Injector devices and methods for their operation for containers having an opening with or for an injection needle. The container is optionally of syringe type with a barrel of substantially constant axial cross-section. In one embodiment, the devices include a penetration arrangement operable to move the needle from a rear position to a forward position, an injection arrangement operable at least to expel container content through the needle, and a transmission and a switch system allowing manual energy applied to the device to manually operate the penetration arrangement and then manually operate the injection arrangement.

The present invention relates to an injector device for containers having an opening with or for an injection needle, the container optionally being of syringe type with a bagel of axially roughly constant cross-section, the opening for the needle being arranged at the barrel front and at least one movable wall, optionally with a piston rod connected thereto, inserted in the barrel, the injector for the containers comprising a) a housing, b) a seat or carrier, arranged for reception of the needle or container and for allowing movement thereof, in relation to the housing, in the axial direction between a rear, needle-covering, position and a forward, needle-exposing, position, c) a penetration arrangement operable to move the needle from the rear position to the forward position, d) optionally a return arrangement operable at least to move the needle in the rearward direction, e) an injection arrangement operable at least to expel container content through the needle and f) at least one control button arranged on the housing and operable to at least initiate operation of the penetration arrangement and/or the injection arrangement.
Although simple in principle injection procedures based on syringe type devices with injection needles require mastering of several discrete steps. Before the mere injection procedure some initiation actions may be required. Filling the syringe with medication withdrawn from a reservoir such as a vial may be needed, taking into account the proper dose to be administered. In order to avoid this step in the actual treatment situation it is common to provide pre-filled syringes, in which case, however, a dose setting or selecting step may be needed. In its first movement the syringe piston may need an extraordinary break-loose force after storage to overcome both internal reshaping resistance and an increased wall friction due to adherence or depletion of lubricant in contact points. For storage and shelf life reasons pre-filled syringes sometimes are delivered in dual or multiple-chamber form, requiring an additional mixing step immediately before treatment. De-aeration and pre-ejection are generally needed to remove gas in the vessel compartment and fill out spaces for example at the front sealing, outlet attachments and the interior of the outlet devices or needles. The injection procedure proper can be said to involve the basic steps of penetrating the skin with the needle, performing the injection of the medical preparation and withdrawal of the needle from the tissue. The target tissue may differ in e.g. subcutaneous, intramuscular, intracavernosal or intravenous injection and require somewhat different injection techniques, including aspiration steps. Typical problems are full needle penetration into the desired target tissue, injection only after proper location of the needle and full injection of the prescribed dose before the needle is retracted. After injection it is nowadays common to shield or destroy at least the needle to avoid infection transmission by inadvertent secondary needle pricks.
These demands can be met also when using the simplest injection devices, such as the common hypodermic syringe, when in the hands of a skilled operator who also may initiate medically relevant corrective measures in case of accidents and malfunction. However, a general treatment trend is to place administration responsibility on the patients themselves, also in the case of child, elderly and disabled persons. In long-term treatment the patient often develop a certain skill but less frequent administration schemes also exist, often including situations of emergency or patient imbalance. Other unique problems in patient selfadministration, as compared to assistant operated administration, is that less suitable and often strained body positions are required and that apprehended or experienced pain or discomfort may interfere with the medically desirable action pattern. In summary, especially the selfadministration requires more sophisticated devices to facilitate the injection procedure and avoid or reduce risks for mistakes. Patients dependent on daily or occasional administrations also have a legitimate need for convenience and devices discrete enough to be brought around in daily life. Yet it is desirable that such sophistication and convenience is kept simple and inexpensive to allow for widespread distribution and inclusion also in disposable devices.
More or less automated devices has since long existed to enable laymen with limited training performing injections with reasonable safety in critical or emergency situations or to provide an option for patients fearing the needle insertion step. Mechanical automation is provided in common autoinjectors. Typically the user is expected to position the device in proper injection orientation against the skin and operate a trigger button. Stored mechanical energy, e.g. in a spring system, may then perform autopenetration into the tissue, autoinjection of the medical and possibly also automatic needle retraction. Simpler systems may not provide autopenetration but assume the user to make the needle insertion. Generally, once triggering has occurred, either intentionally or inadvertently, the operation sequence proceeds irreversibly. Moreover, the dislocation risks are generally high in mechanical devices due to rebound effects and the forced transitions involved, especially as the forces released may have to be dimensioned for the highest foreseeable operation resistance. Besides being expensive and ungainly, these devices rarely give the patient the experience of full control of the injection procedure and the possibility to halt or correct the injection procedure in case of pain or discomfort.
Automated devices based on electronic or electromechanical principles have also been proposed. The known devices may take advantage of automation principles in several respects, such as the precise and reproducible injection possible with electric motors, motor assisted autopenetration and mixing or reconstitution, cartridge identification, sample analysis, injection data collection and manipulation, dose setting, injector orientation relative gravity for proper mixing or de-aeration etc. Certainly this diversity of possibilities make the automated devices in this class useful in many situations, especially for repeated and frequent use, although the devices tend to be too expensive for broad or disposable use. Again, for patients in favor of personal control the automated functions may be adversely experienced.
On the contrary, simpler manual devices may not at all provide the ergonomic, convenience and safety requirements outlined. A syringe type device for example gives no or little assistance in respect of initiating steps, needle penetration or retraction and requires a cumbersome reverse grip for injection on many body sites and offers no safe sequencing of the various steps involved. Numerous so called xe2x80x9cinjection pensxe2x80x9d have been proposed and marketed, mainly for repeated and regular self-administration, e.g. of insulin or growth hormone, in which multi-dose ampoules are inserted and pre-selected doses delivered, typically by manipulation of an end button. These devices are designed for ease of use in everyday life and facilitate repeated dosing bat do not cure the other problems associated with hypodermic syringes. Also known are injection devices with alternative positioning of control buttons for injection For example, the patent specifications U.S. Pat. Nos. 4,444,560, 4,581,022 and 4,820,287 and WO 96/17640 all disclose a lateral lever with a link arrangement to a piston rod, mainly for the purpose of amplifying the expulsion pressure on viscous dental pastes. Pistol type grips with link arrangements for injection are also known, as exemplified by FR 2717697, mainly for ease of gripping instruments for veterinary mass injection. Also known, as exemplified by FR 2586192, are lateral releasable wheels for fine-tuned movements of needle instruments, mainly for laboratory work. All these solutions, however, are not intended for self-administration and are not optimized for such purposes. For example, no solutions are provided for controlled movement of both the needle and the injection mechanism. Simple devices with means for needle movement as well as injection movements are known, as exemplified by U.S. Pat. Nos. 5,425,722 and 5,147,323, but again without consideration to self-administration, e.g. by requiring different grips for the two actions and without securing proper sequencing.
Accordingly there is a continuing need for simple and inexpensive injection devices able to assist the user in the various handling steps involved, preventing or ameliorating mistakes and offering an ergonomic, convenient and non-traumatic product, especially useful for patients under self-administration. Although the present invention may have a more general utility, it will mainly be described against this background.
A main object of the present invention is to avoid the disadvantages of known injection devices as described. A more specific object is to provide an injection device able to perform both a needle penetration and an injection step and possibly also a needle retraction step. Another object is to provide a device dependent mainly only on manual energy for operation. Still another object is to provide a device assisting in the initiation steps preceding the injection procedure. Yet another object is to assist in securing a proper injection sequence. A further object is to provide a device able to give amplified or adapted force in various operation phases. Yet another object is to provide a device suitable for delivery of varying doses. Another object is to provide a device compatible with pre-filled syringes of various natures. Still another object is to provide a device suitable for self-administration. A further object is to provide a device ergonomic in use and convenient to handle. Yet another object is to provide a device allowing for minimum pain or discomfort in use. Still another object is to provide a device giving the user control over the injection procedure, yet with maintained safety. Another object is to provide a simple device of low cost, usable as a disposable device. A further object is to provide methods for operating the devices as described.
These objects are reached with the device and method having the characteristics set forth in the appended claims.
By use of an externally accessible control button linked to the device mechanism in such a manner as to allow the operation of the various phases with manual force applied to the button the overall mechanical design can be kept simple and inexpensive. Making at least part of the mechanism movements in the phases at least partially a function of control button position, the patient is given a feed-back from the actions taken, enabling corrective measures. If for example penetration of the needle through the skin causes pain it is possible to slow down needle insertion, halt the operation or select a new target site. Similarly if pain is experienced from the injection phase the injection speed can be reduced, halted or made intermittent. If the phase movements are reversibly dependent of control button position the cause of discomfort can be fully reversed e.g. allowing under the penetration phase partial or fill needle retraction for correction or postponement of the injection procedure. During the injection phase reversal may allow for example aspiration in intravenous injection. Use of the same control button for both the penetration step and the injection step allows the user to perform complete these phases without grip change, allows use of one hand only, reduces the risk for pain caused by grip change dislocation or rocking and eliminates the cause of improper sequencing through inadvertent operation of the wrong control element or double activation of multiple controls. These advantages are consistent with repeated use and operation of the same control button for the various phases. Such an arrangement additionally serves to give the patient tactile feed-back from the progress and completion of phases, thereby increasing patient control and reducing mistake risks. Furthermore it facilitates mechanical transition between phases and functional adaptations to each phase requirement, e.g. allowing different gear ratios between phases or varying response characteristics within a phase. It also facilitates arrangement of simple mechanical lock and release means for mandatory or non-reversible steps in the procedure chain. Mandatory process steps, complementary to patient controlled steps, serve to assist the user in avoiding hazardous sequencing mistakes and to secure proper completion of a phase before the next is enabled and also serve to train and accustom by guidance an inexperienced user to the expected injection program. It has been found beneficial, especially for self-administration purposes, to devise the control button so as to move when operated at least partially in a perpendicular direction with respect to the needle axis, rather than in a coaxial manner and preferably with a side or lateral position relative to the device housing. The control button will be accessible for compression also by the palm, not only by a finger, resulting in a more stable activation with one or two hands, advantages of general importance to avoid no pain but also of particular importance for patients with reduced hand strength or mobility. Furthermore, the device can be held in the palm equally efficient with the needle pointing forwards or rearwards, broadening the operation range and rendering the device equally useful for patient and assistant use. A control button movement different from the penetration direction reduces the risks for any involuntary phase triggering in the preparative actions when the device is pressed against the skin. For a given ampoule length the arrangement also allows for an overall shorter and more handy device. The general design principles outlined are fully compatible with common single or multiple chamber ampoule types in unfilled or pre-filled form and their required initiation steps. If desired the device can include a dose setting arrangement simply by limiting piston stroke length. A needle retraction capability for increased post-injection safety easily flows from a slight modification of the penetration mechanism. All device features can be realized with low cost means permitting its use for most medical purposes including single shot disposable applications.
