An auto changer is comprised of holders, a movable stocker, a player, a tray, transfer gears, disc detection system, and other parts. A disc is placed on each of the holders, and is loaded into and removed from stocker using the tray together with the holder. The tray is movable while the player is playing back, so that other discs can be loaded and removed. The holder has two holding levers, which hold a disc onto the holder in order to prevent the disc from moving out of position or falling into the unit. When two discs are accidentally placed on the tray and are being loaded into the stocker, the disc detection system detects the two discs and stops the tray in order to prevent damage to the discs or the unit.

1. Field of the Invention
The present invention relates to an auto changer which can store a number of storage media, such as discs, and play back the discs one at a time.
2. Description of the Related Art
In general, an auto changer 10, as shown in FIG. 94, which stores a plurality of storage media, for example, CDs (compact discs) and plays back the stored discs one at a time, is currently used. In the auto changer 10, a stocker 12 which can move vertically and a player 13 for playing back a disc 1 are positioned in a rectangular solid cabinet 11. The stocker 12 can store some discs 1. The player 13 is comprised of a chucking mechanism for discs 1 and an optical pickup. A tray 14 can slide through a portal 14 of the cabinet 11 in order to remove discs 1 from and load discs 1 into the unit.
FIG. 95 shows the order for disc storage and playback operations for the auto changer 10. In the disc storage and playback operations 20, a determination is made whether or not a disc number is specified (in step 421), and when a disc number is specified, a determination is made whether or not a disc 1 is placed on the tray 14 (in step 422).
When a disc 1 is placed on the tray 14, the disc 1 is transferred to a predetermined position in the stocker 12, which is the original position of the disc 1 before the disc 1 was transferred to the tray 14 (in step 423).
The stocker 12 moves so that the storage position of the specified number corresponds to the level of the tray 14 (in step 424), and the disc 1 of the specified number is transferred to the tray 14 (in step 425). In step 425, when there is no disc 1 in the storage position of the specified number in the stocker 12, the same transfer operation as described above is performed. In step 422, when there is no disc 1 in the tray 14, the stocker 12 moves so that the storage position of the specified number corresponds to the level of the tray 14, and the operation described above is performed.
After the disc 1 is transferred in step 425 or when the disc number is not specified in step 421, a determination is made whether or not a tray open/close button has been turned on (in step 426), and a determination is made whether or not a playback button has been turned on (in step 427). Because the tray open/close button and the playback button can not be simultaneously turned on, two of them are checked. For example, when the tray open/close button has been turned on in step 426, the tray 14 is opened (in step 428). A disc 1 can be placed on the opened tray 14.
A determination is made whether or not the tray open/close button has been turned on (in step 429), and when it has been turned on, the tray 14 is closed (in step 430). The presence or absence of a disc 1 on the tray 14 is determined, the determination is displayed (in step 431), and the disc 1 is clamped (in step 432), at which point the disc storage operation is completed.
When the playback button has been turned on in step 427, a determination is made whether or not there is a disc 1 on the tray 14 (in step 433). When there is a disc 1, the playback operation is performed (in step 434). A determination is made whether or not the playback operation is completed (in step 435). When there is no disc 1 on the tray 14 in step 433, the playback operation is completed.
However, with the auto changer 10 currently in use, the disc 1 on the tray 14 is clamped by the chucking mechanism for the playback operation. During the playback operation for the disc 1, the tray 14 cannot be moved, and it is inconvenient for the user who cannot store a disc 1 into the stocker 12 or take out a disc 1 in the stocker 12 during playback.
Further, when the disc 1 is transferred into the player 13 or the tray 14, a push lever which is positioned at the back of the stocker 12 pushes the disc 1 onto the player 13 or the tray 14. Accordingly, space in which the push lever and the other parts are mounted is required, making the unit large.
Moreover, the disc 1 is merely placed on a disc space which is a hollowed area on the tray 14, and when there is a shock or a vibration, the disc 1 may move out of position. In such situation, when the playback operation is performed, the player 13 may clamp the disc 1 out of the appropriate position, damaging the signal recorded area. The disc 1 may also fall inside the unit due to a great shock or vibration, damaging the unit.
Generally, the auto changer 10 plays two kinds of discs, 12 cm discs and 8 cm discs. The mechanism in the unit, for example, the disc area on the tray 14 is designed for the 12 cm disc. Accordingly, when the 8 cm disc is placed on the tray 14, it may easily move out of position and fall inside the unit.
Generally, the auto changer has a sensor which detects the size and the presence or absence of the disc 1. However, when a user accidentally place two discs 1 on the tray 14, the sensor cannot detect both discs 1 and the tray 14 is closed so that the discs 1 are transferred to the stocker 12. Because a compartment in the stocker 12 corresponds to the thickness of one disc 1, one of two discs 1 is not transferred into the stocker 12, remaining at an inappropriate position or falling inside the unit. In this situation, when the stocker 12 is moved or the playback operation is performed, the disc 1 or the unit may be damaged.
Further, when the user accidentally places an 8 cm disc 1b on a tray 14 for a 12 cm disc 1a, the sensor may detect the disc 1 which is being transferred into the unit. However, because the mechanism in the unit, for example, the disc space which is a hollowed area on the tray 14 is designed for a 12 cm disc 1a, the storage operation and the playback operation cannot be correctly performed. In such situation, the disc 1b may move out of position or fall inside the unit, and the problem described above arises.
Moreover, when the power supply to the unit is stopped during operation, the auto changer 10 cannot later recognize the positions of the disc 1, the tray 14, and the stocker 12. When a disc 1 is positioned between the tray 14 and the stocker 12 and the power is supplied again, the stocker 12 moving up or down, may collide with the disc 1 positioned between the tray 14 and the stocker 12, so that the disc 1 may be damaged or fall inside the mechanism, or the unit may damaged.
Moreover, when the data for the storage status is lost due to an electricity failure, a disc 1 on the player 13 may be transferred to a compartment in the stocker 12 where another disc 1 is already stored, during the next operation. In this situation, the disc 1 which was set on the player 13 pushes the other disc 1 stored in the stocker 12, and both of the two discs 1 may be damaged.
Moreover, when a disc 1 in the stocker 12 is played back, the stocker 12 moves up or down in order to transfer the selected disc 1 to the level of the player 13, and the disc 1 is transferred to the player 13 by an appropriate transfer means. When the disc 1 is played back or when the unit is turned off, the stocker 12 remains at that position.
However, when the stocker 12 remains in such position and there is a shock or a vibration, the stocker 12 may fall, and the stocker 12 or the discs 1 stored in the stocker 12 may be damaged.
Moreover, when there is a shock or a vibration, the disc 1 may move out of the player 13 or fall from the stocker 12 onto the player 13, and the unit may be damaged due to such disc 1.


A carbanionic polymer chain that contains polyene mer can be provided with a terminal functionality separated from the polymer chain by a sulfide linkage. The terminally functionalized polymer can be provided by reacting a carbanionic polyene-based polymer with an episulfide compound to provide a polymer with a terminal thiolate moiety, followed by reaction with an epoxide compound that also includes at least one other heteroatom-containing functional group.

Rubber goods such as tire treads often are made from elastomeric compositions that contain one or more reinforcing materials such as, for example, particulate carbon black and silica; see, e.g., The Vanderbilt Rubber Handbook, 13th ed. (1990), pp. 603-04.
Good traction and resistance to abrasion are primary considerations for tire treads; however, motor vehicle fuel efficiency concerns argue for a minimization in their rolling resistance, which correlates with a reduction in hysteresis and heat build-up during operation of the tire. Reduced hysteresis and traction are, to a great extent, competing considerations: treads made from compositions designed to provide good road traction usually exhibit increased rolling resistance and vice versa. Filler(s), polymer(s), and additives typically are chosen so as to provide an acceptable compromise or balance of these properties. Ensuring that reinforcing filler(s) are well dispersed throughout the elastomeric material(s) both enhances processability and acts to improve physical properties. Dispersion of fillers can be improved by increasing their interaction with the elastomer(s).
Certain tests have come to be recognized as correlating certain physical properties of vulcanizates with performance of products, particularly tire treads, made therefrom. For example, higher rebound values and lower loss tangent values (tan δ) at high temperatures have been found to correlate with reductions in heat build-up during operation (hysteresis), higher elastic modulus values at high temperature and strain with better handling performance, and lower modulus values at low temperatures with wet, snow and ice traction. (In the foregoing, "high temperatures" usually are considered to be from ˜50° to ˜65° C. while "low temperatures" from ˜0° to −25° C.)
The section of a polymer chain from the site of the last crosslink to an end of the polymer chain is a major source of hysteretic loss; because a free end is not tied to the macromolecular network, it cannot be involved in an efficient elastic recovery process and, as a result, energy transmitted to this section of the polymer (and vulcanizates in which such a polymer is incorporated) is lost as heat. Ensuring that polymer chain ends are tied to, or otherwise interact well with, reinforcing particulate fillers, is important to many vulcanizate physical properties such as, for example, reduced hysteresis. Chemically modifying the polymer, typically at a terminus thereof, is an effective way of increasing interactivity of fillers and polymers.
Sequential reaction sequences employing siloxanes to provide living polymers with terminal functionality have been described in U.S. Pat. No. 8,063,153 and international patent publ. no. WO 2012/092595. The former also describes that an episulfide compound can be used in place of the cyclic siloxane in the first step of the sequential termination process.

Method of making a functionalized polymer with sulfide linkage


Rigid signs are prepared by a facile method of fixing an image to a rigid substrate coated with a thermally tackifiable coating. The image is readily produced through the use of a computer graphics program, and the image is printed onto a transfer film using a conventional computer printer. The image-bearing surface of the transfer film is then joined in pressing contact with the thermoplastic coating which has been warmed to a softened or tacky state. Upon cooling the thermoplastic coating to a hard, durable state, the transfer film is removed leaving the image securedly affixed to the rigid substrate.

