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US9067051B2 - Valve device for controlling a flow of a fluid through a fluid channel, arrangement and multi-way valve device - Google Patents
Valve device for controlling a flow of a fluid through a fluid channel, arrangement and multi-way valve device Download PDF
cantilevered arm
fluid channel
Andreas Loth
Florian Buehs
Technische Universitaet Berlin
2010-06-02 Priority to DE201010017216 priority Critical patent/DE102010017216A1/en
2010-06-02 Priority to DE102010017216.2 priority
2010-06-02 Priority to DE102010017216 priority
2011-06-01 Application filed by Technische Universitaet Berlin filed Critical Technische Universitaet Berlin
2011-06-01 Priority to PCT/DE2011/075127 priority patent/WO2012022314A1/en
2013-01-15 Assigned to TECHNISCHE UNIVERSITAT BERLIN reassignment TECHNISCHE UNIVERSITAT BERLIN ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BUHS, FLORIAN, LOTH, ANDREAS
A61M39/00—Tubes, tube connectors, tube couplings, valves, access sites or the like, specially adapted for medical use
A61M39/22—Valves or arrangement of valves
A61M39/28—Clamping means for squeezing flexible tubes, e.g. roller clamps
A61M39/284—Lever clamps
A61M37/0076—Tattooing apparatus
A61M39/223—Multiway valves
F16—ENGINEERING ELEMENTS AND UNITS; GENERAL MEASURES FOR PRODUCING AND MAINTAINING EFFECTIVE FUNCTIONING OF MACHINES OR INSTALLATIONS; THERMAL INSULATION IN GENERAL
F16K—VALVES; TAPS; COCKS; ACTUATING-FLOATS; DEVICES FOR VENTING OR AERATING
F16K7/00—Diaphragm valves or cut-off apparatus, e.g. with a member deformed, but not moved bodily, to close the passage ; Pinch valves
F16K7/02—Diaphragm valves or cut-off apparatus, e.g. with a member deformed, but not moved bodily, to close the passage ; Pinch valves with tubular diaphragm
F16K7/04—Diaphragm valves or cut-off apparatus, e.g. with a member deformed, but not moved bodily, to close the passage ; Pinch valves with tubular diaphragm constrictable by external radial force
F16K7/045—Diaphragm valves or cut-off apparatus, e.g. with a member deformed, but not moved bodily, to close the passage ; Pinch valves with tubular diaphragm constrictable by external radial force by electric or magnetic means
A61M2039/226—Spindles or actuating means
Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
Y10T137/00—Fluid handling
Y10T137/8593—Systems
Y10T137/86493—Multi-way valve unit
The invention relates to a valve device for controlling a flow of a fluid through a fluid channel, having a tube (2) made of a flexible material, in which a section of a fluid channel is formed, a valve component (1) assigned to the tube (2), a cantilevered arm (8), which is designed to be reversibly displaceable on the valve component (1) against a restoring force supplied at least partially by the cantilevered arm (8) itself, a squeeze element (10), which is arranged on a distal end of the cantilevered arm (8) for support of the cantilevered arm (8) on the valve component (1) and is configured to control a flow of a fluid through the fluid channel by pressing against an outside surface of the tube (2), optionally up to the closing of the fluid channel, and an actuator (11) which is configured to displace the squeeze element (10) in various control directions against the restoring force on the cantilevered arm (8), so that the pressure of the squeeze element (10) on the outside surface of the tube (2) and thereby the flow through the fluid channel can be regulated. In addition, the invention also relates to a system having at least one valve device and a pressure-applying device as well as a multi-way valve device having multiple valve devices.
The invention relates to a valve device for controlling a flow of a fluid through a fluid channel, a system having at least one valve device and a multi-way valve device.
Such valve devices are used to adjust and modify the volume flow of a fluid through a fluid channel. It is known in this context that the flow of the fluid through the channel is to be controlled by exerting pressure from the outside on a tube in which the fluid channel is formed, such that the pressure is adjusted as a function of a desired volume flow of the fluid through the channel.
In medical technology, dosing of volume flows takes place, for example, through micro-valves or directly through a corresponding pump with which the fluid to be dispensed is acted upon with pressure. Valves are used in medicine and in the cosmetic field, for example, in injection of medically and cosmetically active substances. In addition to the injection of substances for fat reduction or for injection beneath wrinkles, dosed dispensing of a substance is also necessary for application of ink for tattooing or permanent makeup in the cosmetic field. In addition to various vaccinations, medical applications also include, for example, mesotherapy. In these applications, in addition to the simple application of the media, simultaneous administration of multiple media is also provided, so that the media react with one another only after being applied.
The dosing of the fluid may be performed by means of a contact method or a noncontact method. The fluid-dispensing device thus either does or does not come in contact with the skin. Noncontact devices are also referred to as so-called dispensers. The process of delivering the fluid is itself known as dispensing, jetting or pulsing. This dosing serves to apply substances to the skin or in subsequent substance delivery systems (cf. EP 1 882 491, for example). Contacting may be understood as dosing onto or through a surface.
All these applications have in common the need for accurate dosing. Problems are often presented by chemical or fluid properties or particles or variable media.
The document DE 103 37 484 B4 describes a noncontact dosing system, in which a tube is squeezed at a high speed, so that a free-flying droplet of liquid is formed. Dosing frequencies of 50 Hz may be achieved in this way. The design here is an open system without a prepressure. The liquid fills the tube because of the capillary forces, but the maximum dosing quantity and dosing frequency are limited by this design. If there is a backpressure, functioning is very limited or impossible.
The document DE 693 25 591 T2 describes valve systems for switching a flow through flexible tubes. Two positions (bistable open/closed) are selected via a pivotable lever. The liquids should flow through the valve at the coupled flange of this construction, which is manufactured by casting and welding. Possible contamination of the liquid is not prevented, nor can this principle be used as a disposable part or for higher frequencies (>1 Hz).
The document U.S. Pat. No. 3,335,753 describes a valve device in which the flow through a flexible tube is adjustable by means of a squeeze element. The squeeze element is arranged on a rotatably mounted adjusting element, which is operable for displacement of the squeeze element, wherein a restoring force is supplied by a spring.
The document DE 20 2005 009 350 U1 discloses a hose clamp.
A tube valve is known from the document DE 1 707 336.
Document DE 2 353 624 describes a micro-control device for flow of liquids through flexible lines. With the known device, the flexible line is squeezed or released with the help of an operable lever arm.
The document EP 1 699 560 B1 describes one possibility for pipetting extremely small quantities, but is based essentially on a combination of traditional pipetting systems and the known PipeJet method, i.e., a tube deformation, embodied in this case as a pipette tip. It is thus possible here to dose only extremely small particles which fly freely through the air to their destination. This method cannot be used for injections because it is impossible to work at a backpressure.
The document DE 197 06 513 C2 describes a micro-dosing method based on a pressure chamber having a reservoir connection and a fluid outlet. The pressure chamber is reduced in size by a displacement mechanism, so that the fluid is forced to the outlet. A device for detecting the position of the displacement mechanism is essential here.
The document US 2010/0030152 A1 describes a therapeutic micro-needle system, in which multiple cannulas are used instead of one cannula.
The object of the invention is to provide improved technologies in combination with valve devices for controlling a flow of a fluid through a fluid channel, with which reliable control of the volume flow of the fluid is ensured, in particular even in high-frequency operation of the valve device.
This object is achieved according to the invention by a valve device for controlling a flow of a fluid through a fluid channel according to independent Claim 1. In addition, a system of at least one valve device according to independent Claim 16 and a multi-way valve device according to independent Claim 17 is also provided. Advantageous embodiments of the invention are the subject matter of dependent subsidiary claims.
The invention comprises the idea of a valve device for controlling a flow of a fluid through a fluid channel, comprising a tube of a flexible material, in which a section of a fluid channel is formed, a cantilevered arm which is designed to be reversibly displaceable on the valve component against a restoring force that is at least partially supplied by the cantilevered arm itself, a squeeze element, which is arranged on a distal end of the cantilevered arm for supporting the cantilevered arm on the valve component and is configured to control a flow of a fluid through the fluid channel by pressing against an outside surface of the tube, optionally up to the closing of the fluid channel, and an actuator which is assigned to the squeeze element and is configured to displace the squeeze element into various control positions, so that the pressure of the squeeze element on the outside surface of the tube and thereby the flow through the fluid channel can be regulated.
According to another aspect of the invention, a system having at least one valve device and a pressure-applying device, which is in fluid connection to the fluid channel, are provided, said pressure-applying device being configured so that a pressure can be applied to the fluid in the fluid channel.
Another aspect of the invention relates to a multi-way valve device having a plurality of valve devices for controlling the flow of a fluid through a fluid channel.
With the inventive valve device, there is the possibility of individually adjusting and regulating the volume flow through the fluid channel formed in the tube in accordance with the respective use requirements, including in particular a volume flow adjustment with high change frequencies or repeat frequencies. In one possible application, the displacement of the squeeze element produced by the actuator and the resulting change in flow through the tube can also be implemented by means of a corresponding repeating actuator movement, also at a high frequency. The actuator can be designed to conform to the respective use case, thus providing an adequate displacement path for the squeeze element. For example, the squeeze element may be displaced from a first position, in which the fluid channel in the tube is completely open, into a second position, in which the fluid channel is essentially closed. In one type of use with this embodiment, the valve device is used as a so-called closer. A reverse displacement of the squeeze element may also be provided, which then corresponds to an embodiment as a so-called opener.
The cantilevered arm may be designed in one or more parts. Thus, in one embodiment, multiple cantilevered arms are provided and may optionally cooperate.
In one embodiment, the actuator may act directly on the squeeze element, i.e., may couple directly to it in order to displace it. However, it is also possible to provide that the actuator acts on a different section of the cantilevered arm, i.e., couples to it, in order to pivot it against the restoring spring, so that the squeeze element is displaced on the distal end of the cantilevered arm.
The valve device may be used in any devices or device parts to control the flow of a fluid through the fluid channel in a tube. Use in a dosing unit is advantageous in particular, a medical or cosmetic active ingredient being delivered in a dosed manner with this dosing unit in the field of medicine or cosmetics. The dosing device may be embodied in a contact or noncontact design. For example, the dosing device may be integrated into an injection device to control the dosed delivery of an active ingredient under a backpressure. In this embodiment, the valve device is preferably downstream from a cannula that delivers the active ingredient. The cannula punctures the skin and can dispense the active ingredient at a predefined puncture depth, for example. The dosing device can thus be used in a method for dosed delivery of a fluid, in particular for injection into the human or animal body.
The relative movement between the guide and the valve component during use of the valve device in any dosing device, which is implemented as an injection device, for example, in which the fluid may also be dispensed against a backpressure, is preferably accomplished by means of manual operation or with the help of a drive. For example, devices for puncturing human or animal skin have drive mechanisms, which move a puncture device repetitively back and forth at a high frequency. This repetitive movement may then be used for the relative movement of the guide and the valve component to open and close the fluid channel in the tube. Such puncture devices are described in DE 299 19 199 U1, EP 1 495 782 and EP 1 618 915, for example. In addition, the following documents can be cited as examples: EP 1 743 673, EP 2 149 388 and EP 1 882 492. Other technologies may also be used as the drive mechanisms: pneumatics, lifting magnetic drive, drives having rotating motors and translation into a linear movement and a piezoelectric drive. The present invention may also be utilized in its various embodiments, in particular in conjunction with such puncture or injection devices.
According to a preferred further embodiment of the invention, the valve component is formed with a reversibly displaceable cantilevered arm on which the squeeze element is arranged. The cantilevered arm may be designed in one or more parts. For example, in one embodiment, multiple cantilevered arms, optionally cooperating with one another, may be provided. The reverse displacement is preferably accomplished here on the basis of a spring elastic design of the cantilevered arm. For example, the cantilevered arm is reversibly displaced by means of a pivoting movement of the cantilevered arm. In one embodiment, the squeeze element is formed on a distal end in relation to the base of the cantilevered arm, i.e., an area in which the cantilevered arm is mounted. The squeeze element is preferably formed on the cantilevered arm with a protrusion in the direction of the tube, which presses against the tube from the outside. A squeeze surface of the squeeze element assigned to the tube may have any surface contour, for example, a rounded surface, a spherical surface, or a surface with a squeeze edge, which is formed in the area of two surfaces running obliquely to one another. A combination of such surface contours may also be provided, in particular for optimizing the squeeze effect.
In an expedient embodiment of the invention, it is possible to provide for the cantilevered arm to extend along the tube and to optionally form an acute angle with the longitudinal direction of the tube. In one embodiment, the cantilevered arm runs essentially parallel to the longitudinal direction of the tube.
According to an advantageous embodiment of the invention, the actuator having at least one actuator element is selected from the group formed by actuator elements: electrical actuator element, magnetic actuator element, piezoelectric actuator element, pneumatic actuator element, mechanical actuator element and hydraulic actuator element.