Further objects and advantages of the invention will be evident from the detailed description hereinbelow.
In the absence of explicit statements to the contrary, as used herein expressions like xe2x80x9ccomprisingxe2x80x9d, xe2x80x9cincludingxe2x80x9d, xe2x80x9chavingxe2x80x9d, xe2x80x9cwithxe2x80x9d and similar terminology shall not be understood to be exclusively restricted to recited element but shall be understood to allow for the presence of further elements as well and shall be understood to cover any element in integral, subdivided or aggregate forms. Similarly, expressions like xe2x80x9cconnectedxe2x80x9d, xe2x80x9cattachedxe2x80x9d, xe2x80x9carrangedxe2x80x9d, xe2x80x9cappliedxe2x80x9d, xe2x80x9cbetweenxe2x80x9d and similar terminology shall not be understood to cover exclusively direct contact between the recited elements but shall be understood to allow for the presence of one or several intervening elements or structures. The same applies for similar expressions when used for description of forces and actions.
Also as used herein the concept xe2x80x9cmanualxe2x80x9d in connection with force or energy applied to the controls of the device shall be understood to mean that the operator applies, directly or indirectly, the force or energy in a manner controlling the procedure under consideration. It shall be understood to include servo arrangements in which force or energy from another source than the operator, e.g. stored energy in a spring or gas or supplied energy, is used in full or in part in assisting driving of the procedure as long as action of the operator determines the proceeding, although servo assistance is mostly not needed or preferred. In contrast to a xe2x80x9ctriggerxe2x80x9d action, which may be an on/off action, the manual action bears, at least partly or over a limited range, a function relationship to position in the procedure affected.
The injector described herein may be used for a variety of purposes within and beyond the medical area and for any type of preparations, such as chemicals, compositions or mixtures, in any container and delivered for any purpose. For reasons outlined the system has certain special values in connection with medical delivery devices where also the design constraints are more severe than in most other applications. For convenience the invention will be described in terms of this application.
Normally the material to be delivered is a fluid and preferably a liquid, including materials behaving as liquids such as emulsions or suspensions. These observations relates to the final preparation whereas other components, notably solids, may be present before final preparation. The nature of container content shall also be understood to include medical in broad terms and to embrace for example natural components and body fluids pre-filled or drawn into the container although most commonly the medical is factory prepared.
The containers usable in the present injectors generally comprises a container for the preparation and an opening through which the preparation can be delivered and a broad range of container types are useful. A needle, cannula or a similar penetration device, all referred to as xe2x80x9cneedlexe2x80x9d herein, should be in fluid connection with the opening, e.g. by being arranged on, at or with a conduit to the opening Unless a container type in itself includes means for ejecting its content a pimp mechanism may additionally be needed to be further explained. Syringe type containers are preferred for use in the present injector and shall be understood in broad terms and can generally be said to include a barrel having a front part and a rear part defining a general axis, an outlet for the preparation, typically comprising a liquid in broad sense, arranged at the front part and at least one movable wall arranged at the rear part, a displacement of which wall causes the preparation to be moved towards or expelled through the outlet, thereby including an inherent pump mechanism. Barrel shape and movable wall have to be mutually adapted. The barrel of for example glass or plastic may have a substantially constant internal cross-section, with a similarly constant barrel axis, between front and rear pails giving a generally tube-shaped barrel, and most preferably the cross-section is of the common circular type giving a substantially cylindrical barrel. The movable wall is then preferably a substantially shape-permanent, although possibly elastic, body sealingly adapted to the internal barrel surface and preferably of the piston type. At the front end of the barrel the needle is arranged and the invention is preferably used with containers wherein the needle axis is substantially parallel with barrel axis, and most preferably concentric therewith, resulting in that the penetration and the injection movements are substantially parallel. Within these limits and preferences a broad range of syringe type containers can be used with the present injector device, such as ampoules, cartridges, carpoules and syringes. The container need not have a separate piston rod but it is preferred that the injector mechanism can act more or less directly on the container movable wall, although it is fully possible that the container has a piston rod, in the sense of a part protruding from barrel rear end, on which the injection mechanism can act for movement of the piston, since many standardized devices are so designed. The injector can with preference be used with standard container types, e.g. as defined in DIN and ISO standards. Also usable are dual or multi chamber container types, known e.g. for preparations demanding a mixing of two or more components or precursors before administration. The components are kept separated by one or more intermediate walls of different known designs, which walls divide the barrel into several chambers, sometimes placed parallel along cartridge axis but most commonly in stacked relationship along the axis. Unification of the components may take place by breaking, penetrating or opening a valve construction in the intermediate walls. In another known design the intermediate wall or walls are of the piston type and flow communication between the chambers is accomplished by moving the piston to a by-pass section where the interior wall has one or several enlarged sections or repeated circumferential grooves and lands or piston deforming structures in a manner allowing by-flow of rear chamber content into front chamber at displacement of the rear movable wall. The chambers may contain gas, liquid or solids. Generally at least one liquid is present. Most commonly in pharmaceutical applications only two chambers are present and typically contains one liquid and one solid, the latter being dissolved and reconstituted during the mixing operation. For these types of containers it is possible both that the mixing or reconstitution step has already taken place when the container is placed in the injector or that means are provided within the device for unifying the chamber contents before the actual injection process is started.
Positional and directional statements for both the needle, container and the injector, such as xe2x80x9caxialxe2x80x9d, xe2x80x9cfrontxe2x80x9d and xe2x80x9crearxe2x80x9d, shall be understood with reference to tie needle, although when the needle and container are arranged to move together as described for syringe type containers it is equally true to refer to the above described parts of the container.
The needle may be connected to the container front in any manner, e.g. in the known manners of being permanently fixed by gluing, fusing etc. or by an attachment such as a luer connection, threads, threaded splines, snap-on connections or combinations thereof. The container front should be adapted to the attachment type selected, e.g. being of fusible material, being supplemented with a membrane that can be pierced or ruptured or having a front valve or by-pass arrangement. It is clear that the needle either may be connected by the manufacturer for best convenience or by the user prior to injection, e.g. to assure the user maintained sterility, to allow selection of needle type or gauge value or for repeated use of the device. Also in accordance with common practice the needle may be covered by a sterility preserving needle shield to be removed immediately prior to use. Use of standard needles, syringe fronts and attachments is preferred to maintain low costs. However, modifications may be used to achieve special advantages. As in the aforementioned U.S. Pat. Nos. 5,425,722 and 5,147,323 devices the needle need not be attached directly or rigidly to the container but with any other fluid connection. This e.g. in order to allow needle movement independent of the container, which may then be non-movable in the housing, and restrict movements to the needle proper in e.g. the penetration and needle retraction steps, simplifying the mechanism of the device. Unless otherwise indicated this option shall be considered included in the movable seat or carrier concept to be described. In this case the container need not be of syringe type but any container type can be used and injection performed by any pump mechanism, such as container squeezing, positive displacement pumps, e.g. piston/cylinder types, based on aspiration from the container followed by ejection, peristaltic action etc.
The injector device comprises a housing, which shall be understood in broad sense and basically as a point of reference for positional and directional statements for other parts and components. It is preferred, however, that the housing also actually enclose at least the mechanisms of the device and leave exposed mainly the parts that should be accessible to the user, mainly the control button but also auxiliary parts such as dose setting, alarm, arming, triggering and cocking controls. The container can be attached to the housing in such a manner that it remains exposed, although it is preferred that the housing also confines the container, preferably also the needle until penetration is initiated. The housing may be designed to be partially or fully openable and/or closeable to access or close its interior, which may be facilitated by any known separation or openable arrangement, e.g. threaded or hinged parts, possibly with reversible or irreversible locking means. Reversible locking may be used to access the device interior e.g. for adjustment or control or to allow simple insertion or replacement of containers, e.g. to permit reuse of the device, for loading of selected or varying preparation types or doses. As indicated it is often preferred to use the device as a disposable in which case it is preferred to factory load it with the container and a simple closure arrangement is still of value for rational assembly in manufacture. For safety and security reasons an irreversible closure may be of value to prevent any tampering with the used container and needle. In broad terms the housing shape is not critical for the basic function of the device but may influence its ergonomic and convenience properties. The overall shape of the housing can take a variety of shapes depending on among others the internal component layout. As indicated the housing incorporates at least the container and the transmission mechanism between control button and container. As in the prior art most of the mechanism parts can be arranged axially behind the container in which case a minimized housing can take an elongated form. The control button can be designed for axial depression. For the several reasons outlined it is preferred to design the control button for lateral movement relative container axis and for this option it is preferred that at least the control button is located at least partly lateral to container axis and preferably between the container ends, and preferably also at least part of the mechanism is similarly located between the control button and the container. A minimized housing embracing these parts can then be given an axially shorter but laterally wider shape and if said lateral housing, excluding button, extension is considered as xe2x80x9cheightxe2x80x9d, the axial extension as xe2x80x9clengthxe2x80x9d and the dimension perpendicular to these two as xe2x80x9cwidthxe2x80x9d, it is preferred that the maximum height to maximum width ratio is larger than 1, preferably larger than 1.5 and most preferred larger than 2. The maximum length to maximum height can often be kept less than 4, is preferably less than 3 and most preferably less than 2.5. The overall shape described has been found ergonomically suitable, structurally rigid and easy to manipulate and assemble in manufacture.
