.8°±0.2°, 29.2°±0.2°, 29.6°±0.2°, 30.4°±0.2°, and 33.4°±0.2° in an X-ray powder diffraction pattern, as substantially shown in FIG. 1 is provided.
In another aspect, crystalline forms of 2-amino-3-(2,6-diisopropylphenoxycarbonyloxy)-propanoic acid mesylate are provided. In some embodiments, a crystalline form of the mesylate salt of (S)-2-amino-3-(2,6-diisopropylphenoxycarbonyloxy)-propanoic acid having characteristic peaks (2θ) at 4.2°±0.1°, 11.7°±0.1°, 12.1°±0.1°, 12.6°±0.1°, 16.8°±0.1°, 18.4°±0.2°, 21.0°±0.1°, 22.3°±0.1°, 22.8°±0.2°, 24.9°±0.2°, 25.3°±0.1°, 26.7°±0.2°, and 29.6°±0.1° in an X-ray powder diffraction pattern, as substantially shown in FIG. 2 is provided.
In still another aspect, pharmaceutical compositions of the propofol prodrug 2-amino-3-(2,6-diisopropylphenoxy-carbonyloxy)-propanoic acid or a pharmaceutically acceptable salt thereof, or a solvate of any of the foregoing is provided or a crystalline form of any of the foregoing are provided. The pharmaceutical compositions comprise a therapeutically effective amount of 2-amino-3-(2,6-diisopropylphenoxycarbonyloxy)-propanoic acid or a pharmaceutically acceptable salt thereof, or a solvate of any of the foregoing or a crystalline form of any of the foregoing and a pharmaceutically acceptable vehicle. In certain embodiments, a pharmaceutical composition comprising crystalline (S)-2-amino-3-(2,6-diisopropylphenoxy-carbonyloxy)-propanoic acid hydrochloride having characteristic absorption peaks, supra, and a pharmaceutically acceptable vehicle is provided. In certain embodiments, a pharmaceutical composition comprising crystalline (S)-2-amino-3-(2,6-diisopropylphenoxycarbonyloxy)-propanoic acid mesylate having characteristic absorption peaks, supra, and a pharmaceutically acceptable vehicle is provided.
In still another aspect, methods for treating or preventing various diseases or disorders are provided. The methods are useful for treating or preventing diseases or disorders including, but not limited to, headache pain such as migraine, post-chemotherapy or post-operative surgery nausea and vomiting, mood disorders such as depression, and neurodegenerative disorders (e.g., epilepsy, Friedrich's disease, Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Pick's disease, etc.). In certain embodiments methods involve administering to a patient in need of such treatment or prevention a therapeutically effective amount of 2-amino-3-(2,6-diisopropylphenoxycarbonyloxy)-propanoic acid hydrochloride or crystalline forms thereof, or pharmaceutical compositions thereof. In some embodiments, crystalline (S)-2-amino-3-(2,6-diisopropylphenoxycarbonyloxy)-propanoic acid hydrochloride or pharmaceutical compositions thereof with the characteristic absorption peaks, supra, is administered to the patient in need of such treatment. In certain embodiments the methods involve administering to a patient in need of such treatment or prevention a therapeutically effective amount of 2-amino-3-(2,6-diisopropylphenoxycarbonyloxy)-propanoic acid mesylate or crystalline forms thereof, or pharmaceutical compositions thereof. In some embodiments, crystalline (S)-2-amino-3-(2,6-diisopropylphenoxycarbonyloxy)-propanoic acid mesylate or pharmaceutical compositions thereof with the characteristic absorption peaks, supra, is administered to the patient in need of such treatment.
In still another aspect, methods for inducing and/or maintaining anesthesia or sedation in a mammal are provided. In certain embodiments, the methods involve administering to a patient in need of such anesthesia or sedation induction and/or maintenance a therapeutically effective amount of 2-amino-3-(2,6-diisopropylphenoxy-carbonyloxy)-propanoic acid hydrochloride or crystalline forms thereof, or pharmaceutical compositions thereof. In certain embodiments, crystalline (S)-2-amino-3-(2,6-diisopropylphenoxycarbonyloxy)-propanoic acid hydrochloride with characteristic absorption peaks, supra, is administered to the patient in need of such treatment. In certain embodiments, the methods involve administering to a patient in need of such anesthesia or sedation induction and/or maintenance a therapeutically effective amount of 2-amino-3-(2,6-diisopropylphenoxycarbonyloxy)-propanoic acid mesylate or crystalline forms thereof, or pharmaceutical compositions thereof. In some embodiments, crystalline (S)-2-amino-3-(2,6-diisopropylphenoxycarbonyloxy)-propanoic acid mesylate with characteristic absorption peaks, supra, is administered to the patient in need of such treatment.
In still another aspect, methods for making 2-amino-3-(2,6-diisopropylphenoxycarbonyloxy)-propanoic acid and/or crystalline forms thereof are provided.
These and other features of the present disclosure are set forth herein.

