A method and an arrangement for detecting the position of the plane XY of an object, which plane XY is to be scanned, and for its positioning in the focal plane Xxe2x80x2Yxe2x80x2 of a laser scanner, preferably for a laser scanning microscope. According to the disclosure, it is provided in a method of the type described above that, after a rough orientation of the object carried out by placing on an object holder, a laser beam is directed successively in time to at least three different points P1, P2 . . . Pn located in the scan plane XY of the object and, in doing so, each of the reflections proceeding from the points P1, P2 . . . Pn is imaged on a position-sensitive detector, an actual position value is determined at the detector for each reflection and is compared with a stored reference position value, adjustment commands for changing the inclination of the object holder are obtained from the deviations of the actual position values from the reference position values, and the inclination of the object holder is changed on the basis of these adjustment commands until points P1, P2 . . . Pn are located in the focal plane Xxe2x80x2Yxe2x80x2 of the laser scanner.

This application claims priority of International Application No. PCT/EP00/04493, filed May 18, 2000 and German Application No. 199 23 821.9, filed May 19, 1999, the complete disclosures of which are hereby incorporated by reference.
a) Field of the Invention
The invention is directed to a method and an arrangement for detecting the position of the scanned plane XY of an object and for its positioning in the focal plane Xxe2x80x2Yxe2x80x2 of a laser scanner, preferably in a laser scanning microscope.
b) Description of the Related Art
In the last two decades, scanners have achieved an advanced state of the art. Particularly in medical engineering, metrology and, above all, in microscopy, it is becoming more and more common for objects to be scanned by a laser beam. In the biological-medical field, for example, laser scanning microscopes have clear advantages over conventional microscopes which stem essentially from the higher resolution that can be achieved and the possibility of differentiating between determined depth layers.
Accordingly, in fluorescence microscopy, due to the high point intensity of the focused laser beam, it is possible to utilize the sensitivity of photomultipliers for image building when the fluorescence itself is weak. However, XY scanners require very high positioning accuracy in orientating the object to be scanned relative to the focusing plane of the microscope.
The precision with which the plane of the specimen to be analyzed must be brought into the focus of the laser beam in order to prevent intensity losses and avoid deficient image quality increases as depth resolution increases.
To this extent, in connection with the continuing development in this technical field, it is necessary to provide methods and arrangements by which the objects and planes to be scanned can be exactly and, if possible, automatically oriented relative to the focal plane. In general, requirements can no longer be met by the technique, still often applied, of positioning by means of sensitively adjustable manual drives with repeated position correction.
On this basis, it is the primary object of the invention to provide a method enabling an automatic and precise positioning of a scan plane XY in the focal plane Xxe2x80x2Yxe2x80x2 of a laser scanner.
According to the invention, it is provided in a method of the type described above that, after a rough orientation of the object carried out by fixing on an object holder, a laser beam is directed successively in time to at least three different points P1, P2 . . . Pn located in the scan plane XY of the object and, in doing so, each of the reflections proceeding from the points P1, P2 . . . Pn is imaged on a position-sensitive detector, an actual position value is determined at the detector for each reflection and is compared with a stored reference position value, actuating or adjustment commands for changing the inclination of the object holder are obtained from the deviations of the actual position values from the reference position values, and the inclination of the object holder is changed on the basis of these adjustment commands until points P1, P2 . . . Pn are located in the focal plane Xxe2x80x2Yxe2x80x2 of the laser scanner.
The essential advantages of this method consist in that, to a great extent, components which already exist in a laser scanner can be used for determining position, e.g., the position transmitter for the laser beam and the optical elements for transmitting the laser radiation reflected by the specimen to an optoelectronic reception device, followed by an evaluating unit. Further, positioning is not only more exact in this way, but is also substantially faster than in any of the previously known methods.
In a preferred embodiment of the method according to the invention, three points P1(x1;y1), P2(x2;y2) and P3(x3;y3), where y1=y2=x3=0 and x1=xe2x88x92x2xe2x89xa00; y3xe2x89xa00, are sampled, wherein one point P0, where x0=y0=0, lies approximately in the center of the object and/or of the plane XY to be scanned, P1, P2, P3 are preferably points near the edges of the object, and the deviations between the actual position values and reference position values are determined according to the principle of laser triangulation.