The injector further comprises a needle seat, the minimum requirement of which is to allow at least the needle, and preferably needle and container when rigidly connected, to be axially movable in relation to the housing, for penetration purposes, between a rear position and a front position, movement between which positions is used for penetration. The distance traveled between the positions should correspond at least to the desired penetration depth and, when the needle is hidden within the housing before the penetration step, also the distance needed for internal travel to expose the needle tip. The needle seat may comprise guiding structures fixed in relation to the housing, securing the desired needle path, or may alternatively or additionally comprise a carrier movable in relation to the housing and in which the needle or container is retained. Depending on the needle seat design selected the penetration mechanism to be described may act directly or indirectly on the needle, the container or the carrier for propulsion of the needle during penetration and possible needle retraction. Optionally the actual penetration depth is adjustable, e.g. in the seat path or in the penetration mechanism. Alternatively the depth is adjusted by the needle length selected.
As said the device shall incorporate arrangements for at least a needle penetration movement and an injection movement for the container content. Preferably the device also comprises arrangements for needle retraction. It is also preferred to include features assisting the user in the injection initiation steps to be described.
With some similarities to corresponding capabilities in autoinjectors, penetration and injection may take place concurrently, e.g. in simple devices or for the intentional purpose of allowing for an over depth distributed injection. Normally it is desirable to limit injection until the needle has reached or is close to its target location. This feat can be obtained with a force system acting on movable wall or piston rod for both purposes, relying for sequencing on the normally lower needle penetration resistance than fluid ejection flow resistance. Yet it is difficult to avoid at least some leakage during penetration but above all, in case the penetration movement is prevented or jams, injection will entirely fail with preparation expelled on the skin or at improper depth. Hence it is preferred to apply penetration force directly or indirectly on the needle or container, which requires some control mechanism disabling injection force application during most of the penetration phase and enabling injection force only after proper penetration. A needle retraction step can be performed manually, but is preferably made at least semi-automatically in order to guarantee safe hiding of the needle, which can be made e.g. in a manner known per se in which stored energy, typically stored during the penetration movement in a weaker return counterspring, acts to push the syringe back into the injector after completed injection. Again, this function may need a control mechanism enabling action of the return spying only after completed injection, normally accomplished by separation of the penetration and injection forces from the syringe at a certain forward extreme for the piston or piston rods freeing the return spring for action.
The penetration movement shall take place by use of manual energy applied to the control button and a penetration transmission may be needed to transfer the force between the control button and the needle, possibly via container or carrier, as the case may be, and preferably on or via the container barrel for reasons mentioned. In principle any conventional transmission means can be used, e.g. electromechanical, such as electric motors or solenoids, hydraulic, pneumatic etc. system but preferably mechanical means are utilized for simplicity. The transmission may take a variety of forms depending on the button position and mobility. If for example the button is positioned on the housing at the axial extension of the container or needle axis the transmission can be a more or less rigid connection if the button mobility is towards the front or a screw and nut transmission if the button is arranged for rotational movement around said axis. Preferably the button is arranged for movement with at least a component perpendicular to the needle axis, most preferably for needle ejection when moving the button towards the housing, e.g. as a more or less guided translational movement along such a button path or as a rotational movement around a rotation axis, preferably a rotation axis along the housing width direction in which case the push area of the button can be located behind, but preferably in front of, the rotation axis. As said the button is then most preferably positioned lateral to the needle axis but between container end boundaries. In these cases it is preferred to use a transmission able to redirect the force applied to the button, which can be done with any known such transmission arrangement, e.g. wire or belt type arrangement, a link arrangement such as a limb and joint system, a lever arrangement and preferably a wheel, preferably toothed wheel, system in which the button movement rotates the wheel for propulsion of the needle, preferably via a toothed rail. If desired any transmission may contain force transforming parts to increase, decrease or vary the force during the penetration stroke. Known such means can be used, e.g. by adaptation of gear ratios, lever degrees, knee elements or use of cam surfaces. Also the control button itself may be used for leverage, e.g. if hinged and by adaptation of pressure point to force extraction point for the transmission. Generally the penetration step requires only small forces due to the little insertion resistance in soft tissue and it is preferred for good patient control and feed-back that the button stroke length is not too short during this step. Preferably the finger movement on the button to needle movement length ratio is larger than 0.1, preferably larger than 0.2 and most preferably larger than 0.5. Preferably the ratio is less than 10, preferably less than 5 and most preferably less than 1. It is desirable that a definite stop for button movement is provided at full predetermined needle ejection, e.g. by a stop surface arranged anywhere in the chain between button and needle.
The injection movement may take place automatically during or after the penetration movement, which may serve the purpose of reducing the number of step to be performed by the patient or when injection pain is unavoidable e.g. due to irritating compounds in the injected preparation. This result will be obtained if the force application principle is used in which penetration force is applied to the container movable wall, as described, under continued operation of the control button. Alternatively non-manual stored energy may be applied to the injection mechanism, e.g. by a spring or gas pressure system, preferably to be released at the end of the penetration movement, which may require an enabling mechanism at this point similar to those used in autoinjectors, e.g. a structure on the housing releasing a lock between the stored energy drive and the movable wall at a point in the housing corresponding to completed penetration. For reasons mentioned it is preferred that also the injection movement takes place by use of manual energy since it is desirable to give the patient feedback from and control over the injection for corrective measures or speed control as pain or discomfort may result form the injection, especially at larger injected volumes. After use of the control button for penetration such manual injection may take place by use of a separate injection control, for which purpose any known injection mechanism or described transmission may be used. It is, however, preferred to use the control button also for the injection procedure. A transmission is then needed between the control button and the container movable wall, similar to that for penetration, but acting on the movable wall, and any of the transmission principles described may be used also for injection. An entirely separate transmission for the injection can be used but preferably the transmission comprises common parts for the two purposes and most preferably they differ substantially only where necessary, in particular in respect of details for shift between the phases and adaptations for each phase. In the latter regard it might be of interest to adapt the force requirements since these are higher for injection than for penetration. This can be done by increasing the gear or lever ratio. Preferably the finger movement on the button to movable wall movement length ratio is larger than that for finger movement versus needle movement used under penetration. For injection said ratio is preferably greater than 0.2, preferably larger than 0.5 and most preferably larger than 1. Preferably the ratio is less than 20, preferably less than 10 and most preferably less than 5. In case the finger movement tends to be inconveniently long it is possible and preferred to allow for repeated operation of the control button until emptying of the container is complete.
For the simplest operational options described, e.g. when acting on the container movable wall and when using a single button stroke for both phases, it might not be necessary to include any switch system for enabling and disabling respectively or redirecting the forces applied to the control button. To reach most of the preferred capabilities described, however, it is preferred to includes such a switch system. A first desired switch function is a phase shift system allowing the force applied to first act on the needle, directly or indirectly e.g. via container barrel or a carrier, for penetration and then act, directly or indirectly, on the movable wall for injection. A second desired switch function is a reconnect system allowing repeated operations of the control button. These desired functions are to some extent mutually dependent, as for example press and release actions on the button can be used to accomplish a phase shift, e.g. at a certain position for the button movement although it is preferred to use other means than the button, and all possibilities and combinations cannot be enumerated of described in detail. In broad terms phase shift can preferably be made at a certain relative axial location between needle and housing, e.g. corresponding to completed penetration stroke or preferably slightly before to avoid too high tolerance demands on the shift mechanism. Physically the shift can preferably be made by using a structure, with substantially fixed location with respect to the housing, to redirect or unlock the force applied for action on the movable wall, e.g by deflection, rotation or any other mechanism, or preferably by applying force at a constant location, preferably by a wheel, where automatic shift takes place when penetration a movement is completed, e.g. by having the wheel first act on a surface for penetration and then changing over to a surface for injection when penetration is completed, which principle also allows for change of gear ratio. For several reasons, e.g. to secure proper sequencing and avoid inadvertent withdrawal, to facilitate adaptations for later needle retraction and to indicate penetration completion to the user, it is preferred to provide a lock to hold, at least temporary, the needle in the front position, which can be made by any lock structure, e.g. a hook structure, preferably biased for automatic engagement in that position and possibly designed for, or supplemented with, a tactile or audible confirmation of penetration completion. The lock may be permanent, e.g. if no needle return function is present, or releasable with features of the internal mechanism or even manually if used for needle or container front access.
A properly designed phase shirt system, preferably by structures other than the button, as above offers broad freedom for design of the reconnect system and movement pattern for the control button. It is possible to use a single button stroke for both penetration and injection, e.g. to minimize patient actions or for small injection volumes or penetration depths or to allow for aspiration of liquid and in this case no reconnect system need to be present. Among others in order to give the patient phase dependent feedback, arrange for phase dependent adaptations or avoid too long button strokes, it is, however, preferred to use at least two actions on the button, preferably at least one for penetration and at least one for injection, and possibly several strokes within a phase, especially the injection phase as said. This can be accomplished by using the button as part of the phase shift system, e.g. by using the end of the first button stroke for phase shift and further movement of the button for injection. It is preferred, however, to use the phase system principles mentioned other than the button, which permits a more general design of the reconnect system. A general reconnect system may allow two-way button movement. It may allow force to be applied to the transmission during movement in both directions but is preferably designed to be idle in one movement direction, preferably idle when moved away from the housing, for best convenience. Mechanically any known one or two way means may be used, such as clutch, centrifugal or friction based mechanisms, pawl and ratchet mechanisms or preferably a wheel with releasable axis. With any such design the button movements can be repeated freely, e.g. allowing patient mistakes or action individuality, while the phase shift system secures the proper phase sequencing. Reversible phase action is possible. It is for example beneficial that the needle movement during penetration can be reversed in certain situations, e.g. to allow interruption and selection of new injection site if pain is experienced or to allow exposure of the needle or container front for inspection or for needle attachment. Reversible penetration can be obtained e.g. by having a force bias in the needle reverse direction, e.g. a needle retraction spring. During injection a several stroke pumping action is automatically achieved with the general reconnect system, more safely though if rearward movement of the container is prevented, e.g. in the embodiments with fixed container, if not rearward biased or if locked in the foremost position as described. As an additional safety measure during the injection, especially when several stokes are needed, rearward movement of the movable wall can be prevented, e.g. by allowing forward movement only of the parts acting on the movable wall, e.g. by inclusion of a friction element, a one-way ratchet mechanism or by similar means. It is also preferred to bias the button itself towards one of its positions, preferably towards the button start position such as the outer distal position relative the housing, which can be done with simple and inexpensive means, such as a spring in metal, elastomer or plastic.