This invention relates to signs. In one aspect, the invention relates to a method of producing a sign by fixing an image to a rigid substrate while in another aspect, the invention relates to a method in which the image is first printed by electrophotography onto a transfer film in an optically reversed manner and the rigid substrate is coated with a thermally tackifiable substance. In yet another aspect, the invention relates to a method for producing small batches of rigid signs in a facile, quick and inexpensive manner.
Rigid signs comprise an image carried on an inflexible substrate. Such signs are often used in an outdoor setting in which durability of the image is an important quality of the sign.
Rigid signs are typically produced in low volumes, e.g. less than 100 signs at a time, and are typically made by a silk screen printing process. While this process produces rigid signs with acceptable quality, silk screening is not cost effective for small production runs. Silk screening is time consuming and by its very nature, precludes quick order completion. At the moment, a good method does not exist for the rapid preparation of small volume production runs of surface-printed rigid signs.

Method of fixing an image to a rigid substrate


A bicycle shift control device includes a housing, at least one operating lever, a rotatable member, a flexible elongated member, and a gear indicator portion having a window. The rotatable member has a guide member and is disposed within the housing. The rotatable member is configured to rotate in response to movement of the at least one operating lever. The flexible elongated member has a first end portion and a second end portion. The first end portion is connected to the rotatable member for movement therewith and extends at least part-way along the guide portion of the rotatable member. The second end portion is configured for movement along the gear indicator portion with at least a tip of the second end portion of the flexible elongated member being visible through the window of the gear indicator portion.

1. Field of the Invention
This invention generally relates to a bicycle shift control device. More specifically, the present invention relates to bicycle shift control device that includes a gear indicator portion.
2. Background Information
Bicycling is becoming an increasingly more popular form of recreation as well as a means of transportation. Moreover, bicycling has become a very popular competitive sport for both amateurs and professionals. Whether the bicycle is used for recreation, transportation or competition, the bicycle industry is constantly improving the various components of the bicycle. One component that has been extensively redesigned is the bicycle shift control device and gear indicator mechanisms (gear indicator portions).
In recent years, many bicycle shift control devices have included a gear indicator portion providing a cyclist with an indication of the current status of the gears. Specifically, an indicator informs the cyclist of the orientation of the chain relative to the chain rings or sprockets of the front and rear sprockets sets.
Many such gear indicator portions are separate units mounted to the handlebar of the bicycle connected to the bicycle shift control device by a cable or cables. Such configurations can be unattractive. Specifically, too much is mounted to the handlebar of the bicycle. Other configurations include a pin indicator or rotary device built into the bicycle shift control device. Such devices can be complex making them difficult to manufacture and difficult to adjust.
In view of the above, it will be apparent to those skilled in the art from this disclosure that there exists a need for an improved bicycle shift control device that includes a simple gear indicator portion. This invention addresses this need in the art as well as other needs, which will become apparent to those skilled in the art from this disclosure.


A method for analyzing an image recorded by a camera of a vehicle. The method includes a step of reading the image of the camera. Furthermore, the method includes a step of recognizing at least one object in a subsection of the image, the subsection imaging a smaller area of the vehicle surroundings than the image. Furthermore, the method includes a step of transmitting the subsection and/or information about the subsection of the image to a driver assistance module. Finally, the method includes a step of using the subsection of the image and/or the information about the subsection of the image instead of the entire image in the driver assistance module, in order to analyze the image recorded by the camera.

The growing complexity of the demands on the various video-based systems in vehicles requires a necessary "cooperation" of the individual systems with one another. Thus, for example, information of lane recognition may be used for online calibration; the result of the vehicle detection may be used to reduce the number of incorrect classifications in the system for traffic sign recognition, which are caused by speed signs on trucks, for example. The number of cooperations, which are only mentioned here as examples, between various systems may be expanded arbitrarily.
A method for lane detection using a driver assistance system of a vehicle, which includes a sensor system for lane recognition, is described in German Patent Application No. DE 10 2007 034 196 A1, in which measuring points representing lane markings are detected using the sensor system for lane recognition in an area of a traffic space located ahead of the vehicle. An ideal number of measuring points MP is ascertained based on a reference model. A degree of plausibility of the look-ahead range is determined from a comparison between the number of the actually detected measuring points and the ideal number of measuring points.

Method for analyzing an image recorded by a camera of a vehicle and image processing device


A voltage controller has an electrically insulating supporting structure provided with a plurality of electrical connecting terminals. At least one of the terminals has a flexible blade of elongate shape which protrudes inside the structure where a distal end portion of the blade is connected to a circuit housed therein. The supporting structure has a protective formation with at least one strip which has a shape corresponding to that of the blade and which extends in superimposition on this blade.

More specifically, the invention proposes a voltage controller of the type comprising a supporting structure of electrically insulating material, at one end of which there is provided a plurality of electrical connecting terminals, at least one of which comprises a flexible blade of elongate shape which protrudes inside said structure where a distal end portion of the blade is connected to a circuit housed therein.
One problem with this type of arrangement is that the flexing of the flexible blade is not controlled during assembly which can lead to imprecise positioning of the blade requiring additional solder to ensure a good electrical connection.

Voltage controller for an electric cooling fan


Disclosed is a method for manufacturing an organic EL display panel in which a plurality of organic electroluminescence elements each including an organic layer are arranged on an upper side of a substrate. The method includes applying an ink obtained by dissolving or dispersing an organic material in a solvent to a preset application area over the substrate, and cooling the ink applied in the applying within a period until the ink is dried, to lower an ink temperature to a second temperature lower than a first temperature of the ink at a time of application thereof.

The present disclosure relates to a method and apparatus for manufacturing an organic electroluminescence (EL) display panel, more particularly to a technology for forming an organic layer in a film thickness as uniform as possible by an applying (coating) system.
In recent years, developments of an organic EL display panel utilizing light emission by organic EL elements have been made vigorously. The organic EL element includes pixel electrodes (lower electrodes) on a pixel basis, organic functional layers including an organic light emitting layer, and a counter electrode (upper electrode) common for a plurality of organic EL elements, which are sequentially provided over a substrate, and holes and electrons supplied from the pixel electrodes and the counter electrode are recombined in the organic light emitting layer, whereby an organic light emitting material emits light.
Hitherto, the organic light emitting layer in the organic EL display panel has often been formed by a dry process such as vacuum deposition. In recent years, however, attendant on the progress of applying (coating) technology, a technology of forming the organic light emitting layer by a wet process has been spreading.
The wet process is a process in which a solution obtained by dissolving or dispersing an organic light emitting material in an organic solvent (the solution will hereinafter be referred to simply as "ink") is applied to required parts by an applying (coating) device, and is dried to form the organic light emitting layer. The wet process is advantageous on a cost basis in that equipment cost can be suppressed, even in the case of manufacturing a large-type organic EL display panel, and material utilization factor is high.
Examples of the related-art documents include Japanese Patent Laid-Open Nos. 2010-97956, 2012-209138, 2014-225432, and 2010-115577.
However, in order to define pixels while avoiding mixing of inks containing different organic light emitting materials, banks are provided on a substrate. If an ink is applied to an application area surrounded by the banks and is dried as it is, the ink portions in contact with side surfaces of the banks would rise, and a central portion of the organic light emitting layer would be formed in a recessed shape. Thus, it is difficult to make uniform the film thickness of the organic light emitting layer formed inside of the banks.
Therefore, uniformity of light emission in the pixel of the organic light emitting layer may be spoiled, possibly leading to a lowering in light emitting efficiency, deterioration of image quality, and a shortening of the useful life of the organic EL display panel itself.
This problem can be generated in the formation of not only the organic light emitting layer but also other organic layers such as a hole injection layer, a hole transport layer, an electron transport layer, and an electron injection layer, by the wet process.

Method and apparatus for manufacturing organic el display panel


Methods and systems are provided for modifying an application provided by a cloud-based computing system. The application is used by end users of an organization that is part of the cloud-based computing system. A clickstream monitoring module monitors a clickstream generated by each end user as that end user interacts with the application to generate a set of clickstream data for that particular end user. Each set of clickstream data indicates a path of interaction with features of the application by a particular end user. The sets of clickstream data can then be processed at an analytics engine to extract usage patterns that indicate how end users interact with different features of the application during usage of the application. The extracted usage patterns indicate which features the end users interact with and in what order. An artificial intelligence engine can then generate, based on the extracted usage patterns, at least one recommendation for modifying one or more features of the application to tailor the application for use by the end users in view of the extracted usage patterns.