This patent is subject to a terminal disclaimer.

Amino acid derived prodrugs of propofol, compositions, uses and crystalline forms thereof


Disclosed is a three-wheeled vehicle with centrally positioned motor and driver's seat. An exemplary embodiment has a frame for supporting a driver and a multitude of mechanical devices. A pair of steerable front wheels are rotatably affixed to the front portion of the frame. A rear wheel is rotatably affixed along the frame's centerline in the rear portion. A motor is affixed to the frame's centerline. The driver's seat is also affixed to the frame's centerline behind the motor and ahead of the rear wheel, so the driver sitting in the driver seat is in both a recumbent and straddle position.

Performance oriented motorcycles and automobiles are an enormous industry. Countless amounts of money and time are spent refining these vehicles for increased performance. Yet, motorcycles and automobiles have different advantages. Automobiles are inherently stable due to the use of four wheels, while motorcycles are inherently unstable vehicles due to the use of only two wheels. Accordingly, motorcycles require constant balance by a rider and are prone to falling over when controlled by an inexperienced rider. Automobiles are safer vehicles, not only due to their inherent stability but because they have a surrounding frame that can absorb impact during a crash. The rider of the motorcycle has no surrounding frame and will be thrown from the motorcycle during an accident. Due to these reasons, motorcycles are dangerous vehicles to drive on public roads shared with significantly heavier vehicles. Even though a motorcycle is more dangerous, it does have advantages. Due to lighter weight, motorcycles generally accelerate faster and use less fuel. Automobiles are generally heavier and require a correspondingly higher amount of horsepower to match the acceleration of the motorcycle.
Although motorcycles are lighter, they do not actually corner better than automobiles. The automobile is an inherently stable vehicle due to the use of four wheels. At any moment the automobile can perform a sharp turn. For the motorcycle to make a sharp turn, the rider must also lean the bike. To turn the motorcycle, the rider must not only turn the handlebars of the motorcycle, but shift the weight of the motorcycle into the direction of the turn. While cornering, if the weight of the motorcycle hasn't shifted the motorcycle will crash. The time differential it takes to lean the motorcycle to make a turn can mean the difference between avoiding an accident or having an accident. Additionally, an automobile's center of gravity always stays within the width of the vehicle, increasing the vehicle's stability. A motorcycle's center of gravity moves while turning. As the motorcycle turns and leans, the center of gravity moves down and inward into to the turn. The center of gravity actually shifts beyond the tire patch in contact with the road. If a rider hits a patch of loose gravel while turning, the motorcycle can lose traction and come out from under the rider and crash.
Motorcycles also have a cornering disadvantage due to their rounded tire design. A motorcycle tire is shaped like a donut, having rounded edges. The rounded design is necessary to allow the bike to lean while making a turn. The rounded tire creates a small tire patch in the shape of an oval that is in contact with the road. Performance of any vehicle is dependent upon the amount of traction, and traction is directly related to the amount of surface area between the tire and the road. Motorcycles have very small tire patches in contact with the road. The automobile utilizes a generally cylindrical tire shape because the tire does not need to lean to make a turn. The cylindrical tire isn't rounded but rather in the shape of a cylinder. This creates a larger rectangular tire patch in contact with the road. In addition, the cylindrical tire shape is usually wider than the motorcycle tire which adds to the tire surface in contact with the road. The larger amount of area in contact with the road leads to improved cornering, as well as improved acceleration and braking.
Furthermore, motorcycles have a high center of gravity which limits cornering capability. A seasoned motorcycle rider must substantially lean the bike to lower the center of gravity to corner around an aggressive turn. In an automobile, the center of gravity is constant and to make an aggressive turn the automobile driver has only to turn the steering wheel. As can be seen, the motorcycle and automobile each have advantages over the other. It can be seen that there is a need for a vehicle that can combine the strengths of automobiles and motorcycles.
All-Terrain Vehicles (ATVs) are a mix between automobiles and motorcycles. ATVs usually have a motorcycle like engine placed within a frame. The rider sits atop the ATV frame and controls the ATV in a similar manner as the motorcycle. Also, the driver positioning in the ATV is generally similar as that of the motorcycle; being on-top and above the vehicle. The driver seat in an ATV is not meant to keep the rider secured to the ATV. While driving an ATV, the rider will lean his body to make turns. During many maneuvers the rider will not even be seated on the ATV seat. ATVs are intended for off road use as they are not suitable for public roads. ATV's have the wrong tire design for the road, as the ATV tire would prematurely wear away on hard pavement. Also, the ATV has a high center of gravity making it a poor road vehicle to corner. Furthermore, the ATV has tires positioned too close together to provide the stability needed for a road going vehicle. Also, the ATV provides no further protection in a crash than does a motorcycle. Driving an ATV on the road shared with automobiles is as dangerous as driving a motorcycle on the road with automobiles. For some of the above mentioned reasons, it is illegal to drive ATVs on roads used by automobiles and motorcycles.
Past attempts have been made to produce a three-wheeled vehicle. Many designs have utilized two cylindrical tires in the front with a single cylindrical tire in the rear. These vehicles are supported in three places, making them inherently stable. However, a driver and a passenger sit side-by-side in a recumbent position as is similar to the seating position in an automobile. The driver operates the vehicle through the use of a steering wheel and foot controls as is done in an automobile. These vehicles are close in design to the automobile differing with only the use of a single rear wheel. Some vehicles have placed the driver along the centerline in a recumbent position with the engine either completely ahead or completely behind the driver. Once again, the driver operates the vehicle through the use of a steering wheel and foot controls as is done in an automobile. These vehicles are also close in design to the automobile differing by the use of a single rear wheel.
The previously mentioned vehicles have failed to incorporate the driving experience of the motorcycle into an inherently stabilized vehicle. A motorcycle draws some of its appeal due to the unique driver positioning. In a motorcycle the driver straddles the vehicle with his legs. The driver straddles either the engine assembly, transmission assembly, or the gas tank. Straddling the vehicle results in a shorter vehicle, as extra room is not needed to allow a driver to stretch out in the traditional recumbent position of an automobile. Prior vehicles have generally placed the engine either completely ahead or behind of the driver and passenger, resulting in a longer than necessary vehicle. Much of the appeal of the motorcycle is lost when the driver does not straddle the vehicle. Further appeal is lost when the driver is not positioned in the middle of the vehicle. The driver being positioned next to the passenger is an automobile characteristic, not a motorcycle characteristic. Additionally, more of the appeal of the motorcycle is lost when the driver controls the vehicle with a steering wheel and foot controls, as opposed to the traditional motorcycle controls.
None of the previous vehicles have included various features that would be desirable in a single vehicle. It can be seen then that there is a need for a new class of vehicle designed for public road use that combines the best attributes of automobiles and motorcycles. There is a need for a vehicle to accelerate with the ease of a motorcycle due to its light weight, yet also be inherently stable through the use of three wheels. A need exists for a vehicle to have cylindrically shaped tires for increased acceleration, braking and cornering. A need exists for a three-wheeled vehicle to create a more similar driving experience to the motorcycle. A need exists for the vehicle to combine the straddle seating position of the motorcycle along the centerline of the vehicle with the recumbent seating position of the automobile. There is a need for a vehicle that does not require the driver to lean into a turn and has a lower center of gravity than a motorcycle. Furthermore, there is a desire for an inherently stable vehicle to utilize traditional motorcycle controls as opposed to the traditional automobile controls. Additionally, a desire also exists for a vehicle to provide greater safety than a motorcycle. Additionally, there is a desire for a vehicle to have a passenger seat positioned behind the driver seat in tandem where both seats are positioned along the centerline of the vehicle.