For reasons stated a needle return function is preferably included in the injector. With respect to force application for needle retraction similar considerations apply as for penetration, i.e. the force can be applied directly to the needle or its attachment, to container barrel or any carrier for these parts. The needle may be retracted by application of manual energy, e.g. to give the user control also over this action. A separate control may then be arranged, allowing a simple construction and a simple connection between control and needle. For convenience it is preferred to use the control button also for needle retraction, especially if this step shall take place in connection with the injection procedure and for withdrawal from the tissue. A transmission and button reconnect system of principles similar to that for penetration and injection may then be needed. Needle withdrawal from the tissue is rarely a painful task, however, that necessarily need full manual control. For this and other reasons it is preferred make needle retraction at least partially automatic. The function may be semi-automatic in the sense that after a mandatory manual triggering needle retraction proceeds automatically, preferably by release of stored energy, e.g. in the known manner of arranging a return spring biased for rearward needle movement, commonly compressed during the needle penetration step The triggering may take place via a separate control for this purpose but preferably the control button is also used as trigger for needle retraction. The control button may release the needle retraction when it is released after the injection but it is preferred that an additional, repeated, operation of the button is used. For highest safety and ease of operation needle retraction can be fully automatic in the sense that this step follows at a particular point in the injection procedure, without any manual triggering action from the user. The procedure point is preferably when the expulsion of preparation is finished and hence the injection phase completed, which may be when the movable wall bottoms out, in case of container complete emptying, or at a certain movable wall position, in case of partial emptying, the latter useful mainly when the dose can be set or adjusted or for repeated injections from multi-dose containers. Expressed in another way, the movable wall arrival at the predetermined position is taken as the triggering event for needle retraction. Mechanically any part of the injection transmission including the button, which parts has a determined positional relationship to movable wall position, can be used as internal trigger, e.g. to enable release of stored energy for example by unlocking a return spring lock. In case a lock is provided to retain the needle position after penetration, in the preferred manner described earlier, with preference such a lock can be used for enabling of a return spring for action. In case it is desirable to disable the device permanently after needle retraction, e.g. for single use disposable devices, arrangements may be provided to lock the needle in the retracted position in a non-releasable manner, e.g. by any known means, again anywhere in the transmission chain. As part of this feature, or additionally e.g. to indicate the used status to the user, the control button can be locked against further movements, preferably in its compressed position to conserve space. In case no needle retraction function is present, but other safety precautions are relied on, e.g. incineration, for destruction the non-releasable locking can take place after the injection phase.
In order to allow setting of the dose to be ejected, e.g. for partial or repeated injection, a dose setting mechanism can be included. Since the dose setting generally takes place before the actual injection procedure is initiated and without restrictions in device position, controls for this purpose can be arranged more freely than the control button. Although it is possible to include adjustable displacement limitations acting on the movable wall as such, it is generally preferred to provide such limitations for action on the parts earlier in the injection chain. They may be arranged in the control button or anywhere in the injection transmission, but it is preferred to provide separate such limitations. Any common means, known as such in for example injection pens, can be used. If the last part of the transmission affecting the movable wall or the piston rod as the case may be, is regarded as a xe2x80x9cplungerxe2x80x9d arrangement it is for example possible to use an adjustable stop surface for the plunger arrangement, an adjustable space for plunger dead run relative to the movable wall or a combination thereof. It is possible that the injection stroke length, or combined stroke lengths, for the control button varies for different dose settings but preferably dose setting mechanisms are selected in which the stroke lengths are kept constant and independent of the dose setting.
It is also preferred to include in the device features facilitating initiation steps preceding the actual injection. It is possible to deliver the device without any container or needle for later attachment of these parts and in order to facilitate attachment the container site may comprise an attachment such as a push lock, bayonet, threads or any other fit. It is also possible that the needle is pre-mounted on the container but commonly it need to be connected immediately prior to use or allow for replacements and in most cases a needle shield need to be removed prior to use and in all these instances the needle attachment site, most often the container front, need to be accessible to the user. Possibly the device has a compartment for needle storage before attachment. In case of dual or multiple chamber cartridges initiation may require an initial movement of the movable wall to unify and mix chamber contents and although this step may be performed before container attachment to the device it is preferred to allow for this when attached to the device, e.g. allowing the plunger arrangement to be initially movable against the movable wall, e.g. by a temporary release from the transmission, but preferably by making the container axially movable against the plunger when stationary in the housing and most preferably by threaded attachment permitting cautious displacement of the movable wall as described e.g. in U.S. Pat. No. 4,968,299. An initial displacement of the movable wall is also needed to perform de-aeration and pre-ejection, which movement may take place with similar means as for multiple chamber containers. Any initial movement of the movable wall may require high break-loose forces. For any or all of these actions it is beneficial that at least the container front is accessible to the user, which can be arranged for by utilization of the penetration mechanism to at least partially make the penetration movement and preferably temporary lock this position to resist the manipulation steps applied. It is also possible and often preferred to make at least the device front part open or openable through removal, hinged door etc. The displacement of the movable wall for the above mentioned initiation purposes may take place by manually pushing the plunger or the container towards each other in axial direction. It is, however, preferred to arrange for an assisting leverage or gear ratio, for example to increase force for break-loose, reduce speed in mixing or keep the initiation movement short in de-aeration and pre-ejection. Any known leverage principle can be used but a preferred arrangement is use a hinged door for the device front, the closing of which causes the container to move rearwards, preferably under force amplification and preferably under displacement of the movable wall forwards, such as when the wall is substantially stationary in relation to the housing. After closing of the door the needle is preferably hidden within the housing and it may be beneficial to arrange the door so that it cannot be at least fully closed unless the needle is properly attached and further so that the door is permanently and irreversibly locked, and possibly also arranged to block any further change of a dose setting control if present. A door may additionally serve to influence the possible control button movements, in particular to enable or disable movement thereof. For example the button may be inoperable until the door has been fully closed, with any of the additional functions mentioned above, either by being disconnected from the transmission or by being held stationary in a given position by blockage of the button or the transmission. All these arrangements serve to secure a proper sequence of actions and reduce the risks for mistakes or misuse.
The methods for using the device follows from the descriptions made of structures, functions and objects. Below a summary of preferred actions. Any door or closure over the device front is removed or opened. If the container is not pre-assembled in the device housing the operator inserts the container and possibly connects it to attachments provided. If the container is a dual or multiple chamber device mixing operation may be undertaken before attachment to the device but is preferably made when attached or during attachment to the device, preferably by actions involving an axial displacement of the container towards a plunger arrangement in rest abutting the movable wall. Unless a needle is already in place the operator mounts a needle on its seat and possibly removes any needle shield present. The needle is pointed roughly upwards and the movable wall is moved forward to expel air and possibly eject a small preparation amount to assure proper function. Preferably the wall is moved forward by displacing the container rearwards against a plunger arrangement and most preferably by closing a hinged door arranged to also displace the container rearwards. Such displacement may be levered so that the closing length exceeds the container displacement length. Preferably the closing also acts to enable the control button for action. The steps performed should secure that the needle is now hidden within the device. If applicable a dose setting operation may take place at any point up to now. The control button is operated to perform penetration movement to bring the needle to an exposed position. This is preferably made in a single step, without repeated action on the button, and preferably by pressing the button towards the housing, a movement preferably having at least a component perpendicular to the axial direction. The exposed needle may now be inserted into a target object, e.g. human or animal tissue or any other material or device e.g. for laboratory use, but preferably the device front is placed against the receiving object beforehand so that said insertion takes place as a result of the penetration movement. Preferably the needle or container is locked at the penetration end position and it is preferred that an audible or tactile signal is issued, by the locking arrangement or otherwise, to confirm completed penetration to the user. A injection step may now be performed. This can be done with a continued movement of the control button but preferably the button movement pattern is changed for injection, preferably involving release for return to a start position and most preferably so that a new movement from the start position performs the injection. Several injection strokes can be made with the button during injection, especially for larger injected volumes or as an adaptation for weak persons. Completed injection may be sensed as a stop for the button when the movable wall reaches the container end or at abutment of stop surfaces arranged in the transmission. Preferably a needle return step is now performed, either automatically or triggered by the operator. Triggering may be made by a separate trigger, by release of the control button or first when the button is again operated. Although the needle may be removed from the object before the needle return step it is preferred that removal takes place as a result of the needle retraction step.
Although the above method steps have been described as a sequence of given order it is within the spirit of the invention that other sequence orders may be used unless specific statements to the contrary are given.