Today many enterprises now use cloud-based computing platforms that allow services and data to be accessed over the Internet (or via other networks). Infrastructure providers of these cloud-based computing platforms offer network-based processing systems that often support multiple enterprises (or tenants) using common computer hardware and data storage. "Cloud computing" services provide shared resources, software, and information to computers and other devices upon request. In cloud computing environments, software can be accessible over the Internet rather than installed locally on in-house computer systems. This "cloud" computing model allows applications to be provided over a platform "as a service" supplied by the infrastructure provider. The infrastructure provider typically abstracts the underlying hardware and other resources used to deliver a customer-developed application so that the customer no longer needs to operate and support dedicated server hardware. Cloud computing typically involves over-the-Internet provision of dynamically scalable and often virtualized resources. Technological details can be abstracted from the users, who no longer have need for expertise in, or control over, the technology infrastructure "in the cloud" that supports them. The cloud computing model can often provide substantial cost savings to the customer over the life of the application because the customer no longer needs to provide dedicated network infrastructure, electrical and temperature controls, physical security and other logistics in support of dedicated server hardware.
Multi-tenant cloud-based architectures have been developed to improve collaboration, integration, and community-based cooperation between customer tenants without compromising data security. Generally speaking, multi-tenancy refers to a system where a single hardware and software platform simultaneously supports multiple organizations or tenants from a common data storage element (also referred to as a "multi-tenant database"). The multi-tenant design provides a number of advantages over conventional server virtualization systems. First, the multi-tenant platform operator can often make improvements to the platform based upon collective information from the entire tenant community. Additionally, because all users in the multi-tenant environment execute applications within a common processing space, it is relatively easy to grant or deny access to specific sets of data for any user within the multi-tenant platform, thereby improving collaboration and integration between applications and the data managed by the various applications. The multi-tenant architecture therefore allows convenient and cost-effective sharing of similar application feature software between multiple sets of users.
In general, businesses use a customer relationship management (CRM) system (also referred to as a database system or system) to manage business relationships and information associated with the business relationship. For example, a multi-tenant system may support an on-demand CRM application that manages the data for a particular organization's sales staff that is maintained by the multi-tenant system and facilitates collaboration among members of that organization's sales staff (e.g., account executives, sales representatives, and the like). This data may include customer and prospect contact information, accounts, leads, and opportunities in one central location. The information may be stored in a database as objects. For example, the CRM system may include "account" object, "contact" object and "opportunities" object.
There is often a disconnect between how applications are developed on platforms and how end users interact with those applications. In many cases developers fail to understand how their end users will actually use the application. For example, while developers and administrators can go to great lengths to provide prescriptive guidance on how a record should be populated, how end users interact with these applications is sometime not understood. For instance, a large number of sales users may only complete the same four fields on a 15-field record. The additional fields on the record are considered "nice to have" by the application development team, but the sales users find them to be unnecessary when creating sales records. In order to build more useful applications, administrators and developers must be in the mindset of their end users. When this is not feasible they must rely on other methods for application development or seek the recommendations of consulting partners.

Methods and systems for automated, intelligent application process development that recommend how to modify applications based on usage patterns of end users


An optical medium, such as fiber, is tapped to provide an antenna port wherever radio service coverage is desired. Each antenna port is a bi-directional remote unit that receives a digital optical signal from a host unit and transforms the signal to a radio frequency signal for transmission by the remote unit. The remote unit receives radio frequency signals that are converted to digital signals and summed with signals from other remote units and converted to an optical signal for transmission to the host unit.

Various types of wireless communication systems have become prevalent around the world. For example, cellular communication systems cover most major metropolitan areas as well as major highways through remote areas. Cellular systems permit individuals with cellular handsets to communicate with base stations that are connected to the public switched telephone network (PSTN) or some other communication network.
As with any communication system, cellular systems can leave coverage "holes" where the signal from the base stations cannot reach. The holes can be in tunnels, valleys, city streets between tall buildings, or any other location where a radio frequency (RF) signal is blocked.
Placing additional base stations where these coverage holes are located is not always an option. Base stations tend to be very expensive due not only to the cost of the equipment but also because of land acquisition costs. Additionally, large base station antennas may not fit within an area either physically or aesthetically.
One solution to hole coverage is to use smaller remote antennas where coverage is needed but a base station is not warranted or desired. One problem with remote antennas, however, is that coaxial cable cannot be run long distances due to attenuation. Remote antennas are difficult to install along a highway or through a tunnel due to this attenuation problem. Using repeaters may not be an option since this only adds to the expense and complexity of the system. There is a resulting need in the art for a distributed antenna system that does not suffer from attenuation problems.


The present invention provides a method for treating Hemophilia A or B which comprises implanting in fluid communication with the bloodstream of a mammal in need of such treatment a permeable membrane having one or more walls, a hollow chamber therewithin, a plurality of holes extending through the walls of the membrane and permitting fluid to enter and exit the chamber of the membrane, each of the holes being sized so that it is large enough to permit inactive Factor VII to enter the chamber of the membrane and activated Factor VIIa to exit the chamber of the membrane but small enough to prevent fibrinogen from entering the chamber of the membrane, a plurality of supports being disposed within the chamber, and an effective amount of a Factor VII activator or a source of the activator being bound to the supports, wherein inactive Factor VII in blood passing through the membrane becomes activated into Factor VIIa upon contact with the activator within the chamber.. The present invention also provides a method for treating Hemophilia A or B extracorporeally. The present invention further provides methods for treating AIDS as well as permeable membranes for use in the methods above.

Hemophilia A and B are due to a deficiency of Factor VIII and IX, respectively. These factors are required in concert to activate Factor X to Factor Xa by the intrinsic pathway, EQU X+(VIIIa, IXa, phospholipid, CA.sup.++).fwdarw.Xa. (1)
The treatment of choice for these disorders is presently replacement therapy, and is the basis of a one billion dollar per year business worldwide.
Very recently, recombinant Factor VIIa (NOVO, Denmark) has been shown to have therapeutic value for Hemophilia A and B in dogs (Brinkhaus, KM et al. (1989) Proc. Nat. Acad. Sci. (USA) 86:1382-1386), and trials with humans have been initiated (Hadner, U. et al. (1988) Lancet II, 1193; Macik, RG et al. (1988) Blood 72:302a (Abstract 1117)). The mechanism by which Factor VIIa is therapeutic seems to be by direct activation of Factor X to Xa, which then feeds back and activates additional Factor VII to VIIa (Rao, LVM and Rapaport, EI (1990) Blood 5:1069-1073). Both the recombinant (r-) Factor VIIa and the newly generated VIIa then bind to exposed Tissue Factor, and together this complex activates X to Xa by the extrinsic pathway, EQU X+(TF/VIIa, phospholipids, CA.sup.++).fwdarw.Xa. (2)
The extrinsic pathway in hemophilia patients is normal, but since all of Factor VII is in the inactivated state, little or no activation of the extrinsic pathway occurs when needed. Apparently, the intrinsic pathway is needed for tonic activation of Xa and generation of VIIa. The relative rate of conversion of X to Xa by VIIa alone is 15 million-fold less than the rate observed when VIIa is complexed with Tissue Factor (Bom, VJJ and Bertina, RM (1990) Biochem. J. 265:327-336). Nonetheless, the small amount of Xa generated by the administration of r-Factor VIIa is sufficient to reduce bleeding in afflicted patients.
A critical problem yet to be solved is the fact that r-Factor VIIa itself has a short half-life (about 2 hours). This means that sustained, exogenous replacement of this material would be necessary for treating patients. The present invention avoids the need for exogenous replacement (e.g. hourly or daily therapy in the case of accident, or preventive therapy in the event of dental or surgical procedures (Hadner, U. et al. (1988) Lancet II, 1193)) by employing the patient's own Factor VII to generate activated Factor VII (Factor VIIa).
Treatment of human immunodeficiency virus (HIV-1) infection, and of the acquired immunodeficiency syndrome (AIDS), has been developing slowly since the burst of activity culminating in 1988 (see Gallo and Montagnier Scientific American 259 (4): 41-48 (1988); Weber and Weiss Scientific American 259 (4): 101-109) (1988).
The principle targets of the HIV virions are the T-4 type T lymphocytes. The virus attaches itself through interaction between envelope gp120 molecules (McKeating, J. A. and R. A. Wiley AIDS 3 (Surpl. 1) S35-41 (1989); Kieber-Emmons, et al. Biochem.Biophys.Acta. 989:281-300 (1991); Gelderblom, H. R. AIDS 5:617-638 (1991); and Capon, D. J. and R. H. R. Ward Ann.Rev.Immunl. 9:649-678) (1991)), and the CD4 receptor molecules on the cell surface (Sweet, R. W., et al. Curr. Opin. in Biotechnol. 2:622-633 (1991); Grewe, C., et al. J. Acquired Immun. Def. Syndrome 3:965-974 (1990)). The bound virus then enters the cell by fusing with the cell membrane (Dalgleish, A. G., et al. Nature 312:763-767 (1984); Sattenau, Q. J. and Weiss, R. A. Cell 52:631-632 (1984); Robey E. and R. Axel Cell 60:697-700 (1990)). HIV also can enter and reside in macrophages and some neurons, since these cells also express the CD4 receptor on the cell surface (Maddon, P. J., et al. Cell 47:333-348 (1986) and Cheng-Mayer, C. AIDS 4 (Suppl. 1) 549-556 (1990)). AIDS-associated subcortical dementia may begin by the latter mechanism. The CD4 receptor also resides on enterochromaffin cells in the gastrointestinal tract, and may be the reason for the persistent diarrhea which affects 80% of AIDS patients (see descriptions in the American College of Gastroenterology Meeting Highlights, 1990, p. 1 and 6).
Since the CD4 receptor provides the mechanism for specific HIV infection, an attractive strategy has involved possible administration of free r-CD4 receptor or specific subdomains of the receptor (Arthos, J., et al. Cell 57:469-481 (1989) and Sweet, R. W., et al. Curr. Opin. in Biotechnol. 2:622-633 (1991)) to AIDS patients. According to this concept, the freely diffusing CD4 molecules would bind to gp120 sites on the virion surface, and thus save cells with resident CD4 receptors from certain infection. The soluble, secreted form of CD4 also has been shown to block HIV-1 infectivity in vitro (Smith, et al. Science 238: 1704-1707 (1987)). Recombinant CD4 (rCD4) also has been prepared by a number of pharmaceutical houses and Universities, including Genentech, Biogen NV, Columbia University, Smith-Kline-Beachum, the Dana-Farber Cancer Center, and the Basel Institute for Immunology (Yarchoan, et al. Scientific American 259: 110-119 (1988)). However, the large doses of rCD4 necessary to sustain continuous administration rapidly outrun available material. In addition, and perhaps more importantly, since free CD4 molecules bind to Class II major histocompatibility (MHC) antigens on cells (Fleury S., et al. Cell 66:1037-1049 (1991)), its use further compromises the immune system beyond that caused by HIV alone (Weber, J. N. and Weiss, R. A. Scientific American 259:101-109 (1988)).
The present invention avoids the problems associated with continuous administration of free rCD4 by keeping the CD4 molecules in contact with body fluids but out of contact with cells which bind to the CD4 molecules.
Buonocore, L. and Rose, J. K. described the production of soluble CD4. The CD4 was mutated with a signal which caused the protein to be retained in the lower endoplasmic veticulum (ER) (Buonocore, L. and Rose, J. K., Nature, 345, 625 (1990)). This was found desirable because gp160, the HIV envelope protein precursor, and CD4 bind efficiently in the ER. Buonocore and Rose hypothesized that if CD4 was permanently retained in the ER, it might again block the transport of gp160 to the cell surface. They also hypothesized that a gene expressing the mutated CD4 could be used as gene therapy on AIDS patients. Buonocore and Rose, however, did not teach or suggest a practical method or apparatus by which to utilize CD4.
U.S. Pat. No. 5,109,123, issued Apr. 28, 1992 to Reinherz, et al., described modified human CD4 fragments and their use for diagnostic, therapeutic and preventive purposes. For treatment, Reinherz, et al. disclosed the administration of free modified human CD4 fragments. For preventive purposes, Reinherz, et al. described attaching the CD4 fragments to condoms, spermicides, surgical gloves, and containers or other material for receiving, processing, or storing blood.
Sullivan, et al. described the implementation of artificial pancreas in dogs for administering insulin. (Sullivan et al. Science, 252, 718 (1991)). The artificial pancrea incorporated pancreatic islet tissue from healthy dogs and an acrylic housing with a permeable membrane within. The Sullivan, et al. device was connected to the vascular system by graft allowing blood to flow continuously through the device and across the tubular membrane where insulin was released.