Three-wheeled vehicle with centrally positioned motor and driver's seat


Lymphoid dendritic cells with immunophenotype CD8α+ can be produced by a method which comprises culturing human hematopoietic stem cells in a medium containing GM-CSF, followed by culturing in a medium containing IFN-Υ, the lymphoid dendritic cells being useful in various immunotherapies.

Dendritic cells (DCs) are powerful antigen presenting cells(APCs) that orchestrate various immune responses against specific antigens and at the same time suppress auto-immune response by deleting potentially autoreactive T cells. These apparently contradictory functions have been suggested to originate from different subsets of DCs.
Murine DCs can be subdivided into at least two distinct subtypes, myeloid and lymphoid DCs, on the basis of their anatomic localization, transplantation experiments, and cell surface phenotypes. DCs bearing the CD11c+, MHCII+, CD4+, CD8α− cell surface phenotype, called CD8α− myeloid DCs, can be derived from myeloid precursor cells, whereas DCs bearing the CD11c+, MHCII+, CD4−, CD8α+ cell surface phenotypes, called CD8α+ lymphoid DCs, are present in thymus or spleen.
It has been reported that murine CD8α+ lymphoid DCs also produce IFN-γ in response to IL-12 like NK cells(natural killer cells) and T cells (Toshiaki et al., Brief Definitive Report, 189(12), 1981-1986(1999)), Also, when lymphoid DCs such as murine Langerhans cells are injected into CD8α− mice, they are transferred into the lymph node and differentiate into CD8α+ DCs and the differentiated CD8α+ DCs can produce IFN-γ (Miriam et al., Blood, 96(5), 1865-1872(2000)).
Such lymphoid DCs not only induce immune tolerance but function as powerful immunogenic APCs against various allogeneic antigens, activating T helper cell type I response by producing IL-12 and IFN-γ.
DCs are present virtually in all tissues of the body, but in low concentrations, and it is therefore difficult and cumbersome to procure a sufficient amount of DCs for ex vivo manipulation.
Accordingly, various efforts have been made to generate DCs ex vivo from HSCs or monocytes in a large scale, using for example, several cytokines including Granulocyte-macrophae colony stimulating factor (GM-CSF), interleukin-4(IL-4), tumor necrosis factor-alpha (TNF-α) and stem cell factor (SCF). DCs which express CD1a+, CD4+, CD11c+, CD40+, CD54+, CD80+, CD83+, CD86+, HLA class I+, HLA class II+, CD3−, CD8− and CD14− were generated by using GM-CSF (Williams et al., Int. Rev. Cytol., 153: 412(1994); Santiago-Schwarz et al., Nature, 360: 258(1993); and Rosenzwajg et al., Blood, 87: 535(1996)).
However, it has never been reported that DCs of CD8α+ immunophenotype (CD8α+ DCs) are present in human or that CD8α+ DCs can be differentiated from human hematopoietic stem cells(HSCs).