Injection device and method for its operation


In accordance with embodiments of the present disclosure, a system may include a cooling subsystem comprising at least one air mover configured to generate a cooling airflow in the system and a thermal manager communicatively coupled to the cooling subsystem for control of the cooling subsystem and configured to: (i) determine relevant temperature limits of each of a plurality of hardware configurations, the hardware configuration based on a hardware inventory of the system; (ii) determine the lowest temperature limit of the relevant temperature limits; and (iii) responsive to a determination that a real-time temperature is above the lowest temperature limit, take remedial action.

As the value and use of information continues to increase, individuals and businesses seek additional ways to process and store information. One option available to users is information handling systems. An information handling system generally processes, compiles, stores, and/or communicates information or data for business, personal, or other purposes thereby allowing users to take advantage of the value of the information. Because technology and information handling needs and requirements vary between different users or applications, information handling systems may also vary regarding what information is handled, how the information is handled, how much information is processed, stored, or communicated, and how quickly and efficiently the information may be processed, stored, or communicated. The variations in information handling systems allow for information handling systems to be general or configured for a specific user or specific use such as financial transaction processing, airline reservations, enterprise data storage, or global communications. In addition, information handling systems may include a variety of hardware and software components that may be configured to process, store, and communicate information and may include one or more computer systems, data storage systems, and networking systems.
As processors, graphics cards, random access memory (RAM) and other components in information handling systems have increased in clock speed and power consumption, the amount of heat produced by such components as a side-effect of normal operation has also increased. Often, the temperatures of these components need to be kept within a reasonable range to prevent overheating, instability, malfunction and damage leading to a shortened component lifespan. Accordingly, thermal management systems including air movers (e.g., cooling fans and blowers) have often been used in information handling systems to cool information handling systems and their components. Various input parameters to a thermal management system, such as measurements from temperature sensors and inventories of information handling system components are often utilized by thermal management systems to control air movers and/or throttle power consumption of components in order to provide adequate cooling of components.
One limitation of existing thermal control systems are that System ambient operating conditions are static and do not change with changes in configuration of an information handling system. Thus, static ambient limit-based warnings often reflect a portfolio standard support, not a customer-specific configuration. Configuration-based limits are often instead defined in source books or user manuals in which a user may access to better understand server thermal boundary conditions. Thus, changes to fan types in monolithic systems are not accounted for in legacy temperature limit definitions, ambient temperature limits, power capping limits, and other parameters may not be updated as more performance and airflow is available.

Systems and methods for automated configuration restrictions and compliance of temperature


A technique for supporting multi-tenancy in a NAS cluster provides a management database which tracks, for each tenant of the NAS cluster, a tenant-specific list of identifiers of NAS data nodes that are authorized to run NAS servers owned by respective tenants. In response to a request to run a NAS server owned by a particular tenant of the NAS cluster, the technique limits the scope of NAS data nodes on which the NAS server may be run to the ones identified in the tenant-specific list for that tenant in the management database. The management database thus determines where each tenant's NAS servers may be run, and participates in driving NAS cluster activities, such as NAS server provisioning, load balancing, and failover.

Data storage systems are arrangements of hardware and software that include storage processors coupled to arrays of non-volatile storage devices, such as magnetic disk drives, electronic flash drives, and/or optical drives, for example. The storage processors service storage requests, arriving from host machines ("hosts"), which specify files or other data elements to be written, read, created, deleted, and so forth. Software running on the storage processors manages incoming storage requests and performs various data processing tasks to organize and secure the data elements stored on the non-volatile storage devices.
Some data storage systems aggregate data objects in structures known as virtual data movers (VDMs). Each VDM is a collection of user file systems, settings, and one or more network servers, such as a CIFS (Common Internet File System) server, SMB (Server Message Block) server, and/or an NFS (Network File System) server, which provide host access to the file systems. Many VDMs may operate together in a single storage processor and within a single operating system environment. Each VDM typically has an owner, and the owner is typically a tenant of the storage system. As is known, a "tenant" is an entity on whose behalf data are stored, such as a company, some other type of organization, or a user.
In storage systems that support multi-tenancy, each VDM is typically owned by a tenant, and that tenant has exclusive access to the contents of the VDM. Storage systems may segregate VDMs based on tenant, ensuring that no two tenants use the same network server (e.g., CIFS, SMB, or NFS server). For stronger isolation, some storage systems support per-tenant storage pools, i.e., collections of storage resources derived from disk drives in the system. Each tenant may have its own storage pool, or multiple such pools, on which that tenant's VDMs are deployed. As VDMs of different tenants are backed by different pools, such systems provide isolation between tenants at the storage level.