Methods for treating hemophilia A and B and AIDS and devices used therein


In a metal ring for a metal belt of a belt type continuously variable transmission, a relationship is established between a compressive residual stress of a metal ring of an innermost layer imparted by a nitriding treatment and a free state radius of the metal ring nondimensionalized by a minimum winding radius. In the relationship, the sum of a compressive residual stress acting on the inner peripheral face of the metal ring, a compressive stress due to flexure and a contact stress does not exceed the elastic deformation limit of the metal ring. The maximum compressive stress of the metal ring does not become excessive, and an abrasion resistance of the surfaces of the metal ring is guaranteed.

1. Field of the Invention
The present invention relates to a metal ring of a metal belt used in a belt type continuously variable transmission, wherein a free state radius of the metal ring, when cut, is set to increase the fatigue life of the metal ring.
2. Description of the Related Art
A metal belt used in a belt type continuously variable transmission includes a metal ring assembly formed by layering a plurality of metal rings on top of each other, and a plurality of metal elements supported along the metal ring assembly. Tensile stress and compressive stress due to flexure, as well as tensile stress due to tension, act on each metal ring. Specifically, in a wound section wherein the metal ring is wound around a pulley, an outer peripheral face of the metal ring is pulled, and a tensile stress acts thereon. At the same time, an inner peripheral face of the metal ring is compressed, and a compressive stress acts thereon. In a chord section where the metal ring is separated from the pulley, the outer peripheral face of the metal ring is compressed, and a compressive stress acts thereon. At the same time, the inner peripheral face thereof is pulled, and a tensile stress acts thereon. In this way, the stress acting on the inner and the outer peripheral faces periodically varies with the rotation of the metal ring such that the fatigue life of the metal ring deteriorates.
Japanese Patent Application Laid-open No. 2003-126933 discloses an arrangement in which a free state radius Ro of the metal ring is set so that, in a TOP ratio state in which the metal ring receives the most severe load, a corrected stress amplitude σao′ (a stress amplitude σao when a stress center σmo=0) on the outer peripheral face of the metal ring, calculated from the stress amplitude σao and the stress center σmo on the outer peripheral face, coincides with a corrected stress amplitude σai′ (a stress amplitude σai when a stress center σmi=0) on the inner peripheral face of the metal ring calculated from the stress amplitude σai and the stress center σmi of the inner peripheral face.
The inner peripheral face of the metal ring, that is, the innermost layer of the plurality of stacked metal rings, abuts a saddle face of a metal element, which is a transverse element of the metal belt. Accordingly, the maximum compressive stress on the inner peripheral face of the metal ring increases by an amount corresponding to a compressive stress (contact stress) acting on the abutment section. Therefore, during operation of the belt type continuously variable transmission, if the sum of a residual compressive stress of the metal ring due to a nitriding treatment, a compressive stress due to flexure, and a contact stress due to contact of the metal element with the saddle face becomes excessive and exceeds an elastic deformation limit, the metal ring plastically deforms and becomes vulnerable to breaking. The arrangement disclosed in Japanese Patent Application Laid-open No. 2003-126933 does not take into account either the contact stress due to contact with the saddle face acting on the inner peripheral face of the metal ring of the innermost layer, or the relationship between the maximum compressive stress and the elastic deformation limit of the metal ring, leading to a possibility that the life of the metal ring might not be increased as desired.


A new poinsettia plant particularly distinguished by having white colored bracts, medium earliness, a small, thin stem diameter, and small cyathia, is disclosed.

The present invention comprises a new and distinct variety of poinsettia, botanically known as Euphorbia pulcherrima and hereinafter referred to by the variety name 'NPCW13211'. 'NPCW13211' was derived as a selection of a single, white plant among a population derived from irradiated cuttings of the poinsettia CHRISTMAS FEELINGS™ 'Marble' (unpatented), having white bracts with pink centers.
In November 2010, a single white plant was selected in Stuttgart, Germany from irradiated lines of poinsettia CHRISTMAS FEELINGS™ 'Marble'. In February 2011, 'NPCW13211' was first asexually propagated by vegetative cuttings. 'NPCW13211' was found to reproduce true to type in successive generations of asexual propagation via vegetative cuttings in Stuttgart, Germany.


A frame size regulating circuit capable of simultaneously controlling horizontal and vertical sizes to simply vary a frame size includes a key matrix formed by plural keys for simultaneously varying horizontal and vertical sizes of a frame, and a microprocessor which generates plural pulsewidth modulation signals for determining the frame size according to an externally-supplied horizontal sync signal and vertical sync signal and scans a key selected in the key matrix to generate plural frame size variation signals. A frame size determinator part provides a horizontal size determination signal of DC component and a vertical size determination signal of DC component according to the plurality of pulsewidth modulation signals, and a frame size variable part varies magnitudes of the horizontal size determination signal of DC component and of the vertical size determination signal of DC component according to the plural frame size variation signals to vary the size of the frame. Thus, the frame size is simply varied by the key selection of the key matrix.

1. Field of the Invention
The present invention relates to a monitor, and more particularly to a frame size regulating circuit for simultaneously controlling horizontal and vertical sizes of a frame.
2. Description of the Prior Art
Horizontal and vertical sizes of a frame displayed on a CRT of a monitor are determined by externally-supplied horizontal and vertical sync signals.
A conventional frame size regulating circuit of such kind is as illustrated in FIG. 1. Referring to FIG. 1, a reference numeral 1 denotes a microprocessor for providing pulsewidth modulation signals PWM1 and PWM2 for controlling horizontal and vertical sizes in accordance with input horizontal and vertical sync signals Hs and Vs; and 2 is a horizontal size determinator part for shaping and amplifying pulsewidth modulation signal PWM1 to produce a horizontal size determination signal of DC component. A reference numeral 3 denotes a mixer for overlapping the horizontal size determination signal with an externally-supplied distortion correction signal GD, and providing the overlap signal to an unshown diode modulator. A reference numeral 4 denotes a vertical size determinator part for shaping pulsewidth modulation signal PWM2 to provide a vertical size determination signal of DC component; and 5 is a deflection circuit for overlapping the vertical size determination signal with horizontal and vertical sync signals Hs and Vs to provide a deflection signal of triangular waveform.
Horizontal size determinator part 2 is formed by a shaping part 2a for shaping pulsewidth modulation signal PWM1 and an amplifying part 2b for amplifying a DC voltage of shaping part 2a.
Shaping part 2a includes a resistor 21 for biasing pulsewidth modulation signal PWM1, and resistors 23 and 25 which are serially connected with each other for distributing an externally-supplied DC power source Vcc and are connected to the output side of resistor 21 for overlapping a distribution voltage with an output voltage of resistor 21. Also, a resistor 27 biases the overlap signal and a capacitor 29 smooths a bias signal of resistor 27 for providing the DC voltage.
Meantime, amplifying part 2b includes an amplifier 31 for amplifying the DC voltage of shaping part 2a, and resistors 33 and 35 respectively connected between the output side and between the (-) port of amplifier 31 and the (-) port of amplifier 31 and a ground for determining an amplification factor of amplifier 31.
Vertical size determinator part 4 is formed by resistors 41, 43, 45 and 47 and a capacitor 49 which are identical to shaping part 2a of horizontal size determinator part 2.
When horizontal and vertical sync signals Hs and Vs are supplied into microprocessor 1 in the conventional frame size regulating circuit as described above, microprocessor 1 generates pulsewidth modulation signals PWM1 and PWM2 corresponding to horizontal and vertical sync signals Hs and Vs, in which pulsewidth modulation signal PWM1 is supplied to shaping part 2a of horizontal size determinator part 2.
Shaping part 2a shapes pulsewidth modulation signal PWM1 to provide the DC voltage which is in turn supplied to amplifying part 2b. Then, amplifying part 2b amplifies the DC voltage to provide the horizontal size determination signal of DC component.
The operation of horizontal size determinator part 2 which provides the horizontal size determination signal of DC component from pulsewidth modulation signal PWM1 will be described in more detail with reference to FIG. 2. Pulsewidth modulation signal PWM1 is supplied to resistor 21 of shaping part 2a, and resistor 21 biases pulsewidth modulation signal PWM1.
DC power source Vcc is supplied to resistors 23 and 25 which distribute DC power source Vcc and overlap the distribution voltage with the bias signal of resistor 21. The overlap signal is supplied to resistor 27 which biases the overlap signal. The bias signal of resistor 27 is supplied to capacitor 29 which then smooths the bias signal to produce the DC voltage.
The DC voltage is supplied to the (+) port of amplifier 31 in amplifying part 2b, and amplifier 31 amplifies the DC voltage to provide the horizontal size determination signal of DC component. At this time, the amplification factor of amplifier 31 is determined by resistors 33 and 35.
The horizontal size determination signal is supplied to mixer 3 which in turn overlaps the horizontal size determination signal with distortion correction signal GD. The resulting overlap signal is supplied to the diode modulation.
On the other hand, pulsewidth modulation signal PWM2 of microprocessor 1 is supplied to vertical size determinator part 4. Then, vertical size determinator part 4 shapes pulsewidth modulation signal PWM2 to generate the vertical size determination signal of DC component. Here, the procedure of generating the vertical size determination signal of DC component from pulsewidth modulation signal PWM2 is the same as executed by shaping part 2a of horizontal size determinator part 2 in which the DC voltage is generated from pulsewidth modulation signal PWM1.
Thus, the vertical size determination signal of DC component is supplied to deflection circuit 5 which overlaps the vertical size determination signal of DC component with the horizontal and vertical sync signals Hs and Vs. Thereafter, the overlap signal is oscillated to generate the deflection signal of triangular waveform.
In the frame size regulating circuit as described above, however, the horizontal and vertical sizes of the frame is determined at the initial time in accordance with the horizontal sync signal and vertical sync signal, and the initially-determined frame size cannot be simultaneously reduced nor enlarged as desired.