According to a further embodiment of the invention, the actuator is formed with an actuating element which is configured to cause the displacement of the squeeze element in the various control positions by means of an actuator movement along one direction of movement which is essentially perpendicular to the longitudinal direction of the fluid channel, the guide is formed on a wall section. The wall section may be formed on a housing, for example, in which the valve component and the tube are accommodated. According to one embodiment, one housing part with the wall section formed thereon is moved in relation to the valve component during operation, and the guide section of the valve component slides along the guide on the housing part in this process, thereby displacing the squeeze element, which leads to a change in the flow through fluid channel. Conversely, it is possible to provide for the valve component to move in the housing in such a way that again the guide section slides along the guide formed on the housing part, which leads to a displacement of the squeeze element. Both the valve component and the wall section with the guide formed thereon may also move. In this embodiment or in others, it is possible to provide that the displacement of the squeeze element and thus the change in the flow through the fluid channel are repeated at a frequency between about 10 Hz and about 500 Hz, preferably between about 50 Hz and about 150 Hz. Alternatively, the use in a single-puncture mode is also conceivable, in which only a single puncture or a single injection is performed after manual triggering by the user.
In an advantageous embodiment of the invention, it is possible to provide for the valve component to be designed as a micro-valve component. In this way, the valve device is suitable for a micro-dosing device, for example.
A further embodiment of the invention may be provided, in which the squeeze element is designed to surround the tube at least partially.
According to a preferred further embodiment of the invention, the squeeze element is formed by a plurality of partial squeeze elements, which are arranged around the tube. In one embodiment, the squeeze elements are arranged on a shared base. It is possible to provide for the plurality of partial squeeze elements to be moved jointly by means of one or more actuators. This movement may take place similarly and/or simultaneously. In a preferred embodiment, the plurality of partial squeeze elements is formed in a rotationally symmetrical arrangement around the tube. In a further embodiment of the invention, the arrangement of the plurality of partial squeeze elements is embodied essentially according to a pressure-reducing mechanism.
In an expedient embodiment of the invention, it is possible to provide for the at least one part of the plurality of partial squeeze elements to be arranged so they are supported on one another at least in one end position. It is possible to provide here for individual partial squeeze elements to be supported on one another in the end position in which the fluid channel is partially or completely closed by squeezing of the tube, so that further closing of the fluid channel is no longer possible in one embodiment.
According to an advantageous embodiment of the invention, the cantilevered arm is designed to allow a displacement of the squeeze element for opening and at least partially closing the fluid channel in the tube with a high repeat frequency. In particular, such an embodiment provides for a restoring force that supports the high-frequency repetition of the displacement of the squeeze element. Such an embodiment may be formed with the above-mentioned cantilevered arm, for example.
A further embodiment of the invention preferably provides for the valve component to be embodied at least partially as an injection-molded part. Injection-molded parts are inexpensive and can also be manufactured by mass production. In these or other embodiments, it is possible to provide for the valve component to be embodied as a disposable product. In a further embodiment, the injection molding of the valve component may be embodied in a two-component injection molding process (2C injection molding). In one embodiment, the valve device having at least the one valve component, a tube section, the guide section and optionally a cannula connected to the tube section may be designed as a nonreturnable module or as a disposable module. Such a disposable module may be connected to a drive mechanism in a single step.
In one advantageous embodiment of the invention, it is possible to provide for the valve component to be arranged on the tube. In one embodiment, the valve component is designed to sit on the tube, preferably detachably. For example, the valve component may be arranged on the tube by means of an elastic clamping action, which is preferably provided by the squeeze element and the counterpart assigned to the squeeze element. According to a further embodiment, the valve component in this embodiment is designed with a tube guide, along which the tube runs in at least some sections when the valve component is arranged thereon. In one embodiment, the tube guide and the cantilevered arm having the squeeze element run essentially in parallel with the longitudinal direction of the tube, for example, above and below the tube.
A preferred further embodiment of the invention provides that the valve device has a disposable module, which is formed with at least the tube and the valve component. The disposable module preferably consists of these two elements.
In one expedient embodiment of the invention, it is possible to provide that the cantilevered arm is connected to a solid-state hinge.
An advantageous embodiment of the invention provides that the solid-state hinge is formed in a lever configuration.
An advantageous embodiment of the invention may provide that at least one coupling into which a tube end opens is formed on the valve component. The tube in the form of a length of tubing forms a uniform component together with the valve component, such that the tube is installed in the component so that the tube and the valve component are replaceable as a unit. Two such couplings may also be provided on the valve component, these two couplings being assigned to the two tube ends. Connecting pieces may be inserted or screwed into the coupling in order to connect the valve device, for example, to a nozzle, a dispenser, a micro-mixer, a syringe, a reservoir or the like.
In conjunction with the system having at least one valve device and a pressure-applying device, which is in fluid connection with the fluid channel, the integration of this system into a dosing device for dosed dispensing of a fluid may be provided, in particular a medicinal or cosmetic substance. Fluid dispensing may be performed here under the influence of a backpressure, which is important in particular in conjunction with injections. For example, such an injection device is used in combination with a device for tattooing or for creating permanent makeup. In this case, the dispensing of an ink is controlled by the valve device, but the dosing of another cosmetic active ingredient or a medicinal substance may also be provided.
In the case of a multi-way valve device, it may be provided in one embodiment that the fluid channels arranged side by side next to one another are adjusted with regard to the flow passing through them. In one embodiment, an integrated valve component, which serves to control the volume flow in multiple fluid channels, is provided. To this end, the integrated valve component has a plurality of squeeze elements, each being assigned to a tube with the fluid channel formed therein and displaceable by means of an assigned actuator. In a multi-way valve device, intersections between fluid channels may also be designed.
A series connection of multiple valve components may be suitable for increasing the dosing accuracy, inasmuch as the volume between the valve components, for example, contains a fluid under pressure and only the volume stored in between is dispensed by skillful opening and closing. For example, a corresponding valve may consist of tubes of different wall thicknesses or of tube-and-pipe combinations. The "storing" tube section need only be capable of storing energy, which maintains an excess pressure in this section (balloon with an inlet and an outlet). This is of interest for the purely mechanical embodiment in particular. It is possible to connect multiple valve components, which may be utilized to represent multi-way valves, for example (cf. FIG. 3). Other components may thus also be connected after the valve component.
The valve device may also be used for intake or suction. A combination of the two may also be provided, for example, intake and discharge in alternation or in multiple stages in succession (for example, in, in, out, out, out, out, etc.). This may be used for tattoo removal, for example, during which active ingredients are injected into the tattoo and the tattoo pigments are removed by suction. This method of tattoo removal is described as such in the document WO 2005/020828, for example.
One advantage of the invention is the possibility that predosed or variable and/or crystallizing/drying media may be dosed without damaging the system or having to clean it because the fluid transport takes place only in a system that is easy to change.
The valve component and the valve device may be used in a liquid handling system, for example, or in a micro-mixer.
DESCRIPTION OF PREFERRED EXEMPLARY EMBODIMENTS OF THE INVENTION
The invention is explained in greater detail below on the basis of preferred exemplary embodiments with reference to drawings in figures, in which
FIG. 1 shows a schematic diagram of a system having a valve device,
FIG. 2 shows multiple embodiments of a valve component,
FIG. 3 shows a schematic diagram of a multi-way valve device, in which two fluid channels run parallel to one another,
FIG. 4 shows a schematic diagram of a system having another valve device,
FIG. 5 shows a schematic diagram of a valve device according to another embodiment,
FIG. 6 shows a perspective view of a valve device in another embodiment,
FIG. 7 shows a schematic diagram of another multi-way valve device,
FIG. 8 shows a schematic diagram of an application with a valve device in a multi-way embodiment,
FIG. 9 shows a schematic diagram of a valve component in which the squeeze element is arranged on the distal end of the cantilevered arm,
FIG. 10 shows a valve device integrated into a solid-state system,
FIG. 11 shows a schematic diagram of a valve device, in which the tube is arranged in a valve body, such that the tube ends are coupled to couplings, and
FIG. 12 shows a sectional diagram through the valve device from FIG. 11.
FIG. 1 shows a schematic diagram of a system having a valve component 1, which is arranged on a tube 2, in which a fluid channel 4 for a fluid 3 is formed, through which the fluid 3 from a reservoir 5 which is acted upon by pressure reaches a cannula 6, where the fluid is dispensed in dosed form. The reservoir 5 may be, for example, a reservoir for ink, which is used to form a tattoo or permanent makeup. In another embodiment, the reservoir may also contain, for example, a substance for injection under wrinkles.
The valve component 1 is formed with a tube guide 7 on which the tube 2 rests. A cantilevered arm 8 is formed opposite the tube guide 7. A squeeze element 10 is arranged on the distal end 9 of the cantilevered arm 8, pressing on the tube 2 from the outside. The squeeze element 10 is displaced along a direction of movement, which runs essentially across the longitudinal direction of the tube 2, in that an actuator 11 with an operating element 12 cooperates with the squeeze element 10. In the embodiment in FIG. 1, the squeeze element 10 is pressed onto the tube 2 against a restoring force of the cantilevered arm, to adjust the flow of the fluid through the tube 2. The operating element 12 is also displaced against a spring force 13 in the embodiment shown here.
Various types of actuators can be used, for example, a pneumatic, hydraulic, electric, magnetic or piezoelectric actuator element.
The volume flow of a known medium can be adjusted by means of the respective squeeze element 10 by regulating the applied pressure, the opening width and/or the opening time. These parameters influence the amount of dosable substances and/or viscosities. In principle, any liquid and gaseous substances with particles that are not too large in comparison with the inside diameter of the tube can be dosed in this way.
The respective clamping or squeezing device may be operated purely mechanically by operation the clamping device driven by an actuator, which causes the clamp formed by the squeeze element to be opened and closed. The clamping action can be reset in particular via the elastic deformation (restoring force of the cantilevered arm 8) and/or restoring forces of the tube and/or by the pressure of the medium in the tube on the tube wall. Dosing can be performed at high frequencies in this way.
The valve component 1 with the squeeze element 10 may be fixedly connected to the tube 2 or attached to it subsequently. In the latter case, the valve device may be embodied as a multi-way valve. Because of its low manufacturing cost, for example, when made of plastic by the injection molding method, and its better handleability, disposable use is to be given preference but variants comprised of other materials, such as metal, composite materials or the like are also possible.
In its various embodiments, the valve component may operate as an opener or a closer. A continuous change in the volume flow may be achieved. The pressure may be applied to the tube from one or more sides. One-sided is understood here to mean that the volume cross section is limited from one side; for example, the squeeze element presses from one side on a tube that is fixed on a substrate with respect to the squeeze element. In the two-sided case, the valve component to the principle of tongs or forceps is conceivable according (cf. FIG. 4), where the clamping jaws are guided opposite one another.
FIG. 2 shows multiple embodiments of the valve component 1, where the squeeze element 10 is formed with different geometric designs accordingly. In particular a surface form in a squeeze section 20 of the squeeze element 10 facing the tube 2 is designed in a different manner. A rounded surface, a spherical surface, a planar surface and a surface area having a squeeze edge 21 belong here.
FIG. 3 shows a schematic diagram of a multi-way valve device in which a double-valve component 30 having parallel tube guides 31, 32 is formed. A respective squeeze element 35, 36 which presses on the respective tube from the outside is formed on the respective cantilevered arms 33, 34.
FIG. 4 shows a schematic diagram of a valve component 40 in a closed position and in an opened position (cf. left and right sides in FIG. 4), in which a squeeze element 41 with clamping jaws 42, 43 is formed, these being formed on the respective cantilevered arm 8 and being activated with the help of a respective actuator 44, 45. The flow through the tube 2 to a cannula 46 is enabled or closed by operation of the clamping jaws 42, 43.
FIG. 5 shows a schematic diagram with a valve component 50, in which a squeeze element 51 is also formed with two clamping jaws 52, 53, which are formed on the respective cantilevered arm 8 and are displaced with the help of the respective actuators 54, 55 to enable or to suppress the flow through the tube 2 to a cannula 56.
For the actuators 42, 43 and/or 52, 53 shown in FIGS. 4 and 5, actuators based on different operative principles may be used, for example, electrical, pneumatic, mechanical or piezoelectric actuators.
FIG. 6 shows a perspective diagram of a valve device in another embodiment, in which a valve component is formed with a guide 61 in which the tube 2 is arranged. A respective squeeze element 62 is on the outside of the tube 2 and is displaced repetitively with the help of a mechanical actuator 63, in that a rotating component 64 rotates on the mechanical actuator 63. The squeeze element is pressed more or less against the tube 2 because of the surface contour of the rotary component 64, thereby regulating the flow through the tube 2.
FIG. 7 shows a schematic diagram of a system having several valves, each of which is preferably formed with a valve component 1 in one of the embodiments described previously as well as a respective actuator 11. A four-way valve with actuators 11 is formed.
FIG. 8 shows a schematic diagram of a system having a valve device in a multi-way embodiment, in which the squeeze elements 10 are operated in alternation, in that the operating element 12 of the actuator 11 is pivoted (cf. arrow A in FIG. 8).