A method for manufacturing a piston device, comprises the following steps. Processing a first raw material to form a piston with a top surface and a bottom surface. Processing a second raw material to have the diameter of said second raw material slightly larger than the diameter of said piston. Cutting the second raw material into a plural cylinders. Mounting the annular component on the top surface or the bottom surface through the convex portion. The durability and the life cycle of the piston device can be extended by mounting the annular component onto the piston.

The principle of operation of piston within a cylinder, is driving the piston in oscillating movement to reproduce motive force by combusting the fuel, theoretically, the piston must be completely sealed with the inner wall of the cylinder, so the combustion gas is fully sealed from leaking as being effectively used to drive the piston. However, this kind of design will significantly decrease piston life due to excessive wear between the inner wall of the cylinder and piston, thus overheat. Hence the contacting surface of piston must be wear resistant to provide superior protection; such wear resistance process is coated with wear-resistant material.
However, the process for coating the surface of piston device is very complicated, it is not easy to control as to keep the surface of piston uniformly flat after applying wear resistance process in a large surface area, if the surface of piston is uneven after processed, the sealing problem would thus occurs since the piston is not completely sealed against the cylinder. And the surface of piston must completely fit in respect with the cylinder size accordingly after wear resistant process to prevent from leaking, for such reason, the difficulty level of coating wear-resistant material on the piston is inevitably increased.
According to the problem described above, the inventor of the invention herein conducted extensive research and experimentation that culminated in the successful development and design; hence a piston device thereof is addressed as the foundation and the realization for improving described problems.

Method for manufacturing a piston device


A method and apparatus for limiting the movement of a fork bolt when it is in a locking position. The apparatus comprising a latch mechanism for use with a striker, the latch mechanism comprising: a housing being configured to movably receive a fork bolt therein, the fork bolt traveling from an open door position to a closed door position to a locked door position, the fork bolt engaging the striker as the fork bolt moves from the open door position to the closed door position and the locked door position; a protrusion disposed on a surface of the housing, the protrusion having a length corresponding to the movement of the fork bolt from the open door position to the closed door position and the locked door position, the protrusion gradually increasing in height from the surface along the length wherein the protrusion makes contact with the fork bolt as the fork bolt travels from the open door position to the closed door position and the locked door position and movement of the fork bolt.

A typical vehicle is manufactured with a plurality of openable doors. Each door is typically mounted on hinges within a door opening. Each door also includes a latch that generally engages a striker mounted on the door opening frame to releasably hold the door in a closed position.
Vehicle door latches customarily include a lock mechanism that prevents operation of the door latch so that the vehicle door cannot be opened by persons inside the vehicle unintentionally or by persons outside the vehicle who are not authorized. The door lock mechanism itself can also be operated from inside as well as from outside the vehicle.
The door lock mechanism is usually operated from inside the vehicle by a slide or a sill button that is actuated manually and/or electrically. The door lock mechanism is usually operated from outside the vehicle by a key and key lock cylinder or an electronic device.
When a door is fully closed to its primary latched position a fork bolt engages a striker disposed on a frame or other appropriate location of the vehicle. When the fork bolt is in this position the door remains secured in the closed position by the engagement of the striker by the fork bolt. It is desirable to limit the play, tolerance or amount of movement of the fork bolt within the latching mechanism when the same is in this locking position.

Method and apparatus for providing securement in a door latch


A method of processing a collect call. The method includes receiving a request for a collect call from a calling party and transmitting information required pursuant to a detariffing order to a called party.