Managing multiple tenants in NAS (network attached storage) clusters


Producing a silica particle by inhibiting the generation of incompletely reacted materials such as oligomers which have not been grown to the silica particles having the intended particle size. A dispersion liquid of a silica particle is produced by simultaneously adding, to a liquid substantially consisting of an organic solvent, a liquid containing silane alkoxide and a liquid containing an alkali catalyst and water to cause hydrolysis and polycondensations to produce a silica particle. The variation rate of the mole ratio of the alkali catalyst to silane alkoxide in the reaction system for a period from the start to the end of the reaction relative to the initial mole ratio is 0.90 to 1.10; and the variation rate of the mole ratio of water to silane alkoxide for a period from the start to the end of the reaction relative to the initial mole ratio is 0.90 to 1.10.

Field of the Invention
The present invention relates to a method for producing a dispersion liquid of a silica particle, and particularly to a method for producing a dispersion liquid of a silica particle useful for an abrasive used in polishing during formation of a metal wiring layer on a semiconductor integrated circuit, etc.
Description of the Related Art
Various integrated circuits are used for computers and various electronic devices. As they are downsized and become sophisticated, higher density and higher performance have been required for circuits.
To produce a semiconductor integrated circuit, for example, an interlayer film (insulating film) is formed on a substrate such as a silicon wafer, a groove pattern for a metal wiring is formed on the interlayer film (insulating film), a barrier metal layer of tantalum nitride (TaN) or the like is formed by a sputtering method or the like, as necessary, and then a copper film for a metal wiring is formed by a chemical vapor deposition (CVD) method or the like. Here, when a barrier metal layer of TaN or the like is provided, the barrier metal layer can prevent, for example, lowering of the insulation properties of the interlayer insulating film in association with the diffusion of copper or an impurity or the like to the interlayer insulating film and erosion of the interlayer insulating film, and can enhance the adhesion between the interlayer insulating film and copper.
Subsequently, a film of unnecessary copper and barrier metal (occasionally referred to as "sacrifice layer") formed on a portion out of the groove is removed by polishing with a chemical-mechanical polishing (CMP) method and the upper surface is flattened to the maximum extent possible, and thus a wiring/circuit pattern of copper is formed by leaving a metal film only in the groove.
The abrasive used in the CMP method is typically produced by adding an oxidant for increasing the polishing rate of a wiring/circuit metal and an additive such as organic acid to a dispersion liquid comprising a spherical polishing particle consisting of a metal oxide such as silica and having an average particle diameter of about 5 to 300 nm.
When incompletely reacted materials (by-products) such as oligomers of silane alkoxide are present in the dispersion liquid comprising the polishing particle (silica sol), the silica sol has not had a sufficient stability, presumably due to the influence of the incompletely reacted materials such as highly reactive oligomers. Further, thickening, aggregation, white turbidity, generation of a sedimentary gel, etc. sometimes have occurred due to the influence of additives mixed to the dispersion liquid when used as an abrasive. Use of such an abrasive sometimes has resulted in appearance of scratches due to aggregates and has caused a problem by silica components remaining on a substrate after polishing (e.g., see Japanese Patent Laid-Open Publication Nos. 2015-124231, 2012-156393, and 2014-154707). Furthermore, in some cases, the silica sol has adsorbed an additive for enhancing the abrasive property, resulting in reduction in the effect of the additive.
As a method for producing a silica sol in which the generation of incompletely reacted materials such as such oligomers is suppressed, for example, proposed is a method which comprises (a) a step of adding an organic solvent containing tetramethoxysilane and a solvent containing an alkali catalyst and water to an organic solvent containing an alkali catalyst and water to cause hydrolysis and polycondensation of tetramethoxysilane, so as to produce a silica sol; and (b) a step of heating a dispersion medium of the silica sol to a boiling point of water to substitute with water (see Japanese Patent No. 4566645).

Silica particle dispersion and production method of the same


Silicone rubber compositions prepared from polydiorganosiloxane and small amounts of alkali metal hydrogen phosphates or alkali metal hydrogen phosphites improve the properties of the silicone rubber, such as compression set and flame retardancy.

1. Field of the Invention
This invention relates to silicone rubber composition and to silicone rubber. This invention also relates to a method of improving the flame retardancy of a silicone rubber.
2. Background Information
The silicone rubber art is filled with methods and additives which are designed to improve the properties of the silicone rubber. Many of these methods and additives are complex, expensive, and difficult to use. For example in the art of making silicone rubber flame retardant, platinum compounds are added to the silicone rubber composition. Platinum is expensive even in small amounts. Because the amounts of platinum used are small, parts per million, and because it is susceptible to poisoning, care must be taken to avoid materials and environments which can poison the platinum thus making it ineffective as a flame retardant. However, platinum alone is not enough for most applications and additional ingredients are needed to further improve the flame retardant property These additional ingredients might be the rare earth oxides and hydroxides which are also expensive. Other additives which can be used are carbon black and fumed titanium dioxide. The carbon black, although effective in improving the flame retardant property, only allows the production of black or grayish products and many applications require transparent materials or a color other than black or gray, such as in electrical insulation for wiring. Some of the means used to improve the flame retardancy of the silicone rubber destroy the physical properties of the silicone rubber to such a great extent that the silicone rubber becomes unusable for the application for which it was designed.

Silicone rubber containing alkali metal salts of phosphoric acid and phosphorous acid and compositions therefor


The present invention relates to a novel truncated forms of hepatocyte growth factor (HGF) which specifically antagonizes the activity of HGF and to a novel truncated form of HGF that is a partial HGF agonist. In particular, the present invention relates to the purification, molecular cloning, recombinant expression of the truncated HGF variants and related pharmaceutical compositions. The present invention further relates to the utilization of the small HGF variants to either inhibit HGF mitogenesis or stimulate HGF mitogenesis in cells expressing the receptor for HGF.