In preliminary investigations, dispensing frequencies of up to 400 Hz have been achieved. The dosed droplets were separated completely from the end of the tube in either the horizontal position or in the vertical position. Distilled water was used as the test fluid at a pressure of 2 bar ad a tube diameter of 0.7×0.3 mm (outside to inside). Clean separation of the individual droplets was verified using a high-speed camera at a recording frequency of 3,400 Hz. The test setup was made of plastic on a miniaturized scale. The dimensions of the functioning valve device were 4×4×15 mm.
Application fields are found in injection of medicinal and cosmetic substances in particular. Integration into a bundle of complete needles of a puncture or injection device may be provided, just as it is also possible to operate multiple cannulas simultaneously. Examples of cosmetic treatments that can be mentioned include carboxy therapy, i.e., injection of CO2, for example, for fat reduction, injections beneath wrinkles at depths of 1.0 to 4.0 mm using a wide variety of media, tattooing and tattoo removal (cf. EP 04 770 455, which refers only to superficial suction removal there) at depths of 1.0-3.5 mm or application of permanent makeup at depths of 0.3-1.0 mm. Suction removal of skin is conceivable in general for both cosmetic and medical application. Purely medical applications include not only various vaccinations at depths of 0.2-0.6 mm but also mesotherapy at depths of 0.2-10 mm.
The following list represents a selection of possible substances that may be applied: hyaluronic acid, vitamins, Q10, vaccines, therapeutic antibodies, cancer antibodies, diabetes therapeutic agents, hormones, cytokines, biochemical or biological signal substances, antioxidants, hair growth agents, hair growth inhibitors, mineral substances to improve skin tone and skin metabolism, enzymes, coenzymes, amino acids, nucleic acids, inert pigment particles, inert skin fillers, nerve-activating ingredients such as botox or bacterial toxin, diabetic control agents such as color-changing particles, which depend on the glucose level.
For all applications, in addition to the simple administration of media, this simultaneous administration of multiple media is also conceivable; these media should react with one another only after the injection, for example. Some of the applications have in common the introduction or removal of a wide variety of media at a defined depth and/or at a certain point in time. The importance of the precise depth of a vaccination can be seen clearly in the intracutaneous vaccination technique in particular. The active ingredient to be administered as a vaccine loses a substantial portion of its effect when the target depth is exceeded by more than 15%.
In addition to packaging extremely small quantities of medium, such as expensive medications, the desired mixing ratio can be adjusted extremely easily, for example, with several different tube diameters.
Especially in fields such as vaccination technique, even reagents that are very difficult to handle can be used easily because they can be used in a closed container with a valve and therefore do not come in contact with the actual dispenser. It is thus possible to avoid tedious cleaning of the devices.
It is also conceivable to use a sealing liquid, comparable to a cork, for example, a hydrophilic active ingredient and a hydrophobic sealing substance to thus prevent the substance administered from running off. A high-viscosity sealing substance may also be used for this purpose. Alternatively, the closure of the skin may be implemented by coagulation with HF, laser or other thermal effects.
The present invention in its various embodiments can be combined with other technologies, for example, with measurement of the depth of skin layers and automatic adjustment of the optimum puncture depth of the needle. The substances may be injected accurately into the predefined skin strata. The measurement and puncture depth technologies are described in document EP 188 2493, for example.
Based on the simple design, the numerous operating variants and the small design height, the invention can be integrated into a variety of different products with minimal effort.
FIG. 9 shows a schematic diagram of a valve component 1, where the squeeze element 10 is arranged on the distal end of the cantilevered arm 8, and the proximal end of the cantilevered arm 8 is coupled to a solid-state hinge 90. The solid-state hinge 90 has the advantage that it minimizes the forces required to operate the valve. Solid-state hinges in general involve areas of the cantilevered arm 8 which have a reduced stiffness, so that articulated points or kink points are formed. Much shorter levers can be used with the cantilevered arm 8 by means of a solid-state hinge, which supports further miniaturization of the valve device and integration in complex liquid handling systems.
A more extensive miniaturization is possible by presqueezing the tube. For example, if a tube with the dimensions 0.7×0.3 mm is squeezed by 0.2 mm, then the achievable volume flow is approximately 90% of the undisturbed cross section. This reduces the required lever travel from 0.35 mm to 0.15 mm.
Solid-state hinges can be integrated easily during production by injection molding by designing the molds accordingly. Production by micro-milling or eroding is also possible with metallic materials.
The valve device can also be integrated directly into a solid-state system, which is illustrated in FIG. 10, for example. The squeeze element 10 is on the tube 2, through which a liquid flows. A fixed joint system 100 can be operated by means of an actuator, which is diagrammed schematically with the arrow A in FIG. 10. The embodiment shown here illustrates an implementation of a force-distance translation, in which the squeeze element 10 is formed on the lowest lever. The lever design shown in FIG. 10 with the tube 2 included can be produced inexpensively by injection molding, for example.
FIG. 11 shows a schematic diagram of a valve device, in which the tube 2 in the form of a length of tubing is arranged in a valve component 110 and is installed in it so that the tube 2 has tube ends 111, 112, which are surrounded by the valve component 110 at the ends, through which the valve device can be connected to coupling pieces or connections (not shown) which are then preferably inserted or screwed into the couplings 111, 112. The cantilevered arm 8 with the squeeze element 10 is formed in one piece on the body of the valve component 110. The valve device can thus be replaced completely as a unit in one step, which greatly reduces the replacement time and pursues the idea of a modular construction kit for various "fluid components."
FIG. 12 shows a sectional diagram of the valve device from FIG. 11.
The features of the invention disclosed in the above description, the claims and the drawing may be important individually as well as in any combination for the implementation of the invention in its various embodiments.
1. A valve device for controlling a flow of a fluid through a fluid channel, comprising:
a tube of flexible material in which a section of a fluid channel is formed,
a valve component assigned to the tube,
a first cantilevered arm, which is designed to be reversibly displaceable on the valve component against a restoring force which is supplied by the first cantilevered arm at least partially by itself, the first cantilevered arm projecting from a proximate end to a distal end and providing at the distal end a mounting surface that faces towards an outer surface of the tube,
a first squeeze element, which is formed on the mounting surface of the first cantilevered arm and projecting outwardly from the mounting surface is configured to control a flow of a fluid through the fluid channel by pressing against an outside surface of the tube,
a first actuator which is assigned to the first squeeze element and is configured to displace the first squeeze element in various control directions against the restoring force on the first cantilevered arm, so that the pressure of the first squeeze element on the outside surface of the tube and thereby the flow through the fluid channel is regulated,
a second cantilevered arm, which is designed to be reversibly displaceable on the valve component against a restoring force which is supplied by the second cantilevered arm at least partially by itself, the second cantilevered arm projecting from a proximate end to a distal end and providing at the distal end a mounting surface that faces towards an outer surface of the tube,
a second squeeze element, which is formed on the mounting surface of the second cantilevered arm and projecting outwardly from the mounting surface, is arranged on an opposing side of the tube in relation to the first squeeze element and configured to control a flow of a fluid through the fluid channel by pressing against an outside surface of the tube, and
a second actuator which is assigned to the second squeeze element and is configured to displace the second squeeze element in various control directions against the restoring force on the second cantilevered arm, so that the pressure of the second squeeze element on the outside surface of the tube and thereby the flow through the fluid channel is regulated.
2. The valve device according to claim 1, characterized in that the cantilevered arm extends along the tube and forms an acute angle with the longitudinal direction of the tube.
3. The valve device according to claim 1, characterized in that at least one of the first actuator and the second actuator having at least one actuator element is selected from the following group of actuator elements: electrical actuator element, magnetic actuator element, piezoelectric actuator element, pneumatic actuator element, mechanical actuator element and hydraulic actuator element.
4. The valve device according to claim 1, characterized in that at least one of the first actuator and the second actuator is designed with an operating element, which is configured to cause the corresponding squeeze element to be displaced into the various control positions by means of an actuator movement along a direction of movement, which runs perpendicular to the longitudinal direction of the fluid channel.
5. The valve device according to claim 1, characterized in that the valve component is designed as a micro-valve component.
6. The valve device according to claim 1, characterized in that the first cantilevered arm is designed to allow a displacement of the first squeeze element for opening and at least partially closing the fluid channel in the tube at a frequency on the order of 400 Hertz.
7. The valve device according to claim 1, characterized in that the valve component is designed to allow at least partial closing of the fluid channel in the tube.
8. The valve device according to claim 1, characterized in that the valve component is arranged on the tube.
9. The valve device according to claim 1, characterized by a disposable module, which is formed at least with the tube and with the valve component.
10. The valve device according to claim 1, characterized in that the cantilevered arm is coupled to a solid-state hinge.
11. The valve device according to claim 10, characterized in that the solid-state hinge is formed in a lever arrangement.
12. The valve device according to claim 1, characterized in that at least one coupling is formed on the valve component, with one tube end opening into said coupling.
13. A system for controlling a flow of a fluid through a fluid channel, comprising:
a tube of flexible material in which a section of a fluid channel is formed;
a valve component assigned to the tube;
a first cantilevered arm, which is designed to be reversibly displaceable on the valve component against a restoring force which is supplied by the first cantilevered arm at least partially by itself, the first cantilevered arm projecting from a proximate end to a distal end and providing at the distal end a mounting surface that faces towards an outer surface of the tube;
a first actuator which is assigned to the first squeeze element and is configured to displace the first squeeze element in various control directions against the restoring force on the first cantilevered arm, so that the pressure of the first squeeze element on the outside surface of the tube and thereby the flow through the fluid channel is regulated;
a second actuator which is assigned to the second squeeze element and is configured to displace the second squeeze element in various control directions against the restoring force on the second cantilevered arm, so that the pressure of the second squeeze element on the outside surface of the tube and thereby the flow through the fluid channel is regulated, and
a pressure-applying device, which is in fluid connection with the fluid channel and is configured to apply a pressure to the fluid in the fluid channel.
14. A multi-way valve device, comprising:
a plurality of valve devices, each of the valve devices in the plurality of valve devices includes
a first cantilevered arm, which is designed to be reversibly displaceable on the valve component against a restoring force which is supplied by the first cantilevered arm at least partially by itself, the first cantilevered arm projecting from a proximate end to a distal end and providing a mounting surface at the distal end such that the mounting surface faces towards an outer surface of the tube;
a first squeeze element, which is formed on the mounting surface of the first cantilevered arm and projecting outwardly from the mounting surface is configured to control a flow of a fluid through the fluid channel by pressing against an outside surface of the tube; and
a second cantilevered arm, which is designed to be reversibly displaceable on the valve component against a restoring force which is supplied by the second cantilevered arm at least partially by itself, the second cantilevered arm projecting from a proximate end to a distal end and providing at the distal end a mounting surface that faces towards an outer surface of the tube;
a second squeeze element, which is formed on the mounting surface of the second cantilevered arm and projecting outwardly from the mounting surface, is arranged on an opposing side of the tube in relation to the first squeeze element and configured to control a flow of a fluid through the fluid channel by pressing against an outside surface of the tube; and
US13/701,312 2010-06-02 2011-06-01 Valve device for controlling a flow of a fluid through a fluid channel, arrangement and multi-way valve device Active US9067051B2 (en)
DE201010017216 DE102010017216A1 (en) 2010-06-02 2010-06-02 Valve means for controlling a flow of a fluid through a fluid passage arrangement, and multi-way valve device
DE102010017216.2 2010-06-02
DE102010017216 2010-06-02
PCT/DE2011/075127 WO2012022314A1 (en) 2010-06-02 2011-06-01 Valve device for controlling a flow of a fluid through a fluid channel, arrangement and multi-way valve device
US13/701,312 Active US9067051B2 (en) 2010-06-02 2011-06-01 Valve device for controlling a flow of a fluid through a fluid channel, arrangement and multi-way valve device
DE (1) DE102010017216A1 (en)
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Owner name: TECHNISCHE UNIVERSITAT BERLIN, GERMANY
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The Editor stayed here in December 2006 and was very impressed with the standard of bedroom, cuisine, wine list and the friendly-efficiency of the staff. The Metropole commands excellent views of the three main peaks of the Jungfrau Region - Monch, Eiger and Jungfrau - and is located close to the town centre, casino, railway station and wide range of shops.
The Metropole has 95 bedrooms divided into 41 standard and 52 deluxe, all with en suite and of these, 83 have a balcony from which to enjoy the mountain scenery! In addition to the swimming pool, sauna, and solarium, there is a fitness instructor available.
The restaurant "Top of Met" allows you to enjoy your evening meal and look at the sparkling mountain peaks or you can eat in the Restaurant Bellini which offers typical Swiss dishes. Whatever your taste, the wine list is extensive and well worth "exploring".
After dinner there is the Metro Bar near the hotel foyer whilst the Metropole has its own dance club - the "Black and White". No need to panic for that last minute souvenir item before departure as the hotel Metropole has its own large and well appointed shop just off the main entrance area.