In the past, telecommunications companies that offered, for example, long distance telephone service had to file a document called a tariff with the Federal Communications Commission ("FCC"). The tariff document described the rates, terms, and conditions of service associated with various services. Thus, rates, terms, and conditions of service were not conveyed to individual consumers because the tariff document was available for perusal by consumers. Recently, the FCC has "detariffed" certain telecommunications services and thus, telecommunications companies are not required to file tariff documents with the FCC in some cases. Instead, long distance companies must post rates, terms, and conditions of service on an Internet web page and at a specific place of business.
Prior to detariffing, a tariff document took precedence over any private contract. Thus, in essence, the tariff document was a contract between the telecommunications company and its consumers. After detariffing, telecommunications companies can enter into contracts with consumers without regard to a superseding tariff document.
Detariffing presents a potential problem with respect to telecommunications services in which the charges for the services are paid by a party that receives, rather than places, a call. For example, the party receiving a collect call pays the charges associated with the call. Typically, the party that places such a call utilizes a local exchange carrier, a calling card company, or a long distance telephone company with which the party has a relationship. However, the party receiving the call may have no relationship with the company that is utilized by the party placing the call. Thus, because there is no governing tariff document, the party receiving the call may not be aware of the rates, terms, and conditions of service associated with the call. Also, the company that is utilized by the party placing the call may have difficulty trying to collect the charges associated with the call from the party receiving the call because, arguably, the receiving party may assert that no contract was formed between the company and the receiving party.
U.S. Pat. No. 5,859,902 discloses a method for processing collect calls in which the party receiving a collect call is given information about the cost of the call.

Systems and methods for collect call processing


An acoustic transducer, in particular for an ultrasonic sensor, is proposed. The acoustic transducer has a functional group, the functional group encompassing a diaphragm cup and at least one electroacoustic transducer element. The acoustic transducer furthermore has a housing. The diaphragm cup encompasses a vibration-capable diaphragm and an encircling wall, as well as at least one electroacoustic transducer element, the transducer element being embodied to excite the diaphragm to vibrate and/or to convert vibrations of the diaphragm into electrical signals. The diaphragm cup is constituted from a plastic material, the at least one transducer element being integrated into the vibration-capable diaphragm, the transducer element having an electrically active polymer.

Ultrasonic sensors are utilized, inter alia, in automotive and industrial applications in order to sense the environs. Objects in the environs can be detected by the fact that an ultrasonic signal is emitted by the ultrasonic sensor, and the ultrasonic echo reflected from an object is received again. The distance to the object can then be calculated from the transit time between emission of the ultrasonic signal and reception of the ultrasonic echo, and from the known speed of sound.
Ultrasonic sensors typically encompass an acoustic transducer having a diaphragm, a transducer element, and a housing. The transducer element is, for example, a piezoceramic element that causes the diaphragm to vibrate after application of an electrical voltage and, for the reception of ultrasonic echoes, converts the vibrations on the diaphragm, which are excited by the acoustic pressure in front of the diaphragm, into an electrical signal. Acoustic transducers of this kind are known in the existing art (see e.g. DE 10 2012 201 884 A1).
The join between the piezoceramic element and the diaphragm bottom is usually produced by way of an adhesion process. This is subject to failure both during the production process and in operation. The functional group of the ultrasonic sensor, and the housing, are produced as separate individual parts and then fitted together.
DE 10 2013 222 076 A1 describes an acoustic transducer that has a resonator having at least one piezoelectric element. The resonator is embodied in one piece as a diaphragm cup having a diaphragm and an encircling enveloping surface made of the same material. The diaphragm cup is manufactured, for example, from a polymer material such as polyvinylidene fluoride (PVDF), or from a piezoceramic material. One or several regions of the diaphragm are polarized so that piezoelectrically active regions are formed.
Proceeding therefrom, the object on which the invention is based is to describe an acoustic transducer having a simplified manufacturing method and a simplified configuration.

Sound transducer, having a transducer element integrated in a vibration-capable diaphragm including an electrically active polymer


A developing device comprises a latent image carrier that carries a latent image, a toner carrier opposing the latent image carrier while carrying toner to develop the latent image, and plural electrodes arranged in a prescribed direction insulated from each other on the surface of the toner carrier to create an electric field therebetween. An alternating voltage supplying device is provided to supply n number of phases (n ≧2) of an alternating voltage to the plural electrodes, respectively. The alternating voltage changes the electric field to cause the toner to hop and form toner cloud on the surface of the toner carrier. The toner hopping is halted at a prescribed time period during the toner cloud formation.