Accordingly, three points P1, P2, P3 are defined which are advantageously suited to position detection because, first, they are located far apart from each other due to their position at the edges of the object or at the edges of the plane XY to be scanned, which creates favorable preconditions for laser triangulation, and, second, they can be controlled in an uncomplicated manner assuming that point P0 approximately defines the starting position of the laser beam in the coordinate origin of the focal plane Xxe2x80x2Yxe2x80x2.
In triangulation, a light point is projected by means of a laser beam onto the plane of the measurement object to be scanned and the reflected light is imaged on a position-sensitive detector. The position of the reflection on the detector varies depending on the distance between the plane XY to be scanned and the objective, as measured in coordinate Z. The signal emitted by the detector is accordingly a measure for the distance between the reflecting surface and the objective or a measure of whether or not the reflecting point lies in the focus of the objective.
According to the invention, the object is initially oriented in such a way that the laser beam is directed, e.g., on position P0, the scanning device is then controlled in such a way that the laser beam is directed to point P1, a parallel displacement of the object holder in Z-direction is effected, if need be, until the reflection of P1 supplies a definite signal to the detector, the actual position value for point P1 is acquired, the scanning device is then controlled in such a way that the laser beam is directed to point P2, the actual position value for point P2 is now acquired, adjustment commands for tilting the object holder about the Y-axis are now determined from the deviations between the actual position values and reference position values, and the orientation of the X-axis of plane XY parallel to the focal plane Xxe2x80x2Yxe2x80x2 is brought about, the scanning device is then controlled in such a way that the laser beam is directed to point P3, the actual position value for point P3 is detected and, finally, an adjustment command for tilting the object holder about the X-axis is determined from the deviation of the actual position value from the reference position value of point P3 and, accordingly, the parallel orientation of the Y-axis of plane XY relative to the focal plane Xxe2x80x2Yxe2x80x2 is brought about.
In a particularly preferred construction of the invention, the steps indicated above are repeated in order to determine any existing deviations and to readjust in the described manner until no deviations are measurable and the planes XY are adjusted parallel with the focal plane Xxe2x80x2Yxe2x80x2.
Further, it lies within the framework of the invention that after this orientation of plane XY a parallel displacement in Z-direction is carried out, namely, until the reflections of P1, P2, P3 are imaged on the detector with maximum intensity. In this way, it is ensured with great dependability that the plane XY to be scanned is not only oriented parallel to the focal plane Xxe2x80x2Yxe2x80x2, but coincides with it.
It is a further object of the invention to provide an arrangement for carrying out the method steps mentioned above and for determining the position of the scan plane XY of an object and for its positioning in the focal plane Xxe2x80x2Yxe2x80x2 of a laser scanner, preferably a laser scanning microscope.
This object is met, according to the invention, by an arrangement which is outfitted with an object holder for receiving the object, with a photo-sensitive detector for locating the reflections of three points P1, P2, P3 which lie in plane XY and are sampled successively or simultaneously by a laser beam, with an evaluating circuit for determining deviations of the actual position value of each of these reflections from its reference position value on the detector, and with an adjusting device connected with the evaluating circuit for changing the inclination of the object holder relative to the focal plane Xxe2x80x2Yxe2x80x2 of the laser scanner.
The arrangement according to the invention is preferably directed to a laser scanner, known per se from the prior art, which has a mirror supported on a rotatable shaft for deflecting a laser beam in the direction of coordinate Xxe2x80x2 and in which the object holder is displaceable in a straight line in the direction of coordinate Yxe2x80x2, wherein the series of movements can be controlled and monitored by drives which are coupled with position transmitters.
In a preferred embodiment of the invention, the detector is constructed as a CCD line with 256 pixels and is a component part of a triangulation assembly in which there is further provided at least one laser diode as a separate radiation source for sampling points P1, P2, P3, preferably with a laser wavelength xcex greater than or equal to 780 nm and independent control, and optics for coupling the diode radiation, e.g., into the infinite beam path of the laser scanner.