ST. LOUIS (Reuters) - The Federal Reserve has room to keep buying bonds to support the U.S. economic recovery because inflation remains low, St. Louis Fed President James Bullard said on Wednesday.
Bullard told reporters in a news conference he still expects the economy to expand 3 percent this year, a forecast that puts him in the more bullish camp of central bankers.
Yet with inflation running well below the Fed's 2 percent target, Bullard said policymakers can take their time before deciding whether to halt or reduce the Fed's monthly purchases of $85 billion in mortgage-backed and Treasury bonds.
"We don't need to be in any hurry," said Bullard. "We can take our time to make sure the data comes in as strong as we think it will."
Since the Fed first brought interest rates to near zero in late 2008 and then embarked on unconventional monetary easing through bond-buying, Bullard has been an advocate for altering the pace of asset purchases continually in response to incoming economic data.
While the Fed has been focused on the prospect that it might be able to begin tapering purchases towards the end of this year, Bullard did not rule out the possibility that officials would choose to boost the stimulus instead if the economy deteriorates.
"If inflation drifted down in conjunction with renewed economic weakness, the committee might contemplate (an increase)," he said.
The Fed has vowed to continue buying assets until it sees substantial improvement in the labor market.
The economic expansion that followed the deepest recession in generations has been unusually weak, leaving unemployment at historically elevated levels. In February, the jobless rate stood at 7.7 percent, far from the threshold of 6.5 percent that the Fed has set for consideration of eventual rate hikes.
U.S. gross domestic product grew at just a 0.4 percent annual rate in the final three months of 2012 but is expected to have rebounded to around 3 percent in 2013's first quarter.
He acknowledged that the Fed's unorthodox approach carries risks, including possible disturbances to financial stability. But he added there is no evidence currently of "frothy" behavior in financial markets that would lead him to seek a shift in monetary policy.
Separately, Bullard said he remains concerned about the problem of banks that are considered too big to fail and said he supports breaking up the country's largest financial institutions.
"We have not ended the too-big-to-fail problem in the U.S.," Bullard said.