1. Field of the Invention
The present invention relates to a developing device for developing a latent image formed on a latent image carrier, a process cartridge integrally including the developing device, and an image forming apparatus, such as a printer, a facsimile, a plotter, a multifunctional machine including one of the functions of these devices, including one of the process cartridge and the developing device.
2. Background of the Invention
In the past, a developing device employed in an image forming apparatus, such as a printer, a facsimile, a plotter, etc., employs one or two-component developing system. The two-component developing system is very suitable for high speed developing, and is mainly employed in a middle or high-speed image forming apparatus. To obtain a high quality image using the two component developing system, developer needs to be extra ordinarily accurate at a section contacting a latent image formed on the latent image carrier. Thus, a diameter of a carrier particle is decreasing these days, and carrier having a diameter of about 30 micrometer recently comes to be used on a commercial basis.
Since a mechanism can be downsized and lightened, the one component developer is mainly used currently in a low speed image forming apparatus. To form a thin toner layer on a developing roller in the one component developing system, a toner-adjusting member, such as a blade, a roller, etc., contacts toner on the developing roller, so that the toner is discharged by means of friction created between the developing roller and the toner adjustment member. Such a discharged toner thin layer on the developing roller is conveyed to a developing section and develops the latent image on a latent image carrier. A developing system employed here is categorized into two of contact and non-contact types, wherein the former represents that a developing roller contacts a latent image carrier, and the latter does not. As shown in the Japanese Patent Application Laid Open No. 03-100575, to complement defects of the two and one component developing systems, a hybrid system blending these two and one component developing systems has been proposed.
A method of developing a fine uniform dot with high resolution is disclosed in the Japanese Patent Application Laid Open No. 03-113474. The method employs the above-mentioned hybrid system and arranges a wire to which a high cycle bias is applied at a developing section, and causes toner clouding there, so that a dot developing performance is obtained with high resolution. The Japanese Patent Application Laid Open No. 03-21967 proposes a method of forming an electric field curtain on a roller to most efficiently and stably forming toner clouding. The Japanese Patent Application Laid Open No. 2003-15419 discloses a developing device for conveying developer by means of an electric field curtain formed by a traveling wave electric field. The Japanese Patent Application Laid Open No. 9-269661 discloses a developing device including plural magnetic poles, which almost equally attract almost one layer of carrier onto the periphery of a developing roller.
The Japanese Patent Application Laid Open No. 2003-84560 discloses a developing device that periodically (or intermittently) includes plural conductive electrode patterns on the surface of a developer carrier member that carries non-magnetic toner via an insulation section, and causes an inclination of an electric field in the vicinity of the surface of the developer carrier member when a prescribed bias voltage is applied to the electrode, so that the non-magnetic toner is conveyed being attracted to the developer carrier member.
A high quality image is increasingly demanded in the two component developing system. Thus, since a dot size of a pixel is necessarily equal or smaller than a diameter of a currently used carrier particle, the currently use carrier particle further needs to be downsized in view of a reproduction performance of an isolated dot. However, when the carrier diameter is decreased, a magnetic permeability of the carrier particle decreases. As a result, the carrier easily drops off the developing roller. When the dropped carrier particle sticks to the latent image carrier member, not only an image is defective due to toner sticking, but also side effects, such as damaging the latent image carrier member, etc., occur thereafter.
To prevent the carrier drop, many attempts have been made in a view point of material, such as increasing a magnetic permeability of carrier particle, intensifying a force of magnet installed in a developing roller, etc. However, since it is difficult to obtain a high quality image at low cost, development hardly is progressed. In view of a current demand for downsizing, a diameter of a developing roller is increasingly decreased steadily, designing of a developing roller having a strong magnetic field capable of completely suppressing carrier drop becomes difficult. From the beginning, since the two component developing system forms a toner image by rubbing ear of the two-component developer called a magnetic blush, development of an isolated dot tends to be uneven due to un-uniform ear. It is possible to improve an image quality by forming an alternating electric field between a developing roller and a latent image carrier member. However, image unevenness caused by uneven developer ear can hardly be removed completely.
In the one component developing system, since a toner layer thinned by a toner adjustment member on a developing roller has already been pressure contacted the developing roller, a response of the toner to an electric field is extremely slow at the developing section. Thus, forming an intense alternating current field between a developing roller and the latent image carrier is common to obtain a high quality image. However, it is still difficult to develop a latent image with a constant amount of toner, and to uniformly develop a fine dot with high resolution. Further, since the one component developing system causes extremely large stress in toner when the toner layer is thinned on the developing roller, the toner quickly deteriorates during circulation through the developing device. As the toner deteriorates, the toner layer is easily unevenly thinned on the developing roller. Accordingly, the one component developing system is generally not preferable for a high speed and durable image forming apparatus. Even a size and a number of parts of a developing device of a hybrid system increase, some problems can be resolved. However, the developing section also includes the same problem as that using the one component developing system. That is, it is difficult for it to develop a fine and uniform dot with high resolution.
The system of the Japanese patent Application Laid Open No. 03-113474 can realize highly stable and high quality development. However, the developing device becomes complicated. The system of the Japanese patent Application Laid Open No. 3-21967 is significantly excellent in obtaining downsized and high quality image. However, conditions for an electric field curtain and development are too strict to obtain an ideal high quality image. Specifically, when an image is formed on a wrong condition, an expected result does not occur, and a bad quality image is rather provided.
Further, in an image forming process that sequentially superimposes first to third toner images on a latent image carrier, a developing system is needed not to disturb a toner image already formed thereon. By employing either a non-contact type one component developing system or the toner cloud developing system as described in the Japanese Patent Application Laid Open No. 03-113474, respective color toner image can be subsequently formed on the latent image carrier. However, since an alternating current electric field is necessarily formed between the latent image carrier and the developing roller in the both systems, the toner image previously formed on the latent image carrier is partially peeled off and enters the developing device. As a result, an image on the latent image carrier is not only disturbed, but also colors of the toner in the developing device are blended. Such a problem is fatal in creating a high quality image. Thus, the cloud developing is to be realized while the alternating current electric field is not created between the latent image carrier and the developing layer to resolve such a problem.
As a cloud development-realizing method, a system described in the Japanese patent Application Laid Open No. 03-21967 can be effective. However, as mentioned earlier, the method needs to be used under the strict condition, or any of the expected result is not obtained. Further, as described in the Japanese Patent Application Laid Open No. 2002-341656, a method of electro-statically conveying toner using an alternating electric field having more than three phases while omitting mechanical driving for a toner carrier member can be effective. However, this method includes a problem of toner accumulation on a conveyance substrate triggered by toner impossible to electro-statically convey due to some reason. To resolve such a problem, a structure of a secured conveyance substrate and a toner carrier member that moves along the surface of the secured conveyance substrate has been proposed as discussed in the Japanese patent Application Laid open No. 2004-286837. However, a mechanism becomes extremely complex.
In the cloud developing, it is significantly important to obtain sufficient image density avoiding background contamination. The Japanese patent Application Laid Open No. 2004-101933 proposes that when development is executed while forming an advancing wave electric field, an amount of conveyance is controlled by adjusting a frequency of a conveyance voltage or the like. Since the method only adjusts an amount of toner existing in the developing region, and the idea is the same as conventional one or two component development, and accordingly doesn't adjust a clouding condition, it is difficult to control toner uniquely having a weak binding force in the cloud. Thus, a range capable of obtaining sufficient image density without background stein is significantly narrow, or is not obtained depending upon a cloud condition.