It is particularly advantageous when the diode radiation has a Gaussian intensity profile and the actual positions of the diode beam reflected by points P1, P2, P3 on the CCD line are defined by the centroid of the Gaussian function. The steps for determining the centroid are known from the prior art and are therefore indicated only briefly herein.
First, the pixel with maximum intensity and the level of the base signal are determined on the CCD line. The half-height of the Gaussian function is calculated from these values and the intersections of the Gaussian function with the half-height are determined, wherein linear interpolation is carried out between the pixels. The mean value between the intersections approximates the centroid. By means of interpolation, the centroid is obtained with a resolution which is better than the pixel size and is only limited by the noise and deviations of the measurement signal from the assumed Gaussian function.
According to the invention, it is further provided that a storage is provided in the evaluating circuit with reference position values (associated with points P1, P2, P3), wherein the reference position is preferably defined in each instance in the center of the CCD line and, further, the evaluating unit has a subtracter, wherein an actual position value and a reference position value are applied to the inputs of this subtracter during every evaluation, with reference in each instance to one of the points P1, P2, P3, and a difference signal can be taken off at the output of the subtracter as an adjusting signal for the adjusting device coupled with the object holder.
The adjusting device is advantageously constructed in such a way that it has three drive elements which can be advanced separately in the direction of coordinate Z, each drive element being mechanically connected with the object holder via a separate articulation point A1, A2, A3. The articulation points A1, A2, A3 and points P1, P2, P3 lie in plane XY. Further, articulation points A1 and A2 are located along with points P1 and P2 on the same straight line which also passes through the coordinate origin P0 and accordingly forms the X-axis, while points A3, P3 and the coordinate origin likewise lie on a common straight line, namely, the Y-axis.
Due to this arrangement in connection with the separate controllability of the drive elements, it is ensured that the object holder can be tilted about the Y-axis, for example, when the articulation points A1 and A2 are controlled in opposite directions, while articulation point A3 remains stationary relatively. Further, this makes it possible to tilt the object holder in a defined manner about the X-axis insofar as only articulation point A3 is controlled and articulation points A1 and A2 remain stationary relatively.
This construction of the adjusting device according to the invention has the advantageous result that the angle adjusting movements about the X-axis on the one hand and Y-axis on the other hand can be carried out independent from one another and the X-axis need no longer be readjusted while the Y-axis is moved, and vice versa.
It is further advantageously provided that the drive elements are piezoelectric drives or, in an alternative construction, precision-movement threaded spindles coupled with rotating drives. Further, the adjusting mechanism can be constructed in such a way that the drive elements engage in recesses of the object holder, the drive elements contact the object holder within the recesses based on a ball-and-socket principle, and the drive elements and object holder are biased or pretensioned relative to one another elastically by means of springs so that they are mounted without play.
Of course, different constructions of the drive elements are possible: for example, pins which are displaceable in guides and which contact articulation points A1, A2, A3 on the one hand and are in contact with cam surfaces on the other hand, wherein the cams are driven by stepper motors which are outfitted with corresponding gear units for achieving the required precision.
For the sake of completeness, it is noted that while the invention has been explained with reference to the triangulation principle for detecting the laser radiation reflected by points P1, P2, P3, this does not rule out the use of other means for detecting the position of these reflections. In this respect, it is merely noted that it is possible to direct a collimated symmetric laser beam vertical to plane XY and to image the reflection on a quadrant diode via a cylindrical lens. In this regard, the ellipticity of the focus on the quadrant diode is a measure for the deviation of the position of the point acted upon by the laser beam from the focal plane. A contrast determining process can also be applied, for example, in which the distance between points P1, P2, P3 is changed during scanning until a contrast function derived from the determined image has reached its maximum. A simple contrast can be determined as well as the frequency spectrum of the image information.
The invention described above can be applied in a particularly advantageous manner for scanning the bottoms of microtiter plates and biochips containing fluorescing specimens. However, it must be taken into account in this regard that the laser radiation is reflected twice, namely, once by the underside and a second time by the inner side of the bottom of the plate. In other words, depending on spatial resolution, one or two laser reflections can appear on the CCD line. Since the inner side is closer to the specimen to be scanned, this reflecting surface is preferably used for orientation.