Design structures, method and systems of powering on an integrated circuit (IC) are disclosed. In one embodiment, the system includes a region in the IC including functional logic, a temperature sensor for sensing a temperature in the region when the IC is powered up and a heating element therefor; a processing unit including: a comparator for comparing the temperature against a predetermined temperature value, a controller, which in the case that the temperature is below the predetermined temperature value, delays functional operation of the IC and controls heating of the region of the IC, and a monitor for monitoring the temperature in the region; and wherein the controller, in the case that the temperature rises above the predetermined temperature value, ceases the heating and initiates functional operation of the IC.

1. Technical Field
The disclosure relates generally to integrated circuits (ICs), and more particularly, to design structures, method and systems of powering on an integrated circuit (IC).
2. Background Art
Use of integrated circuits (IC) is ubiquitous. While the potential markets for products derived from a semiconductor technology have increased, so have the costs associated with bringing a semiconductor circuit family and/or IC to market. Use of today's IC technologies in such a diverse product set has forced an increase in operational temperature range from 0° C. to 100° C. in prior technologies to a wider temperature range from −55° C. to 125° C. in present technologies. For a typical present generation semiconductor technology, this temperature envelope expansion results in a change in the temperature-driven threshold voltage (Vt) variance of transistors from less than 70 millivolts to greater than 125 millivolts. The increase in Vt variance coupled with the scaling of supply voltage at a greater rate than Vt in succeeding technologies may result in circuits with functionality problems or poor performance characteristics over one or more process/voltage/temperature extremes. Traditionally, in the circuit design process, these functionality and performance problems result in substantial increases in design time, cost and risk and may add weeks to months to the design cycle for complex circuit functions.
Furthermore, the cost of supporting a wide temperature range does not stop at circuit design level, but continues to add cost and schedule delay in the design of the ICs which utilize the circuits. Here, support for a wide temperature range puts pressure on timing closure of critical paths within the IC, forcing iterative synthesis/optimization, circuit placement and routing. Colder temperatures speed semiconductor performance which stresses hold time specifications in which the time data must remain valid after a clock edge has locked the data into a sequential latch element. Chip-level designers are required to correct hold-time problems by adding additional buffering delays in the logic path to slow the data arrival at the sequential element. While necessary to prevent early-mode timing problems, these buffers consume space and power, and in some instances, cause timing problems during closure under worst case process/voltage/temperature conditions. In many cases resolving chip-level timing issues caused by increases in the temperature envelope may result in a final IC that operates at higher power and is larger, and as a result more costly to manufacture than an IC without the requirement of a wide operational temperature range.
While the high side of the temperature range is often set by the anticipated power density of ICs manufactured in a technology and the thermal limitations of semiconductor packaging, the low side of the temperature range is most often set by the external environment temperature at the moment the IC is powered-on, which is outside the control of the circuit, IC or system designer.

This patent is subject to a terminal disclaimer.

Design structures of powering on integrated circuit

International Business Machines Corporation


Magazine extensions have an extension body having a floor panel, a right side wall, and an opposed left side wall, and a front wall, the right and left side walls each including linear engagement facilities each configured to engage the floor plate attachment facility, the extension body defining a chamber between the right and left side walls and rear of the front wall, and open in an upward direction, the linear engagement facilities being operable to constrain movement of the extension body between an attached condition in which the chamber is registered with the internal passage, and a detached condition, a door slidably and removably connected to the extension body and having an upper door edge, the door movable between an attached condition in which the door spans between front or rear portions of the right and left side walls, and a detached condition.

A magazine is an ammunition storage and feeding device within, or attached to, a repeating firearm. The magazine functions by moving the cartridges stored in the magazine into a position where they may be chambered by the action of the firearm. Most magazines designed for use with a reciprocating bolt firearm utilize a set of feed lips which stops the vertical motion of the cartridges out of the magazine but allows one cartridge at a time to be pushed forward (stripped) out of the feed lips by the firearm's bolt into the chamber.
Some form of spring and follower combination is almost always used to feed cartridges to the lips, which can be located either in the magazine (most removable box magazines) or built into the firearm (fixed box magazines). As the firearm cycles, cartridges are moved to the top of the magazine by a follower driven by spring compression to a feed position. In most firearms, the magazine follower engages a slide-stop to hold the slide back and keep the firearm out of battery when the magazine is empty, and all rounds have been fired. Box magazines may be integral to the firearm or removable.
A detachable box magazine is a self-contained mechanism capable of being loaded or unloaded while detached from the host firearm. They are inserted into a magazine well in the firearm receiver usually below the action, but occasionally positioned to the side or on top. When the magazine is empty, it can be detached from the firearm and replaced by another full magazine. This significantly speeds the process of reloading, allowing the operator quick access to ammunition.
Increased ammunition capacity is highly desirable for a variety of firearm usage scenarios, including competitions and self-defense. Numerous magazine extensions have been developed that replace the OEM box magazine body's base plate to provide additional ammunition capacity. A variety of problems have existed with many of the designs. One example is unreliability of the connection between the magazine extension and the box magazine's body, which causes the spring, follower, and ammunition to fall out of the bottom of the box magazine's body. Another is inadequate spring tension to properly feed ammunition from the box magazine resulting from use of the OEM box magazine's spring with a magazine extension. Finally, many existing extensions require special tools to install and remove the magazine extension from the box magazine's body. Many competitive shooters prefer to disassemble, inspect, and clean their magazines in between competitions. A forgotten special tool makes this impractical, and even with the special tool, the removal and reassembly processes can be time-consuming. Most existing extensions also include extremely small set screws and pins, which are prone to being easily dropped. Some existing extensions also have the disadvantage of not being removable to enable servicing of the attached magazine.
Therefore, a need exists for a new and improved magazine extension that provides additional ammunition capacity with a reliable connection to a box magazine body and toolless removal and assembly. In this regard, the various embodiments of the present invention substantially fulfill at least some of these needs. In this respect, the magazine extension according to the present invention substantially departs from the conventional concepts and designs of the prior art, and in doing so provides an apparatus primarily developed for the purpose of providing a magazine extension that provides additional ammunition capacity with a reliable connection to a box magazine body and toolless removal and assembly.
The present invention provides an improved magazine extension, and overcomes the above-mentioned disadvantages and drawbacks of the prior art. As such, the general purpose of the present invention, which will be described subsequently in greater detail, is to provide an improved magazine extension that has all the advantages of the prior art mentioned above.
To attain this, the preferred embodiment of the present invention essentially comprises an extension body having a floor panel, a right side wall, and an opposed left side wall, and a front wall, the right and left side walls each including linear engagement facilities each configured to engage the floor plate attachment facility, the extension body defining a chamber between the right and left side walls and rear of the front wall, and open in an upward direction, the linear engagement facilities being operable to constrain movement of the extension body between an attached condition in which the chamber is registered with the internal passage, and a detached condition, a door slidably and removably connected to the extension body and having an upper door edge, the door movable between an attached condition in which the door spans between rear portions of the right and left side walls, and a detached condition, and the upper edge of the door when in the attached condition abutting a lower portion of the elongated magazine tube to prevent forward movement of the extension body from the attached condition, and enabling movement of the extension body to the detached condition when the door is removed. There are, of course, additional features of the invention that will be described hereinafter and which will form the subject matter of the claims attached.
There has thus been outlined, rather broadly, the more important features of the invention in order that the detailed description thereof that follows may be better understood and in order that the present contribution to the art may be better appreciated.
The same reference numerals refer to the same parts throughout the various figures.


To provide a barium powder preparation and application thereof to an extremely high density barium suspension, processes for producing them, and a method of upper gastrointestinal examination, wherein double contrast radiography can be carried out on-the-fly without the use of a gastric tube and the injection of any parasympathicolytic, only by one slow rolling operation with the patient on the table. A barium powder preparation obtained by mixing specified proportions of large, medium and small component particles which are produced from large, medium and small particles of pure barium sulfate having specific particle properties, by adding Gum Tragacanth and Carrageenan in specified amounts and at a specified ratio, kneading their mixture under specified kneading conditions to fragment the molecules of Gum Tragacanth and Carrageenan and coat the particles with them, and drying and sterilizing the particles, and a barium suspension prepared by suspending the above barium powder preparation in water at an extremely high density are used.