In an unusually candid interview yesterday, United States Ambassador to Cambodia William Heidt questioned whether the Cambodian government ever had "an honest desire" to form a relationship with the US, as Prime Minister Hun Sen continues to claim the superpower backed a purported "revolution".
In a 40-minute interview with VOA Khmer, Heidt said the Kingdom has given the US "clear signals" over the last two years that they are "not interested in a positive relationship".
The comments are the strongest statements to come out of the US Embassy in Phnom Penh since a September press conference where Heidt denied accu-sations that the US had colluded with opposition leaders to overthrow the government.
The government has justified the imprisonment of opposition leader Kem Sokha and the dissolution of his Cambodia National Rescue Party by saying that it was conspiring with the US to undertake a so-called "colour revolution". Meanwhile, Hun Sen and a host of senior leaders have repeatedly called attention in recent months to the American war legacy in Cambodia, ultimately leading the US government to withdraw funding to support the Cambodian Mine Action Center in the country's east.
Government spokesman Phay Siphan said Heidt's remarks yesterday convey a "wrong assumption" and could "inflame" the relationship between the two countries.
"We want to keep everyone as friends, not foes. The ambassador sends a signal wrongly as to what Cambodia expects from the US," Siphan said.
Siphan added that while the government still believes the US conspired to topple it, those alleged nefarious actors may have been specific groups within the US, rather than the government "as a whole".
As the divide between the US and Cambodia seemed yesterday to grow ever wider, Prime Minister Hun Sen arrived in Beijing to attend a four-day political forum held by China's ruling Communist Party.
Sry Thamrong, an aide to Hun Sen, said the premier hopes to use the trip to attract Chinese investment for roads, bridges and a proposed Skytrain. The delegation includes tycoon Kith Meng, Deputy Prime Minister Hor Namhong, Minister for Public Works and Transportation Sun Chanthol, Minister of Commerce Pan Sorasak and Council for the Development of Cambodia head Sok Chanda Sophea.
According to government news agency Agence Kampuchea Presse, Hun Sen will also deliver a speech on "independence against foreign interference".
Paul Chambers, a lecturer at Naresuan University's College of Asean Community Studies, said Heidt's comments could be a sign of Washington's waning patience with Cambodia's tilt toward China.
University of New South Wales professor and regional security analyst Carl Thayer said relations between the two countries are on a "downward trajectory" despite assurances from both sides that they are seeking friendly relations.
"There is no way back at the moment in repairing US-Cambodia relations," Thayer said. In his interview, Heidt also criticised the dissolution of the CNRP and addressed the US's decision to withdraw $1.8 million in funding from the National Election Committee.
Updated Thursday, 30 November, 6:47am.