It may also be advantageous under certain circumstances when there is a second laser diode (in addition to the laser radiation source provided for fluorescence microscopy of the specimen) in the triangulation assembly instead of only one; although only one needs to be active at any time, the widely different apertures of different objectives can be taken into account in this way.
In another development, a mechanical shutter can be provided which blocks the microscope laser beam during the orientation of the plane XY. This prevents unwanted bleaching of the specimen.
The invention will be explained more fully in the following with reference to an embodiment example.

Method and array for detecting the position of a plane scanned with a laser scanner


A next-generation mobile communication system is disclosed, including a high-speed cell searching method and apparatus using a distributed sample acquisition scheme (DSA) and a differentially-coherent phase shift keying (DPSK)-based DSA (hereinafter referred to as D2SA) in a direct sequence code division multiple access (DS/CDMA) system. The high-speed cell searching apparatus uses the D2SA technique using the 2b-ary DPSK modulation instead of the quadrature modulation to simultaneously convey b (b≧1) state samples for the SRG that generates the long-period PN sequences in the next-generation DS/CDMA system using the DSA technique, and employs the data constellation pre-rotation technique to provide the certainty of the channel estimation. A high-speed cell searching method using the apparatus is also provided.

1. Field of the Invention
The present invention relates generally to a next-generation mobile communication system. In particular, the present invention relates to a high-speed cell searching method and apparatus using a distributed sample acquisition scheme (DSA) and a differentially-coherent phase shift keying (DPSK)-based DSA (hereinafter referred to as D2SA) in a direct sequence code division multiple access (DS/CDMA) system.
2. Background of the Related Art
Generally, in a DS/CDMA communication system, a receiver is required to synchronize (Psuedo-Noise) PN sequences prior to detection of data. Mostly, the PN sequence synchronization is performed by two steps of code acquisition and code tracking in sequence. Here, regarding the code acquisition, research for a high-speed acquisition technique to shorten the acquisition time has been made with great interest and anxiety.
The most basic code acquisition technique proposed up to now is a serial search. This method has an advantage that its implementation is not complex, but has a disadvantage that since the acquisition time is directly proportional to the period of the PN sequence being used, acquisition time is quite long when the period of the PN sequence is long.
Meanwhile, a parallel search has been proposed to acquire the PN sequences having a long period. However, this parallel search has a disadvantage that its implementation becomes complicated in proportion to the reduced acquisition time.
Ultimately, a hybrid method, which properly balances the acquisition speed and the complexity of implementation by adequately combining the serial search and the parallel search for the high-speed acquisition of the PN sequences, has been proposed. Another high-speed acquisition method based on state estimation of a shift register generator (SRG) has been proposed as well.
The acquisition technique based on the state estimation of the SRG acquires rapid acquisition by sequential estimation. This technique sequentially performs a hard detection of the received PN sequences a large number of times, carries them as temporary register state values of the receiving part SRG, and then finally decides whether or not it is synchronized through a confirming process. In theory, this technique has an advantage that it can greatly reduce the acquisition time without increasing the implementation complexity in comparison to the serial search. However, it has a disadvantage that its performance abruptly deteriorates when it is based on a coherent detection of the PN sequences and has a low signal-to-noise ratio (SNR). Thus, it is improper to apply this technique in a general code division multiple access (CDMA) environment.
Because of this, an acquisition technique based on a new state estimation has been proposed. This technique, named a distributed sample acquisition (DSA) technique, reduces the acquisition time of the long-period PN sequences using hardware having minimal complexity in the conventional DS/CDMA type cellular system.
According to this DSA technique, the transmitting part generates an igniter sequence having a relatively short period, and transmits the igniter sequence with state samples of the long-period PN sequences being carried thereon. The receiving part first acquires the igniter sequence, demodulates the state samples carried thereon, and corrects the SRG state of the receiver through a comparison-correction circuit at every accurate time point. In this way, synchronization of the PN sequences is performed.
A pair of SRGs having the same structure are provided in the transmitting/receiving part to perform the synchronization by carrying the same state values, i.e., L values stored in the SRG having the length of L. Therefore, they can transfer the state samples of the transmitting part SRG to the receiving part using the DSA technique. As a result, this technique can acquire the PN sequence much faster than the existing technique that performs the synchronization at the time point where the maximum correlation value for the PN sequences is detected.