1. Field of the Invention
The present invention relates to a novel barium powder preparation and application thereof to an extremely high density barium suspension used mainly for upper gastrointestinal double contrast examination, processes for producing them, and a method of X-ray examination applicable mainly to the diagnosis of early gastric cancer and peptic ulcer using said extremely high density barium suspension as a contrast medium.
2. Background Art
The X-ray examination of the stomach, duodenum and esophagus, especially for the double contrast method, requires highly skilled operation using gastric tubes, due to the fuzziness of the barium sulfate suspension (referred to simply as "barium" hereafter) used as a contrast medium, or its excessive or insufficient adhesion to the gastric mucosa, as is often the case. Improvement has long been awaited, as no ideal barium is commercially available yet. Although new products claiming "high density" have been released for the last few years, their densities in practical use are only about 200 W/V%, and fall short of addressing the aforementioned problems.
The environment surrounded by gastric mucosa is unique and severe, containing free acids and some mucus in an ordinary way. The mucosal surface is covered with the protecting layers of mucus, such as Mackintosh's barrier mucus and Katsuyama's surface mucous gel layer (SMGL), and not easily accessible. Even a time-tested barium with a density of 140 W/V% (Baritogen DX, tradename of Fushimi Seiyakusho Co. Ltd.) would require, for a double contrast examination, a number of rigorous body rolling operations to wash out the mucous layers, in addition to the use of a gastric tube to remove the free gastric mucus, to obtain a preferable result.
Body rolling is an operation to change the patient's posture by turning the patient's body on a horizontal table by 90.degree. alternately to the bilateral sides from the supine position. If the amount of mucus is large, it needs to be sucked out through a gastric tube. However, it is practically not easy to suck out dense gastric mucus. For example, the insertion and removal of a gastric tube may be difficult in some patients. Also, inserting a gastric tube may induce unexpected secretion of gastric juice or peristalsis, bringing about an adverse effect. Furthermore, the double contrast examination requires time-consuming air injection through a gastric tube while monitoring the amount of injection using a large cylinder. Therefore, a significant amount of parasympathicolytic usually needs to be administered in advance to suppress the peristalsis and mucous secretion during the injection intramuscularly and, at times, both intramuscularly and intravenously. These complicated procedures make most non-specialists hesitant to use this examination method.
There is a huge amount of literature, including books and journals, on the detailed procedures available in Japan. For example, the rolling method for double contrast radiography has been frequently described with diagrams called "Stomap" and detailed explanation, such as the position, direction and angle of posture change.
Weirdly, however, no clear description has been provided on the speed of rolling. Instructions previously given require to roll as quickly as possible, rock or wash, or swing the hips as an Hawaiian dance. These seemingly descriptive but quite vague expressions may not help a lot in practice.
As mentioned above, the double contrast radiography of the stomach depends largely on the skills of the operator, due to the complexity of the conditions such as the complicated environment of the gastric mucosa, difference in barium density, visco-elasticity of individual contrast medium, and rolling method. From the viewpoint of rolling mechanics in double contrast examination, a barium density of 140 W/V% or less requires quick and repeated rolling until the barium forms a desired thin layer over the gastric mucosa in order to remove the mucus. However, excessive rolling may result in insufficient adhesion of the barium to the gastric mucosa, as the barium density may decrease due to dilution by the mucus.
The lately commercialized high-density agents with rated barium densities of 200 W/V% or over have a common disadvantage of easily precipitating and forming sludge. This overly high visco-elasticity hampers spreading of the medium and makes it a too thick layer and, therefore, visualizes only the gastric folds but not the gastricae area. A super-high density agent (tradename: EZ-HD) produced by an U.S. company with a barium density of 250 W/V% has the disadvantage of forming an excessively thick barium layer that cannot be reduced no matter how quick or repetitively rolling is done.
A high-density preparation of barium sulfate used as an X-ray double contrast medium is available from China (manufactured by National Chintao Tonfon Chemical Factory). The supplied technical document says it may be used for the X-ray double contrast examination of the esophagus and stomach. In use, 500 g of powder are mixed with an appropriate amount water and stirred for 5 minutes to make a suspension. It needs to be stirred again immediately before use for uniformity. Combination with an effervescent agent (Chintao No. 3) is recommended for a better result. In the supplied barium density dilution table, 39 ml of water is used to prepare a 300 g of 280 W/V% suspension with a total amount of 107 ml and a viscosity of about 300 mPa.multidot.s. Assuming 1 cp as 1 mPas.multidot.s, the viscosity is twice that of the applicant's extremely high density barium, which is 150 cp (see Table 7) at an equal density of 280 W/V%.
An analysis by the applicant revealed that the agent contains almost no small particles and is composed chiefly of large particles which have a specific surface area of 0.206 m.sup.2 /g and a particle size distribution with a steep peak at 10 .mu.m. Its scanning electron microscope image shows that it is made of crushed particles of natural barite. Unknown additives account for a mere 0.05%. The biggest problem is that, because it is made of crushed particles, the appearance is not clear white, unlike commonly available agents, posing a risk of contamination by foreign matter other than pure barium. A second problem is that it easily precipitates, as is the case for agents composed of large particles and no small particles. The large particles are similar to the large component particles of the present invention, but slightly larger. The rated density excludes the additives. As mentioned above, this barium sulfate has an apparent viscosity twice as high and no distinctive properties.
Also, another technology related to high-density barium has been proposed (Laid-open Japanese Patent Application No.60-54919, "A Process for Producing Barium Sulfate with Increased Fluidity and Density Suitable as a Contrast Ingredient in X-Ray Contrast Medium, Products Obtained by the Process, and an X-Ray Contrast Medium Produced Therefrom").
The technology can be summarized as follows: First, the pure barium (synthetic) used as a material is impregnated with ammonium sulfate and other salts, and sintered at a high temperature of 800 to 1200.degree. C. This step removes the edges of the crystals to make their surface round and flat, allowing significantly efficient packing. The preferred particle size of the material is 1 to 5 .mu.m. After the above step, a suspension of this powder, to which an appropriate amount (3%) of a few composite assistants have been added, has a density of 200 W/V% and a viscosity no more than 1000 mPas.multidot.s. Assuming 1 cp as 1 mPas.multidot.s, this barium sulfate has an extraordinarily high viscosity. The detailed description of the invention refers to barium sulfate agents obtained from crushed natural barite, or so-called crushed particles, and points out, by citing the argument by E. Miller, that "regrettably they generally do not meet the standard purity of the medical literature (Pharmacopoeia) as they contain excessive amounts of heavy metals."
Also, another technology related to high-density barium has been proposed (Laid-open Japanese Patent Application No.60-61537, "An X-Ray Contrast Medium").
This X-ray contrast medium is a powder agent having two peaks in the particle size distribution, one of which is in the large and the other of which in the small region, containing lignin sulfonic acid and alkali citrate as surfactants to decrease the viscosity and increase the stability of the barium suspension. Both of these two additives have been known to decrease viscosity (former in West German Patent No. 2028025, and latter in U.S. Pat. No. 3,216,900). However, the technology seeks a synergistic effect of using them together. For the particle size distribution with two peaks, Vol. 35, p.95, Journal of the Osaka Medical School, 1976, by the applicant is cited.
As a result, a viscosity of 60 sec (DAB8) was obtained at 2.5 g/ml (250 W/V%). Compared to the viscosity of 80 to 110 sec of the aforementioned Chinese barium sulfate at 250 W/V%, it is significantly low. However, no reference is made to the viscosity at an extremely high density of 260 W/V% or above, or to specific clinical performance.

Extremely high density barium suspension as a contrast medium for upper gastrointestinal examination


Disclosed is a combination of two or more lipase enzymes, and its use for treating a lipid digestion deficiency and/or a digestive disorder. At least one lipase enzyme has a pH optimum at an acidic pH value, while at least one other lipase enzyme has a pH optimum at an alkalic pH value.