The original Club 950 Lucky Number was located at 950 W. Wrightwood Ave from the 1980s to about 2000. Subsequent reincarnations at 2122 W. Lawrence (2001) and 1931 N. Milwaukee (2007) are not pictured. Photo at top left shows the front of the club (possibly in the 90s, as patron Aadam Jacobs recalls that the awning was not present in the 80s). Top right photo shows the mural on the side of the building around the corner. Middle photo shows the site in 2011, the building still standing but with a different façade. Bottom photo shows the site sometime after mid-2011, when the business became Barn & Company and part of the building was demolished to make room for an outdoor dining area. Hüsker Dü played the original 950 Lucky Number on 06 Aug 1981, 29 Dec 1981, 09 Jan 1982, and 11 Mar 1984.


text:
Q: JavaMail Transmission of Large and Binary MIME Messages(rfc3030) I need to exchange with one of mail server, using RFC3030 for large mime messages.
Original task is: if MIME message size > 80MB, I need to use RFC3030.
How I understand, JavaMail can't do this "from the box"?
Maybe I can create some handler or extension for JavaMail that implement RFC3030?
Please help. I don't know what to do.

A: A quick look into SMTPTransport confirms: Plain old JavaMail does not support BDAT, it will always try to send with  DATA command like this:
this.message.writeTo(data(), ignoreList);
finishData();

If you're not afraid (and have no legal reason not to) to tinker with core JDK classes, you could override the methods data() and finishData() as they're both protected (source code from here):
/**
* Send the DATA command to the SMTP host and return
* an OutputStream to which the data is to be written.
*
* @since JavaMail 1.4.1
*/
protected OutputStream data() throws MessagingException {
  assert Thread.holdsLock(this);
  issueSendCommand("DATA", 354);
  dataStream = new SMTPOutputStream(serverOutput);
  return dataStream;
}

/**
* Terminate the sent data.
*
* @since JavaMail 1.4.1
*/
protected void finishData() throws IOException, MessagingException {
  assert Thread.holdsLock(this);
  dataStream.ensureAtBOL();
  issueSendCommand(".", 250);
}

In order to support RFC3030, I'd suggest you start off by buffering the whole message into an ByteArrayOutputStream which you'll need to determine the size of the message to be sent. If "small" -> do as SMTPTransport would have done. If "big", split the bytes into chunks and send them in BDAT style. I'd suggest to end with 0 lentgh LAST BDAT and code
protected void finishData() throws IOException, MessagingException {
  assert Thread.holdsLock(this);
  dataStream.ensureAtBOL();
  issueSendCommand("BDAT 0 LAST", 250);
}

-- EDIT --
Here's a very unsophisticated first approach, lots of things to do better. Most important a chunking-as-you-go implementation for the outputStream sending out chunks of data while the message.writeTo() keeps filling it. Filling up a big byte[] just to split it up into chunks later is very, very bad in terms of memory footprint. But it's easier to read that way as all of chunking and sending happens in one place. Please note that this example uses reflection to access serverOutput field in Oracle's SMTPTransport. So it might break anytime with no warning with any new release of JavaMail. Also my Exception handling does not follow RFC-3030 for now as no RSET is performed if BDAT fails.
package de.janschweizer;

import java.io.BufferedReader;
import java.io.ByteArrayOutputStream;
import java.io.IOException;
import java.io.OutputStream;
import java.io.PrintWriter;
import java.io.StringReader;
import java.lang.reflect.Field;

import javax.mail.MessagingException;
import javax.mail.Session;
import javax.mail.URLName;

import com.sun.mail.smtp.SMTPOutputStream;

public class SMTPTransport extends com.sun.mail.smtp.SMTPTransport {

    //We can have our own copy - it's only used in the methods we override anyways.
    private SMTPOutputStream dataStream;

    private ByteArrayOutputStream baos;

    public SMTPTransport(Session session, URLName urlname, String string, boolean bool) {
        super(session, urlname, string, bool);
    }

    public SMTPTransport(Session session, URLName urlname) {
        super(session, urlname);
    }

    protected OutputStream data() throws MessagingException {
        assert(Thread.holdsLock(this));
        if(!supportsExtension("CHUNKING")) {
            return super.data();
        }
        baos = new ByteArrayOutputStream();
        this.dataStream = new SMTPOutputStream(baos);
        return this.dataStream;
    }

    protected void finishData() throws IOException, MessagingException {
        assert(Thread.holdsLock(this));
        if(!supportsExtension("CHUNKING")) {
            super.finishData();
            return;
        }
        this.dataStream.ensureAtBOL();
        dataStream.flush();
        BufferedReader br = new BufferedReader(new StringReader(new String(baos.toByteArray())));

        try {
            //BAD reflection hack
            Field fServerOutput = com.sun.mail.smtp.SMTPTransport.class.getDeclaredField("serverOutput");
            fServerOutput.setAccessible(true);
            OutputStream os = (OutputStream)fServerOutput.get(this);

            //Do the Chunky
            ByteArrayOutputStream bchunk = new ByteArrayOutputStream();
            PrintWriter pw = new PrintWriter(bchunk);
            String line = br.readLine();
            int linecount = 0;
            while(line != null) {
                pw.println(line);
                if(++linecount % 5000 == 0) {
                    pw.flush();
                    byte[] chunk = bchunk.toByteArray();
                    sendChunk(os, chunk);
                    bchunk = new ByteArrayOutputStream();
                    pw = new PrintWriter(bchunk);
                }
                line = br.readLine();
            }
            pw.flush();
            byte[] chunk = bchunk.toByteArray();
            sendLastChunk(os, chunk);
        } catch (Exception e) {
            throw new MessagingException("ReflectionError", e);
        }
    }

    private void sendChunk(OutputStream os, byte[] chunk) throws MessagingException, IOException {
        sendCommand("BDAT "+chunk.length);
        os.write(chunk);
        os.flush();
        int rc = readServerResponse();
        if(rc != 250) {
            throw new MessagingException("Something very wrong");
        }
    }

    private void sendLastChunk(OutputStream os, byte[] chunk) throws MessagingException, IOException {
        sendCommand("BDAT "+chunk.length+" LAST");
        os.write(chunk);
        os.flush();
        int rc = readServerResponse();
        if(rc != 250) {
            throw new MessagingException("Something very wrong");
        }
    }
}

With this META-INF/javamail.providers
protocol=smtp; type=transport; class=de.janschweizer.SMTPTransport; vendor=Jan Schweizer;

redpajama_set_name: RedPajamaStackExchange


We are BLACKSQUARE, an award winning creative design studio. Based in Stirling, but with a global outlook, our design philosophy is simple: we work closely with our clients to create innovative design with character and relevance.
Our portfolio shows our creative approach to working with a range of clients, from global brands to start-ups, delivering outstanding design results every time.
BLACKSQUARE also provides a comprehensive photography and video service, specialising in a stunning and creative approach to everything from portraits and product shots to catalogues and audio visual presentations.


Today we will be deploying 1.27a for Warcraft III. As with Diablo II, this patch focuses on modern system compatibility. It's exciting to bring some additional support to another core Blizzard game, and we thank you for your encouragement and patience as we continue working behind the scenes on these types of updates.
Please be aware that while we are working on a balance change and new map pool, that work is still in progress and is not part of this patch. We'll have further details on that as development progresses.