1. Field of the Invention
The present invention relates to naturally occurring truncated forms of Hepatocyte Growth Factor (HGF), which are encoded by alternative HGF mRNA transcripts. In particular, the present invention relates to a small HGF variant, HGF/NK2, which is a competitive antagonist of HGF, and HGF/NK1, which is a partial agonist of HGF.
2. Background Information
Hepatocyte growth factor has hormone-like activity and is released in response to partial hepatectomy and liver injury and is presumed to be an important mediator of liver regeneration (Nakamura et al., FEBS Lett. 224: 311 (1987); Gohda et al., J. Clin. Invest. 81: 414-419 (1988); R. Zarnegar and G. Michaelopoulous, Cancer Research 49: 3314-3320 (1989)). Its ubiquitous expression by stromal fibroblasts and demonstrated ability to stimulate DNA synthesis in melanocytes and endothelial cells as well as epithelial cells suggest that this factor plays a role in paracrine regulation of cell growth as well (Rubin et al., Proc. Natl. Acad. Sci. USA 88: 415 (1991)). Reports showing that scatter factor has high amino acid sequence identity to HGF over restricted regions, suggested that HGF may also be involved in modulating cell-cell interactions and migration (E. Gherardi and M. Stoker, Nature 346: 288 (1990); Weidner et al., J. Cell Biology 111: 2097-2108 (1990)). This has been borne out by subsequent studies that verify the identity of scatter factor and HGF.
Structurally, HGF resembles plasminogen in that it possesses characteristic kringle domains (Patthy et al., FEBS Lett. 171: 131-136 (1984)) and a serine protease-like domain (Miyazawa et al., Biochem. Biophys. Res. Commun., 163: 967-973 (1989); Nakamura et al., Nature 342: 440-443 (1989)). Like plasminogen, HGF can be processed by proteolytic cleavage, generating a heterodimeric molecule comprised of a heavy- and light-chain covalently linked by disulfide bonds (Nakamura et al., Nature 342: 440-443 (1989) and Miyazawa et al., Biochem. Biophys. Res. Commun. 163: 967-973 (1989)) The possibility that its actions might be mediated by a receptor tyrosine kinase was suggested by its rapid stimulation of tyrosine phosphorylation of cellular proteins in target cells (Rubin et al., Proc. Natl. Acad. Sci. U.S.A. 88: 415 (1991)). Recent studies have directly identified the HGF receptor as the c-met protooncogene product (Bottaro et al., Science 251: 802 (1991)), whose structure resembles that of a membrane-spanning tyrosine kinase (Park et al., Proc. Natl. Acad. Sci. USA 84: 6379-6383 (1987); Chan et al., Oncogene 2: 593-599 (1988)).
There is accumulating evidence that the positive effects of growth factors on cell proliferation can be counteracted at a variety of levels both intracellularly (Moses et al., Cell 63: 245-247 (1990) and at the cell surface (Hannum et al., Science 343: 336-340 (1990), Eisenberg, et al., Nature 343: 341-346 (1990); Carter et al., Nature 344: 633-637 (1990)). Thus, the potential exists to find an antagonist to HGF which would negatively regulate the growth factor""s proliferation effects. The invention described herein relates to small HGF variants and their corresponding transcripts. Characterization of one of these HGF variants, HGF/NK2, has revealed that it is a competitive antagonist of HGF action and thus establishes a novel regulatory mechanism whereby the same gene encodes both an agonist and antagonist of growth factor action. Characterization of another HGF variant, HGF/NK1, revealed that it is a partial agonist of HGF in vitro.
Although those of skill in the art of the invention possessed knowledge of HGF, no one knew about or could have predicted the existence of alternative mRNA transcripts encoding the claimed variants. Indeed, the inventors discovered HGF/NK1 and HGF/NK2, none of the work related to HGF even remotely suggested that a small transcript, particularly one, such as HGF/NK2, that is an HGF antagonist, or HGF/NK1, that is a partial HGF agonist, existed.
Thus, in one embodiment, the invention relates to a substantially pure HGF variant that is a truncated form of HGF comprising the N-terminal and first two kringle domains of HGF, and that specifically inhibits HGF-induced mitogenesis.
In another embodiment, the invention relates to a substantially pure HGF variant that is a truncated form of HGF comprising the N-terminal and the first kringle domain of HGF, and that is a partial HGF agonist.
In yet another embodiment, the invention relates to a method of inhibiting HGF induced mitogenesis in cells expressing the receptor for HGF, comprising contacting the cells with a mitogenesis-inhibiting amount of the HGF variant HGF/NK2, such that HGF induced mitogenesis is inhibited when the HGF variant binds the receptor for HGF on the cells.
In another embodiment, the invention relates to a method of stimulating mitogenesis in cells expressing the receptor for HGF, comprising contacting the cells with a mitogenesis-stimulating amount of HGF/NK1, such that mitogenesis is stimulated when the HGF variant binds the receptor for HGF on the cells.
In another embodiment, the invention relates to an isolated and substantially pure DNA molecule that encodes HGF/NK2.
In another embodiment, the invention relates to an isolated and substantially pure DNA molecule that encodes HGF/NK1.
In another embodiment, the invention relates to a recombinant vector comprising the above DNAs.
In another embodiment, the invention relates to a host cell stably or transiently transfected with the above described DNA in a manner allowing expression of the protein encoded by the DNA.
Another embodiment of the invention relates to a method of producing a recombinant HGF variant, comprising culturing the above host cell in a manner allowing expression of a protein and isolating the protein from the host cell.
In another embodiment, the invention relates to a method of producing the above described substantially pure HGF variant protein, the method comprising the following steps:
(i) culturing HGF variant-producing cells in a culture medium under conditions such that HGF variant is produced;
(ii) concentrating the culture medium so that a concentrate is formed;
(iii) contacting the concentrate with heparin under conditions such that HGF variant in the concentrate binds to the heparin, whereby a heparin-HGF variant complex is formed;
(iv) separating the heparin-HGF variant complex from the concentrate;
(v) treating the heparin-HGF variant complex under conditions such that the HGF variant dissociates from the heparin so that a solution of free HGF variant is formed;
(vi) fractionating the solution by sizing chromatography and/or reverse phase HPLC so that HGF variant is separated from the remaining components.
In another embodiment, the invention relates to a method of producing a substantially pure and biologically active Hepatocyte Growth Factor (HGF) variant comprising the steps of:
(i) disrupting HGF variant-producing bacteria that have been cultured in a culture medium under conditions such that HGF variant is expressed, so as to produce a first HGF variant protein-containing suspension;
(ii) recovering the protein from the first suspension and, washing and solubilizing the recovered protein, wherein the solubilizing is performed with a denaturant and reducing agent, and wherein a second protein-containing suspension is produced;
(iii) fractionating the second suspension by sizing chromatography with a solvent containing a denaturant and a reducing agent;
(iv) removing the denaturant from the fractions of step (iii) and pooling selected fractions containing denatured HGF variant;
(v) purifying said HGF variant in the pooled fractions by reverse phase chromatography;
(vi) lyophilizing the purified HGF variant of step (v) and redissolving the lyophilized HGF variant with denaturing and reducing agents;
(vii) serially diluting and then incubating the redissolved lyophilized proteins in refolding buffer, and then removing the denaturant by dialysis, so as to produce a third suspension containing biologically active proteins;
(viii) concentrating and then purifying said dialyzed proteins in the third suspension by sizing chromatography, so as to produce several fractions containing biologically active HGF variant; and
(ix) pooling and then concentrating the fractions containing biologically active HGF variant.
In a further embodiment, the present invention relates to therapeutic applications of the above described HGF variant that inhibits mitogenesis. Such applications could be used in proliferative disorders including both cancer and non-malignant conditions, in which HGF is excessive. The method comprises specifically blocking the action of HGF by administering a therapeutic amount of the HGF variant or by inducing the endogenous expression of increased amounts of the inhibitor.
The present invention also relates to therapeutic methods that decrease the overproduction of the HGF variant that inhibits mitogenesis. Such methods are applicable where HGF variant is inappropriately produced at high levels in a setting of impaired cell renewal. The method comprises specifically blocking the synthesis or action of the HGF variant by either contacting inhibitor HGF transcripts with antisense oligonucleotides or contacting inhibitor HGF protein with antibodies specific for the inhibitor molecules.
In yet another embodiment, the present invention relates to ex vivo methods of stimulating the growth of cells expressing the receptor for HGF. After proliferation, such cells can be transplanted into a subject in need of such cells. Such methods involve contacting the cells with growth-stimulating amounts of HGF/NK1 in culture prior to transplantation.
In yet another embodiment, the present invention relates to in vivo and in vitro methods of screening chemotherapeutic agents by using HGF/NK1 or HGF/NK2 as a carrier for chemotherapeutic agents that may be toxic to cells expressing the receptor for HGF. Because both HGF/NK1 and HGF/NK2 bind specifically to the HGF receptors on cells and are not themselves toxic, HGF/NK1 or HGF/NK2 can be used to carry potential toxins to such cells, thereby permitting evaluation of the efficacy of various toxins as chemotherapeutic agents.
In yet another embodiment, the invention relates to pharmaceutical compositions comprising either a mitogenesis-inhibitory amount of the HGF/NK2 or mitogenesis-stimulating amount of HGF/NK1 and a pharmaceutically acceptable carrier.

DNA encoding truncated hepatocyte growth factor variants

The United States of America as represented by the Department of Health and Human Services


A dueling or racing roller coaster ride has tracks which approach or cross over each other at near miss locations. A controller system controls the timing of launch of a roller coaster vehicle on each track to better achieve consistent simultaneous arrival of the roller coaster vehicles at the near miss locations, to provide increased thrills and excitement to the riders. The control system determines the loaded vehicle weight via current draw on the track side vehicle motors. The control system generates a vehicle performance parameter, based on past vehicle speed over the track, to compensate for roller resistance and aerodynamic factors. The vehicle weight information and performance parameters are used to determine which vehicle to launch first, and the amount of delay between launching the vehicle on the first track and launching the vehicle on the second track, to better achieve simultaneous arrival at one or more locations.

Roller coasters have long been some of the most well liked rides at amusement parks. Roller coasters normally have an endless track loop. Riders load and unload at a platform or station, typically at a low elevation. At the beginning of each ride cycle, a roller coaster car or a train of cars, is generally towed or moved up a relatively steep incline of an initial track section to the highest point on the entire track. The car is then released from the high point and gains kinetic energy, which allows the car to travel entirely around the track circuit or loop, and return back to the loading/unloading station. The roller coast track typically includes various loops, turns, inversions, corkscrews and other configurations intended to thrill the riders.
Racing or dueling rolling coasters typically have two side by side endless track loops, with the tracks parallel to each other. In this way, a roller coaster train on the first track can "race" with a roller coaster train on the second track. This well known "racing" feature provides added thrills and excitement for the riders. Generally, the roller coaster trains and tracks in dueling or racing coasters are made to be nearly as equivalent as possible, to provide for more competitive "racing". If one coaster train or track is consistently faster than the other, the racing coasters will increasingly be spaced farther and farther apart, as they progress over the track, and the sensation of racing will be lost.
In the operation of racing coasters, each coaster is towed on its track to side by side high points. The coasters are then launched or released simultaneously. As the coasters are propelled purely via gravity, the coasters will be evenly matched only if the coaster speed related variables (such as coaster payload, coaster wheel bearing efficiency, coaster wheel concentricity, wind resistance, coaster tire to track resistance, etc.) are comparable. If the combinations of these variables are comparable, then the racing coasters will be evenly matched, and will travel at the same speed over their tracks. However, these combinations of variables will more often than not result in one coaster train being significantly faster than the other, thereby undesirably reducing the advantages of racing coasters. Consequently, some of the excitement and thrills intended in the design of the racing roller coasters is often lost due to these types of variables.
Accordingly, it is an object of the invention to provide an improved racing roller coaster. Other objects and advantages will appear hereinafter.