Developing device, process cartridge, and image forming apparatus


The present invention provides anti-human ICOS antibodies with increased effector function. The invention further relates to pharmaceutical compositions, immunotherapeutic compositions, and methods using therapeutic antibodies that bind to the human ICOS antigen and that may mediate ADCC, CDC, and/or antibody-dependent phagocytosis (opsonization) for the treatment and prevention of T cell-mediated diseases and disorders, such as, but not limited to, chronic infection, autoimmune disease or disorder, inflammatory disease or disorder, graft-versus-host disease (GVHD), transplant rejection, and T cell proliferative disorder.

ICOS is a type I transmembrane protein comprising an extracellular (Ig) V-like domain. ICOS serves as the receptor for the B7h co-stimulatory molecule. ICOS expression is low on naïve human T cells but becomes upregulated within hours after TCR engagement. ICOS expression persists on activated T cells subpopulations such as Th1, Th2, and Th17 CD4+ cells.
Given that ICOS expression is concentrated on activated T helper cell populations, the therapeutic use of an anti-ICOS antibody with enhanced effector function holds the promise of improving the efficacy of treatment and prevention of T cell-mediated diseases and disorders, such as, but not limited to, chronic infection, autoimmune disease or disorder, inflammatory disease or disorder, graft-versus-host disease (GVHD), transplant rejection, and T cell proliferative disorder using therapeutic anti-ICOS antibodies with enhanced effector function.

Anti-ICOS antibodies and their use in treatment of oncology, transplantation and autoimmune disease


A printing control terminal device includes a user interface to receive a command to print an XPS file on an XPS viewer, an analyzing unit to analyze at least one of a print ticket, a core property, and a digital signature included in the XPS file, and to distinguish a first setting information to be applied to a printing job and a second setting information not to be applied to a printing job, a conversion unit to convert at least one of the print ticket, the core property, and the digital signature corresponding to the second distinguished setting information to be applied to the printing job, a driver to generate print data using the second converted setting information and the first setting information, and a communication interface to transmit the generated print data to the image forming apparatus.

1. Field of the Invention
The present general inventive concept relates to a printing control terminal device, and a method of printing an XML (extensible markup language) paper specification (XPS) file. More particularly, the present general inventive concept relates to a printing control terminal device and a method of printing an XPS file to generate print data for an XPS file to minimize losing information included in the XPS file.
2. Description of the Related Art
Generally, an image forming apparatus such as a copier, a printer, a facsimile, or a multi function peripheral (MFP) which integrates the functions of the copier, printer, facsimile, etc., operates to print the print data generated by a terminal such as a computer onto a recording sheet.
Image forming apparatuses which have been recently introduced support direct printing on print data written in a printable document format (PDF), a tagged image file format (TIFF), a joint photographic experts group (JPG), or the like. The direct printing refers to a process where a printing job is directly performed only by transmitting a document to be printed to an image forming apparatus without executing an additional application program on a terminal device such as a personal computer (PC), a laptop computer, a personal digital assistant (PDA), a digital camera, or the like.
There is an XPS file which supports such a direct printing. An XPS file is an electronic file having a fixed-layout that preserves document formatting and can be shared, and refers to a zip-formatted file which includes all kinds of data and resources described by systematizing all resources required for documents or operations in a directory structure and by writing the references therebetween in XML.
However, the operation of converting an XPS file into print data capable of being recognized by the image forming apparatus is needed in order that the image forming apparatus on which an XPS emulator is not mounted outputs such an XPS file. There has been a problem that information set on an XPS file is lost since a conventional printer driver generates print data using only the data provided by an application program. For instance, if a printing option '4-up' is set on an XPS file, a conventional printer driver cannot perform a printing job suitable for an intention of a user due to a default '1-up'.
In addition, a conventional driver performs a printing job without authorization even when information on a digital signature is set on an XPS file, causing a problem regarding security.
Moreover, when a printing control terminal device on which an XPS driver is not installed outputs an XPS file through an XPS viewer, the printing control terminal device loses information set on the XPS file.