I've put together a classic blue and white tablescape just for all the BLUE lovers.
'Iceberg' roses from my garden picking up the candle light.
Sapphire juice pitcher , bud vase, S&P, mini disc pitcher and individual sugar bowl.
Be sure to take time in your day to stop and smell the roses.
They perfume your environment and enrich your soul.
Thanks for coming by to see me today!
That vintage tablecloth is perfect. Love the blues with it. Looks clean and crisp!
For a person without much Blue you sure put together one gorgeous table. I love the shades of blue and the white. Lovely!
lovely set of blues!!! every photos are great...thanks for sharing, and happy Monday to you!
you might like to visit my blog for a giveaway!
Totally in love with the roses. And, the blue pitcher. I have one in yellow. Mine is a Fiesta, is yours?
HOW bright & cheery! That tablecloth is amazing!
I want to come over for dinner!
That is absolutely delightful... I hope my guests don't ever go to your place first!
Oh, Candy, what a beautiful table! Those roses must smell so lovely. Happy Blue Monday.
Not much blue???!!!! Just gorgeous. Love your table. I can smell the roses!
Candy, Your tablecloth is lovely and you have put together a beautiful table. Love your roses, too!
That vintage tablecloth is terrific - wish they were still making them like that!
Every detail simply lovley!Your own picked roses are divine!!
Your photos made me smile. Everything is just so beautiful and makes one happy just to look at.
Wow so pretty stuff and my fav color blue. Happy blue Monday.
Too gorgeous Candy! Love the blues-I could kick myself for not starting my Fiesta habit earlier!
love it! all of it are beautiful and elegant :) thanks for sharing!
Love it! That tablecloth is really pretty and I love the cobalt blue stemware.
Beautiful blue table and i love the closeups of the flowers.
Thanks to all of you for your lovely comments on my BLUE contribution! It is really tough to find blue around here, must be that I had so much blue back in the 60's that I just rarely have anything blue now!


Alonso insisted that the established format adapts to the new ways of tourism and combines innovation, excellence and creativity, but also allows the development of the same business than in a large international fair with a lower cost. As far as Turespaña's director, Antonio Bernabé, is concerned, he considers that this event as the most important in Andalusia and in Spain and stated that these type of projects fit in with the new promotion strategy and have become one of the key factors in the positive evolution that Spanish tourism is registering.
This event starts on the 26th of October and ends on the 30th. The first two days are dedicated to commercial contacts and the development of a training day aimed to the professionals of the sector. After these two days of work, each buyer will be able to choose the product or destination that he/she prefers. This way, the participators can choose between ten 'post tour' in the eight provinces that include sectors like sun and beaches, culture, languages, middle cities, interior and nature, congresses or golf.


text:
Analysis: Russia's Veiled Threat Toward Iran
In Russian diplomatic codes, the denouncement of the uranium enrichment in the facility near Qom is a clear message to Iran to start cooperating with the international community.
Eli Shvidler
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In a rare announcement Tuesday, the Russian Foreign Ministry expressed 'regret' over Iran's nuclear development program. This announcement serves, in Russian diplomatic language, as a severe warning to the Iranian leadership far beyond the simple "regret and concern" it stated over the commencement of uranium enrichment at an underground site at Fordo, near the Shi'ite Muslim holy city of Qom.
Russia 'regrets' reported Iran nuclear activity in Qom facility
Turkey stops Iranian trucks carrying arms to Syria, report says
The comment, which says that Russia "recognizes that Iran is continuing to ignore the demands of the international community" that it respond to their concerns regarding its nuclear program, in effect carries a harsh denunciation of a country adamantly supported by Russia until just a few days ago.
Iranian President Mahmoud Ahmadinejad listens to Russia's new ambassador to Tehran, Levan Djhagaryan, at the presidency office in Tehran, Dec. 13, 2011.Credit: AP
Iran's claim that it notified the International Atomic Energy Agency about works near Qom getting underway cannot hide Russia's severe lack of satisfaction with Iran. According to Russia, Iran continues to push itself into a corner in the international arena, and that it will be very difficult to extract itself from there in times of need.
Experts on the history of Russian diplomacy would notice the heavy weight of the word "Tehran" in the condemning message. It is a known practice of Russian diplomacy to use the name of a country's capital many times in a statement, in order to present a particular subject in a negative light. Those with a good memory will certainly remember the diplomatic cables of the Soviet era, which starred Washington and Tel Aviv as in aggressive contexts.
"Hopefully, Iran will listen to our opinion about the need for further close cooperation with the Agency and the soonest beginning of serious negotiations on the Iranian nuclear program with the Sextet without preconditions," the Russian Foreign Ministry said. This wording presents a clear – if not scathing – warning in Russian diplomatic terms, as the Foreign Ministry called on all sides to prevent harsh and uncalculated steps.
Without expressing sympathy toward the opposing side, Russia chose on Tuesday to clarify to Iran that it would be solely responsible for troubles that are likely to come its way in the near future. Russia made it clear that it no longer takes for granted Iran's claims that the West's reaction to its nuclear program is "exaggerated and fueled for years by clear political motives."

redpajama_set_name: RedPajamaCommonCrawl


"As a new blogger, I quickly realized my content has to stand out and reach an audience. I discovered that Pinterest was an immense search engine that drove the most traffic to the major bloggers. Tasty Pins has been critical in implementing my Pinterest SEO strategy. I can write separate alt text and Pinterest text to optimize my pins for both Google and Pinterest search. My new pins since implementing Tasty Pins have received more engagement and viewing."