A toroidal shaped impact assembly (10) for use in a hydraulic food cutting system is disclosed. Impact assembly (10) includes frustum shaped housing (22), an attachment plate (28) for mounting the assembly within a hydraulic food assembly, and a toroidally shaped impact ring (20). Food products such as peppers (12) are suspended in water and accelerated into assembly (10) where the aligned whole peppers impact against ring (20) thereby breaking apart into food pieces and an unattached seed pod or core.

1. Technical Field
This invention generally relates to a method and apparatus for removing the cores from food products and for breaking food products into smaller pieces. More particularly, this invention relates to a toroidal shaped impact assembly for use in a hydraulic food cutting machine.
2. Background Art
Peppers, more particularly bell peppers, of whatever color, red, green or yellow, jalapeno peppers and pimento peppers have traditionally been thought of as vegetables. They are actually a fruit, in that they are the developed ovary of the blossom of the flowering plant. As such, they are connected at one end to the stem of the blossom, and at the other end, the blossom end, are found the remains of the petals and stamen of the original blossom. Contained within the developed ovary, or fruit, are the developed seeds caused by fertilization of the ovule that were originally contained within the undeveloped ovary.
Commercial processing of peppers has always been a difficult, labor intensive and time consuming process. The primary problem was how to remove the pepper core consisting of the stem end, seed pod and seeds, hereinafter collectively referred to as the core. Two basic methods have been developed to core peppers.
The first method involves the use of some sort of a rotating coring knife, over which the pepper is positioned, stem down, so that the coring knife can bore in cutting out the core and the seed pod. The second method is in more common use today, particularly where there is no need to retain the original configuration of the pepper as a unitary piece. This method involves crushing the peppers and then hand sorting out either the broken usable pieces, or the opposite, hand separating the remains of the cores. The broken pieces are then washed and usually conveyed on for further processing, such as dicing, for inclusion in prepared food products whether canned, frozen, freeze dried or whatever.
A common characteristic to peppers which enables the crushing process to be used, is the fact that the wall of the pepper is brittle enough in its cellular composition that it will break, after some initial plastic deformation, if enough force is impacted against the wall of the pepper.
These two prior art methods and processes for coring peppers can generally be described as mechanical approaches, since they both involve the use of mechanical machines to either crush the peppers or to bore out the stem and core.
Not used in the prior art is a second category of food cutting apparatus, generally known as the hydraulic food cutter. Hydraulic food cutters are used primarily in the potato industry to cut french fries. In general terms, they include a vortex or feed tank containing water into which whole potatoes are conveyed and dumped. A centrifugal food pump draws suction from the tank, and pumps the water and suspended potatoes into an acceleration tube, which is the converging end of the venturi. The food product is then accelerated in the venturi, and impinges upon a fixed array of stationary blades which cut the potato into pieces, usually french fries. The cut food pieces and water then pass into a deceleration tube, which is the divergent end of the venturi, from where they are deposited onto a dewatering conveyor.
The water passes through the dewatering conveyor to a collection tray, and is eventually recycled back into the feed tank. The cut food pieces, or french fries, do not pass through the conveyor, and are conveyed off for further processing.
Hydraulic food cutting devices are high capacity cutting machines and are not labor intensive, usually only requiring one operator to monitor hydraulic cutter operation.
Hydraulic food cutting devices have not been used in the past to cut peppers because of the absence of a workable cutting blade for peppers.
An object of the present invention is to develop an impact assembly which can be used within a hydraulic cutter machine for purposes of breaking peppers into pieces and removing the cores and seed pods therefrom. The second object of the present invention is to develop a modified hydro cutting system wherein the dewatering conveyor can be used for enhanced seed separation and a flotation tank can be used for core and stem separation.
Another object of the present invention is to provide an apparatus that can be used to concentrate the number of solids suspended in a fluid medium flowing through a venturi without significantly reducing the speed of pressure parameters of the fluid as it passes through the venturi.

Apparatus for breaking and coring food products


If a rectifier having Walk-in characteristics is directly connected to a dc-dc converter, an output current of the rectifier violently fluctuates because of the Walk-in characteristics of the rectifier. The Walk-in characteristics have been improved by connecting an apparatus in parallel with the rectifier. The apparatus includes a storage battery and a switch. During the Walk-in period, the switch is closed and the storage battery supplements the capacity of the rectifier. After that, the switch is opened and the storage battery is charged by a current flowing through a diode and a resistor.

1. Field of the Invention
The present invention relates to an apparatus for improving rise characteristics of a direct current power supply source in order to supply a load with a direct current having efficient rise characteristics, even when a direct current power supply having "Walk-in" characteristics, wherein a capacity for supplying power gradually increases after starting and reaches a rated value after more than several seconds, is used.
2. Description of the Related Art
In equipment such as communication facilities, power is fed in the form of a direct current to each unit. The direct current is usually obtained by rectifying an alternating current such as commercial power, with a rectifier.
Among such kinds of rectifiers, there is one that cannot supply maximum rated power immediately after starting but reaches the rated power after several to several tens of seconds have elapsed. The reason why the rectifier is given such a characteristic is that a generator generating an alternating current fed to the rectifier is in danger of stalling if the generator is over-loaded immediately after starting, and thus, that danger must be avoided. This characteristic of rectifiers is called a "Walk-in" characteristic.
On the other hand, on a load side, though various load states are supposed, in a general case, the load is often an electronic circuit including a power supply board. In the case of the power supply board as an example, a circuit construction including a dc-dc converter is widely employed in general power supply boards. A power supply board having a circuit construction including a dc-dc converter usually has rise characteristics such that circuits do not operate while an input current is below a certain threshold value, and normally operate if the input current is above the threshold value.
If the dc-dc converter having such rise characteristics is directly connected to the aforesaid rectifier, an output current of the rectifier violently fluctuates as discussed later. In the case of communication facilities, the violent fluctuation of the output current of the rectifier causes communication errors or generation of alarm transmission, or in a worst case, causes a breakdown of the facilities.

Apparatus for improving rise characteristics of direct current power supply


A modularized electronic system such as notebook or palmtop for packaging and assembling a plurality of internal and external modules comprises at least one upper case assembly and one lower case assembly for clamping the internal modules in between. Each internal module comprises a module head, a module body and a near port. The module head further comprises a connector on its bottom and is vertically plugged in a receptacle on a PCB board assembly attached to the lower case assembly. The lower case assembly further comprises a U-shaped opening on top of a side panel behind the module assembly for the attachment of the rear port. The upper case assembly further comprises a module clamping device under its top panel which is removably attached to the upper end of the module assembly when the external enclosure case is closed whereby the module assembly and the PCB board assembly are horizontally clamped between the upper and lower case assemblies. The new mounting mechanism allows complete internal and external modularization for portable computers.

This invention relates to both the electronic module design and the related mounting mechanism of an electronic system, and more particularly, to an electronic system comprising a plurality of internal and external electronic modules and an external enclosure case for mounting all these modules.
The electronic packaging designs for many notebook or subnotebook computers have been dramatically improved by many computer vendors to increase their modularity and manufactureability. Many electronic modules such as hard drive, battery, modem, mouse, keyboard, etc, are externally attached to the portable computers and can be installed or replaced by users directly. But such external module solutions can only be used to partially modularize a portable computer externally. Many internal components such as motherboard, daughterboard, etc, and the internal mounting mechanisms are also greatly simplified by those portable computer vendors for easy assembly and handling. But unfortunately most of those internal components and mounting mechanisms designs can only be used in a product-by-product base and can not be used as a uniform internal module and mounting mechanism design.
Lack of a proper internal module design not only prevents the complete internal modularization, but also makes the external modularization difficult. Most of the existing external modules are too closely tied to their internal hardware and case ID design. Their dispositions are mostly fixed because all their internal hardware and mounting mechanisms are also fixed. If a new ! internal module and mounting mechanism design can be provided to completely modularize all the internal components, the external modules and their mounting mechanisms can also be created according to the new internal module and mounting mechanism. Besides, if proper I/O port options can also be provided in the new internal module design, many existing external modules can be designed as new internal modules and thus can get better protection from the external enclosure case.
Modularity and reliability become more and more important when the portable computers are more frequently used in many fields. It is important to provide the computer users a flexible and reliable solution so that they can configure the computers according to their needs, and assemble or even maintain such computers by themselves. Such goal can not be achieved if a portable computer can not be completely modularized internally and externally. Apparently, the modular designs used in existing portable computers can not achieve this goal. New internal and external modules and the related mounting mechanisms must be devised to achieve it.

Modular electronic packaging for internal and external modules