Printing control terminal device and method of printing XML paper specification (XPS) file


A thin film transistor and a method of fabricating the same capable of reducing stress of a substrate caused by a metal layer of the drain and source electrodes, the thin film transistor including a substrate; a semiconductor layer disposed on the substrate and including source, drain and channel regions; a gate insulating layer disposed on the substrate including the semiconductor layer; a gate electrode disposed on the gate insulating layer to correspond to the channel region of the semiconductor layer; an interlayer insulating layer disposed on the substrate including the gate electrode, and having contact holes connected with the source and drain regions of the semiconductor layer; and source and drain electrodes connected with the source and drain regions through the contact holes, wherein the source and drain electrodes include a first metal layer, a second metal layer, and a metal oxide layer interposed between the first metal layer and the second metal layer. Accordingly, the thin film transistor can reduce stress of the substrate caused by a metal layer of the source and drain electrodes, thereby improving yield of an organic light emitting diode display device.

1. Field of the Invention
An aspect of the present invention relates to a thin film transistor and a method of fabricating the same, and more particularly, to a thin film transistor and a method of fabricating the same, capable of reducing stress of a substrate caused by a metal layer from source and drain electrodes, thus increasing yield of devices when manufacturing the thin film transistor of an organic light emitting diode display device.
2. Description of the Related Art
In general, an organic light emitting diode display device (OLED) includes an anode, an organic emissive layer disposed on the anode, and a cathode disposed on the organic emissive layer. In the OLED, when an electrical current is applied to the anode, a hole is injected into the organic emissive layer from the anode, and an electron is injected into the organic emissive layer from the cathode. The hole and electron injected into the organic emissive layer are recombined in the organic emissive layer to create an exciton, and when such an exciton transitions from an excited state to a ground state, light is emitted.
Generally, the organic light emitting diode display device is classified into a passive matrix type and an active matrix type depending on the manner of driving N×M number pixels disposed in the form of a matrix.
In the active matrix type, a pixel electrode defining an emissive region and a unit pixel circuit for programming current data or voltage data to the pixel electrode are disposed in a unit pixel region. Since the unit pixel circuit includes at least one thin film transistor, the unit pixel circuit supplies a constant current regardless of the number of pixels of the organic light emitting diode display device so that it provides stable luminance and low power consumption characteristics, thereby easily realizing a high-resolution large-size display.
FIG. 1 is a cross-sectional view illustrating a related method of fabricating a thin film transistor of an organic light emitting diode display device.
Referring to FIG. 1, a buffer layer 11 is formed on a substrate 10, and then a semiconductor layer 12 is formed on the buffer layer 11.
A gate insulating layer 13 is formed on the semiconductor layer 12, and a gate electrode 15 is formed on the gate insulating layer 13 to correspond to a predetermined region of the semiconductor layer 12.
Subsequently, impurity ions are injected into the semiconductor layer 12 using the gate electrode 15 as a mask, thereby forming source and drain regions 12a and 12b, and defining a channel region 12c interposed between the source and drain regions 12a and 12b at the same time.
An interlayer insulating layer 16 is formed on the entire surface of the substrate including the gate electrode 15 and then etched to form contact holes 17 exposing each of the source and drain regions 12a and 12b in the interlayer insulating layer 16.
Next, a metal layer for source and drain electrodes is deposited on the interlayer insulating layer 16 and then patterned to thereby form source and drain electrodes 18a and 18b contacting the source and drain regions 12a and 12b, thereby fabricating a thin film transistor.
FIGS. 2A and 2B are cross-sectional views illustrating a related metal layer for source and drain electrodes.
Referring to FIG. 2A, the source and drain electrodes are formed of a metal, such as molybdenum (Mo), tungsten (W), molybdenum-tungsten (MoW) or titanium (Ti), and these metals are formed by sputtering at a high temperature and crystallized to have a regular direction in the shape of a column.
Accordingly, after forming the source and drain metal layers using a metal such as molybdenum, as illustrated in FIG. 2A, the substrate is bent by stress caused by the change in thermal expansion coefficient due to orientation of the metal layer and temperature drop.
Such a phenomenon occurs frequently as the thickness of the substrate becomes thinner. Moreover, when a photoresist is coated on the metal layer to pattern the metal layer, the substrate may be broken.

Thin film transistor and method of fabricating the same