Basel, October 20, 2018 - Novartis today announced positive results from the global Phase III SOLAR-1 trial evaluating the investigational alpha-specific PI3K inhibitor BYL719 (alpelisib) in combination with fulvestrant. The trial evaluated the efficacy and safety of alpelisib in postmenopausal women with PIK3CA mutated hormone-receptor positive, human epidermal growth factor receptor-2 negative (HR+/HER2-) advanced or metastatic breast cancer that progressed on or after an aromatase inhibitor with or without a CDK4/6 inhibitor. These data will be presented today at the official press briefing at the European Society for Medical Oncology (ESMO) 2018 Congress and as a late-breaker during the Presidential Symposium (Abstract LBA3_PR).
In patients with PIK3CA mutated HR+/HER2- advanced breast cancer, BYL719 plus fulvestrant demonstrated a median progression-free survival (PFS) of 11 months (95% CI: 7.5-14.5 months) compared to 5.7 months (95% CI: 3.7-7.4 months) for fulvestrant alone. BYL719 plus fulvestrant reduced the risk of death or progression in those patients by an estimated 35% compared to fulvestrant alone (HR=0.65; 95% CI: 0.50-0.85; p<0.001). Overall response rate (ORR), indicating a reduction in tumor size of at least 30%, was more than doubled in patients with measurable disease who received BYL719 plus fulvestrant (36%) compared to those receiving fulvestrant alone (16%).
"The results from SOLAR-1 are the most encouraging observed to date from a trial evaluating a PI3K inhibitor for patients with PIK3CA mutated HR+/HER2- advanced breast cancer," said Fabrice André, MD, PhD, research director and head of INSERM Unit U981, and professor in the Department of Medical Oncology at Institut Gustave Roussy in Villejuif, France. "These data have the potential to allow physicians to address an unmet need in this patient population by using a biomarker-driven treatment to inform their sequencing decisions."
PFS treatment effect was consistent across all subgroups, and regardless of whether aromatase inhibitor treatment was given, with or without a CDK4/6 inhibitor. The significant PFS improvement demonstrated with BYL719 plus fulvestrant in patients with a PIK3CA mutation was not observed for patients without the mutation.
"We are excited about the meaningful results seen in SOLAR-1 and about the possibility to reimagine what potential treatment options could look like for patients living with PIK3CA mutated HR+/HER2- advanced breast cancer - some of who were previously treated with a CDK4/6 inhibitor," said Samit Hirawat, MD, Head, Novartis Oncology Global Drug Development. "We are actively engaging in discussions on these results with health authorities worldwide."
Most adverse events were mild to moderate in severity and generally manageable through dose modifications and medical management. The discontinuation rate of BYL719 plus fulvestrant due to adverse events was 5% compared to 1% for fulvestrant alone. The most common all-grade adverse events (>=30%) were hyperglycemia (64% vs 10%), diarrhea (58% vs. 16%), nausea (45% vs. 22%), decreased appetite (36% vs. 11%) and rash (36% vs. 6%). Of these, the most common grade 3/4 events (>=5%) were hyperglycemia (37% vs. <1%), rash (10% vs. <1%), and diarrhea (7% vs. <1%).
The SOLAR-1 trial is ongoing to evaluate secondary endpoints, including overall survival. Further analysis from SOLAR-1 will be presented and discussed at future medical congresses.
Studies have established the role of PI3K signaling in several processes for cancer progression, including cell metabolism, growth, survival and motility. Activation of the PI3K pathway in breast cancer is associated with resistance to endocrine therapy, disease progression and poorer prognosis,.
Currently, there are no approved PI3K inhibitors for breast cancer.
SOLAR-1 is a global, Phase III randomized, double-blind, placebo-controlled trial studying investigational BYL719 in combination with fulvestrant for postmenopausal women with PIK3CA-mutated HR+/HER2- advanced or metastatic breast cancer that progressed on or following aromatase inhibitor treatment with or without a CDK4/6 inhibitor.
The trial randomized 572 patients. Patients were allocated based on tumor tissue assessment to either a PIK3CA-mutated cohort or a PIK3CA non-mutated cohort. Within each cohort, patients were randomized in a 1:1 ratio to receive continuous oral treatment with BYL719 (300mg once daily) plus fulvestrant (500 mg every 28 days + Cycle 1 Day 15) or placebo plus fulvestrant. Stratification was based on visceral metastases and prior CDK4/6 inhibitor treatment.
The primary endpoint is local investigator assessed PFS using RECIST 1.1 for patients with the PIK3CA mutation. Secondary endpoints include but are not limited to overall survival, overall response rate, clinical benefit rate, health-related quality of life, efficacy in PIK3CA non-mutated cohort, safety and tolerability.
This press release contains forward-looking statements within the meaning of the United States Private Securities Litigation Reform Act of 1995. Forward-looking statements can generally be identified by words such as "potential," "can," "will," "plan," "expect," "anticipate," "look forward," "believe," "committed," "investigational," "pipeline," "launch," "encouraging," or similar terms, or by express or implied discussions regarding potential marketing approvals, new indications or labeling for BYL719 or the other investigational or approved products described in this press release, or regarding potential future revenues from such products. You should not place undue reliance on these statements. Such forward-looking statements are based on our current beliefs and expectations regarding future events, and are subject to significant known and unknown risks and uncertainties. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those set forth in the forward-looking statements. There can be no guarantee that BYL719 or the other investigational or approved products described in this press release will be submitted or approved for sale or for any additional indications or labeling in any market, or at any particular time. Nor can there be any guarantee that BYL719 or such other products will be commercially successful in the future. In particular, our expectations regarding BYL719 and such other products could be affected by, among other things, the uncertainties inherent in research and development, including clinical trial results and additional analysis of existing clinical data; regulatory actions or delays or government regulation generally; global trends toward health care cost containment, including government, payor and general public pricing and reimbursement pressures; our ability to obtain or maintain proprietary intellectual property protection; the particular prescribing preferences of physicians and patients; general political and economic conditions; safety, quality or manufacturing issues; potential or actual data security and data privacy breaches, or disruptions of our information technology systems, and other risks and factors referred to in Novartis AG's current Form 20-F on file with the US Securities and Exchange Commission. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise.
Novartis is reimagining medicine to improve and extend people's lives. As a leading global medicines company, we use innovative science and digital technologies to create transformative treatments in areas of great medical need. In our quest to find new medicines, we consistently rank among the world's top companies investing in research and development. Novartis products reach nearly 1 billion people globally and we are finding innovative ways to expand access to our latest treatments. About 125,000 people of more than 140 nationalities work at Novartis around the world. Find out more at www.novartis.com.
 Andre F, Ciruelos EM, Rubovszky G et al. Alpelisib + fulvestrant for HR+, HER2- advanced breast cancer: Results of the Phase III SOLAR-1 trial. Presented at the European Society for Medical Oncology (ESMO) 2018 Congress (Abstract LBA3_PR) on October 20, 2018.
 Sabine V, Crozier C, Brookes C, et al. Mutational analysis of PI3K/AKT signaling pathway in tamoxifen exemestane adjuvant multinational pathology study. Journal of Clinical Oncology. 2014;32:2951-2958.
 Courtney KD, Corcoran RB, Engelman JA. The PI3K pathway as a drug target in human cancer. J Clin Oncol. 2010;28(6):1075-1083.
 Miller TW, Rexer BN, Garrett JT, Arteaga CL.Mutations in the Phosphatidylinositol 3-Kinase Pathway: Role in Tumor Progression and Therapeutic Implications in Breast Cancer. Breast Cancer Res. 2011.
 Saal LH, Johansson P, Holm K. Poor prognosis in carcinoma is associated with a gene expression signature of aberrant PTEN tumor suppressor pathway activity. PNAS. 2007;104(18):7564-7569.
 Thorpe LM, Yuzugullu H, Zhao JJ. PI3K in cancer: divergent roles of isoforms, modes of activation, and therapeutic targeting. Nature Reviews Cancer. 2015;15(1):7-24.
 Fritsch C, Huang A, Chatenay-Rivauday A et al. Characterization of the novel and specific PI3K alpha inhibitor NVP BYL719 and development of patient stratification strategy for clinical trials. Molecular Cancer Therapeutics.2014; 13(5):1117-1129.


text:
Tram Haus Lodge At Jay Peak Launches, Softly, For The Holidays
14th December 2009 | Roger Leo, Executive Editor
Resorts in this article: Jay Peak
[R192R, Jay] is opening its new, slopeside Tram Haus Lodge with 42 studios, and one- and two-bedroom suites. Rates vary, depending on type of accommodation, and time of visit. For example, the Tram Haus is charging $99 per person per night, double occupancy for a studio Dec. 18 to 24, which includes lodging and lift tickets. Another example: The Tram Haus is charging $578 per night for two adults for two nights in a studio suite anytime between Dec. 25 and 31, which includes lodging, lift tickets for two days, two dinners, and two breakfasts.
The Tram Haus offers indoor heated parking, access to the fitness center and spa, and all-day day care.
Suites include slopeside access, sweeping views up the mountain or down the valley, fireplaces, kitchens, and flat-panel TVs.
Dining is available at three places: Aroma's Café for coffee, sandwiches and light fare; The Tower Bar featuring small plates, beer, wine, and spirits; and Alice's Table, a unique restaurant featuring big views and locally inspired cuisine.
The Tram Haus Lodge is the first new resort facility to open in a multi-year, four season, $100 million development plan. Construction has started on a new Ice Arena, Nordic Center, and Golf Clubhouse, scheduled to come online by the early spring of 2010.
Winter has arrived at Jay, as at most of the Northeast, thanks to some natural snowfall and lots of good snowmaking weather. Jay Peak averages 379 inches of natural snowfall each winter, which the resort's operators like to point out is more than either Steamboat Springs (336 inches), Vail (346 inches), or Mont Tremblant (150 inches).


Staying Vertical 2016 movie drama free download.
Awards: 2 win & 7 nominations.
The film Staying Vertical is a touching drama with elements of comedy by French director Alain Guiraudie.
The main hero Léo is a filmmaker who is constantly in search. He needs inspiration to shoot a new film this time. As a result, he goes to the South of France. Soon Leo acquainted with one of the local shepherdesses Marie, who was very cheerful and sociable. Leo seduces the girl, and then leaves her. She gives birth to his child after 9 months. Leo can not leave his profession, because is a creative person. He can not stay at home for long. Marie lives through postpartum depression heavy. Moreover, once she leaves him alone with the child. The man was somewhat taken aback at first, but then he realized that this is a happiness. Now the main character of the movie Staying Vertical is waiting for a series of unexpected and unusual acquaintances and painful search for inspiration for the new film.


Happy Easter 🐣 For Easter dessert, we are currently baking a GF Meringue Wreath that will be topped with cream, berries and Easter eggs (of course!) 🍓 I've never been successful in making a good meringue, so I trialled a new recipe and learnt lots of tips and tricks before making this! It's so simple to make and only contains 4 ingredients (egg whites, sugar, corn flour and vinegar) but there are so many components that affect the meringue. I will keep you posted on the finished product (it's currently in the oven) 😀 Have you tried making meringues before?
Cucumber contributes greatly to human health in so many ways. . In fact fruits in general. Eat more fruits and stay healthy.
קבלו את נופר שלנו שלא מוותרת לעצמה ועל עצמה :) יום פילאטיס שמח!