Digestive disorders play an increasingly greater role in the general medical and internal medical practice. Such digestive disorders are in many cases the consequence of a more or less pronounced deficiency in so-called pancreatic enzymes. In a healthy state, these enzymes are synthesized in the pancreas by highly specialized cells, the so-called acinic cells, and secreted by exocytosis through juice glands and the main pancreatic duct into the duodenum. The daily amount of pancreatic secretion is about 2 liters. In addition to fat digesting lipase, the pancreatic secretion also contains enzymes for the digestion of proteins (trypsin, chymotrypsin and carboxypeptidases) and carbohydrates (α-amylase). The secretion of pancreatic enzymes is exactly controlled by endogenous control mechanisms by means of hormones, such as gastrin, secretin and pancreozymin. This control system can be disturbed by a large number of causes to result in a reduction of pancreatic enzyme secretion or in a complete subsiding of the exocrine pancreatic function. This in turn causes that the chyme is not digested in the small intestine, and a digestive disorder occurs. This disease of the digestive tract, which is also referred to as exocrine pancreatic insufficiency (EPI), can have different causes. In addition to dyspepsia caused by medicaments, chronic atrophic gastritis and chronic pancreatitis, frequently caused by alcohol consumption, disorders caused by surgery (e.g., Billroth I and II, vagotomy, pancreas resection) and cystic fibrosis are etiologic factors of pancreatic insufficiency. At any rate, chronic digestive disorders are of considerable social-medical and thus economic importance, because the symptoms frequently cause the patients to be nondescript and have a shortened expectation of life.
Pancreatogenic digestive disorders and especially EPI cause a lot of complaints in the patients, such as diarrhea, mass stools, sensations of repletion, upper abdominal complaints, weight loss etc.
Irrespective of the causes and the manifestation of pancreatogenic digestive disorders or EPI to avoid malnutrition related morbidity and mortality, it is pivotal to commence a substitution therapy with enzymes as soon as EPI is diagnosed. This means that the lacking enzymes, predominantly lipase, protease and amylase, but also other enzymes, must be supplied externally. In the therapy, the enzymes are taken in orally by the patient mostly in the middle of the meal and go through the stomach and arrive in the small intestine, where they perform digestion of the chyme and thus adopt the function of the lacking endogenous pancreatic enzymes. The preparations employed must contain a sufficient amount of enzymes. In addition, the enzymes must be provided in an enteric formulation, have a small particle size and be completely bioavailable in the digestive tract. For treating digestive disorders based on the lacking of pancreatic enzymes often pancreatic enzyme replacement therapy (PERT) based on the substitution/replacement of the leading enzyme lipase and the protease, is used. For PERT a wide variety of enzyme preparations are already on the market. These are partly based on pancreatic enzymes from pigs, such as the preparations Combizym®, Festal®, Pankreon®, Kreon®, Panzytrat®, Meteozym® or Enzym-Lefax N® Preparations containing pancreatic enzymes, so called pancreatic enzyme products or PEPs, are mostly obtained from pigs from slaughter, for example, pancreas, of pigs. The final product of the preparation process is pancreatin. PEPs are composed of porcine lipase, amylase, and protease and are used in patients with EPI secondary to cystic fibrosis, chronic pancreatitis, and pancreatectomy.
In 1938, PEPs were exempted from the Food, Drug, and Cosmetic Act of 1938 and never underwent a formal Food and Drug Administration (FDA) review process (Giuliano C A L Dehoome-Smith M L, Kale-Pradhan P B (2011) Pancreatic enzyme products: digesting the changes. Ann Pharmacother. 45(5):658-66.
PEPs from pig origin cannot be employed with patients suffering from digestive disorders who have a pig protein allergy. In addition, pigs are considered a natural reservoir of human-pathogenic influenza viruses and a vast number of viruses from porcine origin, so that contamination of pancreatin with such viruses cannot be ruled out. In other words, pancreatic tissue, which would present slaughter waste, if not further processed, can exhibit a high degree of viral contamination. In consequence based on its natural origin, the pancreatic tissue, pancreatin and PEP also can be contaminated with viruses from porcine origin. It has to be emphasized that the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) sets a very high standard in its guideline ICH Topic Q 5 A (R1) and demands as the best reasonable assurance that the product is free of virus contamination. The Center for Drug Evaluation and Research (CDER) of the US FDA already requested intensive risk mitigation strategies for lipase containing PEPs like Creon.
This, because there is a risk for contamination of PEPs with Porcine Parvovirus and Porcine Circovirus as well as significant number of swine viruses that are known human pathogens.
Unfortunately, neither manufacturer thus far has found any viral inactivation method that can successfully demonstrate acceptable virus clearances of PEP without also degrading or reducing the pancreatic enzymes, particularly lipase, to unacceptable levels. Due to further limitations associated with analytical testing of such a complex biological material, like pancreatin, it will be difficult to determine what degradants may be introduced into the product as a result of any added viral clearance steps. In conclusion, process steps that can be effective against viruses have a high potential for changing the nature of PEPs, thus having a potentially serious impact on the drug's quality, safety and efficacy. However, because there are almost no alternative resources on the market for lipases than PEPs, they still represent the only permitted drug compositions for the treatment of EPI.
In addition, for particular groups of patients, a disadvantage of the use of PEPs is the origin from pig. Usually, the pancreas of pigs is used, which cannot be tolerated by patients of Judaic or Islamic religion due to religious instructions. Furthermore pancreatin is a homogenate from the cells of pancreatic tissues (usually from pigs). Due to the rupture of a large number of acinic cells, it contains, in addition to pancreatic enzymes, a wide variety of other enzymes and proteins as well as further high and low molecular weight compounds. The composition of pancreatin is due to its industrial preparation process. To obtain pancreatin, pancreas of pigs are deep-frozen as quickly as possible after slaughtering, collected and broken up mechanically. For the stabilization and activation of the enzymes, various additives are added to the homogenate. This is followed by defatting with organic solvents, such as acetone, the removal of fibrous substances, and dewatering and drying by lyophilization. In view of the problems associated with the management of organic solvents and the costs thereof, there thus remains a need for a method of enzyme production which minimises the use of organic solvents or work without of organic solvents. For the preparation of particular dosage forms, further galenic processing may be effected into micropellets, tablets, capsules, pastes, creams, gels, oils or other formulations. Frequently, pancreatin based PEPs are mixed with various support materials and buffer substances. Further, granulated pancreatin is coated with acid-stable films or lacquers for protection against the low pH value of human gastric juice. The two latter processing steps are to ensure that the acid-labile PEPs can fulfill their digestive function at the target site, the duodenum (small intestine), but prevent the enzymes from being active in the acidic upper Duodenum of many pancreatitis Patients.
A newer PEP, which contains lipase, is Zenpep®. Zenpep® is a combination of porcine-derived lipases, proteases and amylases from pigs for slaughter indicated for the treatment of EPI due to cystic fibrosis or other conditions. In opposite to common marketed PEPs for EPI, Zenpep® does not show great variability in the amount of enzymes included in each capsule. The variability of the common PEPs is due in part to the manufacturer practice of overfilling capsules to account for enzyme degradation that occurs over the course of the product's shelf life. Variability in the product's enzyme content can lead to inconsistent therapeutic effects by either providing too much or too little of the required enzymes, which may lead to the suboptimal treatment of the patient's EPI. In addition, overfilled products may increase the risk of fibrosing colonopathy, which has been associated in some reports with long-term exposure to high-dose PERT. These problems can be avoided by the application of Zenpep®. However, Zenpep® contains the same porcine pancreatic lipase like common PEPs. In consequence porcine pancreatic lipase in Zenpep® becomes efficient only in the presence of porcine colipase in the duodenum. Thus, Zenpep® also nearly an unpurified protein mixture from pigs for slaughter, because purification in the manufacturing process would lead to a potential loss of the colipase. Additionally, Zenpep® can also contain viral contamination and, because of the necessary precipitation and defattening steps, residual organic solvents as described for PEPs. In consequence, as for common PEPs for PERT, porcine pancreatic lipase in this composition can be contaminated with viruses and/or organic solvents.
In order to circumvent the use of pig pancreatic tissue as source for lipase and protease, some researchers suggested the use of enzymes from fish or other marine animals generally described in FR No. 1015566, as well as compositions of enzymes from the gastrointestinal tract of krill (crustaceans from the class Euphausiaceae) and capelin fish (U.S. Pat. No. 4,695,457). However these natural resources are difficult to handle and to process for characterized enzyme preparations in industrial scale and in consequence enzyme preparation containing lipases from these origins never reached the market.
Due to the problems of contamination with viruses and organic solvents characterizing conventional enzyme preparation from pig pancreatic tissue, the use of microbially-derived enzymes as alternatives to porcine-derived PEP has been proposed. For example, U.S. Pat. No. 6,051,220 describes compositions comprising one or more acid stable lipases and one or more acid stable amylases, both preferably of fungal origin. United States patent application 2004/0057944 describes compositions comprising Rhizopus delemar lipase, Aspergillus melleus protease and Aspergillus oryzae amylase.
In part, some enzyme preparations therefore also contain microbial enzymes from mold extracts, such as Nortase® and Combizym®. In spite of their resistance to acid and although they do not depend on colipase, their clinical efficacy is low due to rapid intraluminal inactivation by bile salts and proteases.
A recombinant enzyme preparation in development, which contains a bile salt stable lipase, is a drug with the brand name Kiobrina, which is a recombinant human bile-salt-stimulated lipase (rhBSSL). This rhBSSL shall improve the digestion and absorption of essential fatty acids, such as long-chain poly-unsaturated fatty acids but also cholesterol esters in the human gut. rhBSSL is expressed and produced in mammalian cells and is developed by Sobi for enzyme therapy to improve growth and development in preterm infants receiving pasteurized breast milk and/or formula. The rationale for substitution of rhBSSL in pasteurized breast milk or infant formula is to restore the natural lipase activity level that is either lost on pasteurization or totally absent in formula. A disadvantage is, that the enzyme is active only in the presence of primary bile salts, which are often insoluble and, thus, not available in the duodenum, especially under the condition of exocrine pancreatic insufficiency. Furthermore the developing company Sobi announced that clinical data show that the rBSSL did not meet its primary endpoint and, thus, the rhBSSL is does not fulfill its function for enzyme substitution therapy in the human gastrointestinal tract.
Another recombinant lipase for the treatment of exocrine pancreatic insufficiency is the crystallized, purified cross-linked Pseudomonas/Burkholderia cepacia lipase with of molecular weight of 30 kDa, which is part of an enzyme composition named ALTU-135/TheraCLEC®/Trizytek®/Liprotamase®)/Sollpura®) (now with the brand name Sollpura®) developed by Anthera Pharmaceuticals and which is also disclosed in U.S. Pat. No. 7,718,169.
This microbial lipase is of bacterial origin, which is described in United States patent application 2001/0046493, can be produced by recombinant DNA technology. The enzyme is secreted in the culture medium, and requires a complex production process for purification and crystallization in order to stabilize the enzyme for administration in the human gastro intestinal system. After crystallization, the lipase crystals have to be chemically and covalently cross-linked in order reach sufficient acid stability. In vitro studies suggest that this modification called cross-linked enzyme crystals (CLEC) process increases stability of the lipase and that the cross-linked lipase is insoluble at acidic pH representative of the stomach. However, it has been shown that diffusion effects have been a serious problem for the practical use of crystalline enzymes (Alter, G. M., Leussing, D. L., Neurath, H. Bert L. Vallee, B. L., 1977) Kinetic Properties of carpoxipeptidase B in solution and crystals. Biochemistry 16 (16): 3663-3668). Furthermore it has been shown, that CLEC lipases show a significantly reduced enzyme activity on certain substrates compared to soluble enzymes (Margolin, A. L. (1995) Novel crystalline catalysts. Trends in Biotechnology 14 (7): 223-230). Moreover, the Pseudomonas/Burkholderia cepacia lipase has a broad pH optimum from pH 4-8 with a strong decline of activity for pH values larger than 8. However, Pseudomonas/Burkholderia cepacia lipase is not active under pH conditions significantly larger than pH 8. In consequence this enzyme cannot support the digestion of lipids under strong alkaline conditions (larger than pH 8.5 or higher). One other problem for Pseudomonas/Burkholderia cepacia lipase is, that the enzyme is a protein from a pathogenic bacterium. Pseudomonas/Burkholderia cepacia (explanation: formerly known as Pseudomonas cepacia, the bacterium now is known as Burkholderia cepacia) is an important human pathogen which most often causes pneumonia in immunocompromised individuals with underlying lung disease such as cystic fibrosis or chronic granulomatous disease.
Patients with cystic fibrosis are at risk for acquiring the well known "Burkholderia cepacia syndrome and in consequence the so called "Burkholderia cepacia syndrome" is a serious condition in patients with cystic fibrosis that does not always respond well to treatment.
In the case of such a Pseudomonas/Burkholderia cepacia infection long-term active memory is acquired following infection by activation of B and T cells, while some of their offspring become long-lived memory cells. Throughout the lifetime of human, these memory cells as part of the "adaptive immune system", remember each specific pathogen encountered and can mount a strong response if the pathogen is detected again.
Under the conditions of oral treatment with Pseudomonas/Burkholderia cepacia lipase the oral uptake of enzymes from Pseudomonas/Burkholderia cepacia as part of enzyme replacement therapy (in the case of cystic fibrosis) represents an incorporation of exogenous antigens. The antigens will be detected by the adaptive immune system as pathogens and would result 1. in the activation of the immune system (so called immunological memory), 2. the generation of antibodies against the enzymes and 3. the risk of an exaggerated immune response in the intestine mucosa including potential allergic and autoimmune reactions and sepsis.
This risk of an of exaggerated immune response in the case of a medication of cystic fibrosis with Pseudomonas/Burkholderia cepacia enzymes would be counterproductive for the treatment of patients and would exacerbate the patients' health situation.
The combination of insufficient efficacy and the risk of the above described detrimental side effects have already raised serious concern of regulatory agencies. In 2011, the Gastrointestinal Drugs Advisory Committee of the Food and Drug Administration (FDA) of the US Department of Health and Human Services rejected the finding that Sollpura®'s (the enzyme preparation with Pseudomonas/Burkholderia cepacia lipase) benefits outweighed its risks, arguing that additional efficacy data were needed before it could conclude that it worked in patients better than existing porcine derived pancreatic enzyme products.
Finally it has been shown that there is substantial evidence that Sollpure is less efficacious than the porcine-derived PEPs and appears to expose patients with EPI to greater risk (Carome M. Wolfe S. Testimony to the FDA Gastrointestinal Drug Advisory Committee regarding liprotamase—risk: benefit assessment; ethics of further clinical trials. Washington D.C.: Public Citizen Research Group. Jan. 12, 2011)
Moreover, the U.S. Pat. No. 5,998,189 discloses a recombinant acid stable dog gastric lipase produced in E. coli and claims the expression of acid stable dog gastric lipase in E. coli as well as in other prokaryotic and eukaryotic expression systems. Additionally, the expression and extraction of this acid stable dog gastric lipase in transgenic corn has been demonstrated Zhong, Q., GU, Gu, Z. and Glatz, C. E. (2006) Extraction of recombinant dog gastric lipase from transgenic corn seed. J. Agric. Food Chem. 54: 8086-8092).
However, dog gastric lipase shows a very low pH optimum at pH 4 with a very narrow pH profile from pH 3-pH 5 (Carriere, F., Moreau, H., Raphel, V., Laugier, R., Benicourt, C., Junien, J.-L. and Verger, R., 1991) Purification and biochemical characterization of dog gastric lipase. Eur. J. Biochem. 202: 75-83)
The goal of an enzyme preparation containing lipase displaying the highest efficacy at the lowest dose, and characterized by a well-defined safety profile, remains of great importance to all patients suffering from pancreatic insufficiency, including those in the cystic fibrosis community.
TABLE 1Summary enzyme preparation for PERT approachespHname and brandoptimum nameofon marketsourceenzymeslipaseremarkslimitationsPEPs (Creon®,Pancreatin pancreatic enzymes from pig7 to 8no biotechnologicalCotazyme®,orprocess, noUltrase®, Viekase®pancreatic contaminationetc.)extractprocess, sodrugcontamination withproductsviruses and bacteriafrom pigare possible due topancreasnon-sterilized tissuetissuefrom slaughterhouseZenpep®Pancreatin pancreatic enzymes from pig with7 to 8no biotechnologicalordefined enzyme activityprocess, nopancreatic containmentextractprocess, sodrugcontamination withproductsviruses and bacteriafrom pigare possible due topancreasnon-sterilized tissuetissuefrom slaughterhouseno producttissuelypolytic and proteolytic enzymesno pHno biotechnologicalfromfrom gastrointestinal tractoptimumprocess, nokrill anddisclosedcontainmentcapelinprocess, sofishcontamination withviruses and bacteriaare possible due tonon-sterilized tissuewith waste characterof the natural sourceNortas®/Combizym®Microbial-Rhizopus oryzae/delemar lipase,6.6 toRhizopusmouldAspergillus melleus protease and7.5oryzae/delemar is anfungusAspergillus oryzae amylaseopportunistic humanpathogen, potentialimmune reaction ifpreviousPseudomonas/Burkholderia cepaciainfection, lipaseunstable underphysiological bilesalt concentrationsKiobrina®recombinant human bile salt stable7.3 tocomplex andlipase (MBSSL)8.6expensiverecombinantproduction processin animal cell linesALTU-Microbial- Recombinant8.5 tocross-Pseudomonas/Burkh135/TheraCLEC®/culturePseudomonas/Burkholderia9linkedolderia cepaciaTrizyt®of E. colicepacia lipaseenzymeopportunistic humanek®/Liprotamase®/bacteriacrystalsPathogen potentialSollpura®(CLECimmune reaction ifprocess)previousPseudomonas/Burkholderia cepaciainfection, lowactivity under acidicconditionsno productMicrobial-acid stable dog gastric lipase3 to 5low activity undercultureproduced in E. colialkaline conditionsof E. coli(http://www.google.com/patients/bacteriaU.S. Pat. No. 5,998,189)Merispase®transgenic acid stable dog gastric lipase in3 to 4low activity undercorntransgenic cornalkaline conditionsno productMicrobial-acid stable Tetrahymena lipases3.5 tolow activity underculture4.5alkaline conditionsof T.therrnophila
In most patients, lipid digestion cannot be completely normalized by current standard therapy. Furthermore the production of lipases for human administration is cumbersome and expensive. The instant invention addresses these issues.

Use of enzymes with a wide pH activity range as medicaments for promoting digestion


In a process for continuously making disposable wearing articles, a first web which will be finally cut into a series of sheet members that are contiguous to one another in a transverse direction, and that define an outer surface of the article, is continuously fed in a first machine direction. A second web having a Ω-shaped cross-section forming individual adhesive taper strips is fed in a second machine direction orthogonal to the first machine direction. The second web is periodically cut in a second cross direction orthogonal to the second machine direction to obtain composites. After the composite is fed to and attached to the first web, the first web is cut together with the composite so as to bisect the length of the composite.

The present invention relates to a process for continuously making disposable wearing articles such as disposable diapers, disposable training pants or disposable pants.
EP 1 132 325 A2 discloses an apparatus adapted to attach adhesive tape strips to a continuous web comprising a series of diapers being still contiguous to one another in its one direction intermittently in one direction of the continuous web. In the case of this apparatus, continuous web comprising a series of adhesive tape strips being still contiguous to one another is introduced between a cutter roll and an anvil roll and thereby cut into the individual adhesive tape strips. These adhesive tape strips are fed and attached to the continuous web of disposable diapers running in one direction. A feed speed of the continuous web of the adhesive tape strips is substantially equal to a rotational speed of the anvil roll and these speeds are lower than a running speed of the continuous web of disposable diapers. The anvil roll lies immediately below the continuous web of disposable diapers and rotates to the running direction of this continuous web. The adhesive tape strips run in the same direction as the continuous web of disposable diapers runs and successively bonded to the continuous web of disposable diapers.
Japanese Patent Application Publication No. 1986-287645A discloses a tape applicator adapted to feed tape strips each having a predetermined length in a web running direction and to attach the tape strips to the running web. The tape strip is fed in a direction orthogonal to the web running direction and then fed in the web running direction before attached to the web. This applicator is adapted to attach the tape strips to the web so that a plurality of the tape strips may be spaced apart from one another parallel to one another. The speed at which the tape strips are fed in the web running direction is equal to the running speed of the web.
In the above-cited references, the adhesive tape strips are fed in the same direction as the web runs and attached to the web. When it is desired to attach the adhesive tape strips to the web of disposable diapers contiguous to one another at positions corresponding to both side edges of the individual diapers according to the above-cited known art, the web running direction should be orthogonal to the transverse direction of the individual diapers. In other words, the above-cited Publication disclose none of processes adapted to attach the adhesive tape strips to the side edges of the individual diapers at a high efficiency.

Process for continuously making disposable wearing articles