Since the high-speed acquisition using the DSA technique as described above is performed prior to the phase estimation of the carrier, coherent demodulation cannot be used for transferring information. Thus, an orthogonal modulation has been conventionally used for modulating information. According to the conventional high-speed acquisition using the DSA, the orthogonal modulation which uses 2b-ary orthogonal symbols to simultaneously transfer b (b≧1) state symbols for the SRG that generates the long-period PN sequences has been employed.
As a result, in the conventional base station (i.e., transmitter), 2b-ary orthogonal symbols corresponding to the b state symbols for the SRG are generated at the respective sampling time points, and these symbols are spread by the relatively short-period igniter sequences to broadcast them through a pilot channel.
Meanwhile, in the mobile station (i.e., receiver), 2b correlators (or, matched filters) are used for acquiring the igniter sequence. Specifically, the mobile station confirms whether the maximum value among the correlator output energies for each phase exceeds a predetermined threshold value as it changes the phase of the igniter sequence. If the maximum value of the 2b correlator output energies exceeds the threshold value for a specified phase, the mobile station declares that the igniter sequence is acquired, and then confirms which correlator has the maximum output energy in a state that the phase of the sequence is fixed. Then, the detection of the 2b-ary quadrature symbols is performed. Finally, the synchronization of the scrambling sequence is effected by decoding the detected quadrature symbols into b state samples, and using these state samples for the state correction of the mobile station SRG (it generates the long-period PN sequences).
FIG. 1 is a block diagram illustrating the selective structure of a related art parallel sampling despreader provided in a receiver in the next-generation DS/CDMA system using the general quadrature-modulation-based DSA technique. FIGS. 2A and 2B are drawings illustrating respective operation modes of a decision logic circuit used in the related art next-generation DS/CDMA system using the general quadrature-modulation-based DSA technique. Specifically, FIG. 2A shows the decision logic circuit which operates in an igniter sequence acquisition mode, and FIG. 2B shows the decision logic circuit which operates in a state sample detection mode.
The state signal r(t) having arrived at the receiving part is despread by 2b quadrature symbol correlators, integrated for a symbol time with integrators 60, 61 and 62) and then converted into input values |Yj|(j=0, 1, . . . , 2b−1) of the 2b decision logic circuits by taking their absolute values. In the actual implementation, the absolute value is generally obtained via absolute value units 63, 64 and 65 by multiplying the in-phase (I-phase) value and the quadrature-phase (Q-phase) value of the output of the integrating section and then obtaining a square root value thereof. At this time, the correlation signal used for correlating with the state signal in the j-th quadrature symbol correlator is a conjugate complex signal of the spread quadrature signal mj(t), that is obtained by multiplying the quadrature symbol signal sj(t) and the igniter sequence signal c(t) used for the quadrature modulation in the transmitting part. The value |Yj|(j=0, 1, . . . , 2b−1) are then input to the decision logic section 69.
FIGS. 2A and 2B illustrate the operation of the decision logic section 69 in FIG. 1. The decision logic circuit operates differently in the igniter sequence acquisition mode and in the state sample detection mode. In the igniter sequence acquisition mode (i.e., the step prior to the igniter sequence acquisition), the maximum value among the 2b input values |Yj|(j=0, 1, . . . , 2b−1) is compared with the predetermined threshold value R0. If the maximum value is larger than the threshold value, the decision logic circuit declares the sequence phase consistent state H1, and goes to the acquisition confirmation step. If the maximum value is smaller than the threshold value, the decision logic circuit declares the sequence phase discrepant state H0, and checks whether the next sequence phase is consistent.
In the state sample detection mode (i.e., the step after the igniter sequence acquisition), the decision logic circuit determines which value is the maximum value among the 2b input values |Yj|(j=0, 1, . . . , 2b−1), and detects the corresponding quadrature state symbol Sj. This state symbol is demapped by b state samples.
The high-speed acquisition using the related art DSA technique has various problems. For example, if the number (b) of the state samples simultaneously sampled and transmitted by the SRG that generates the long-period PN sequences is increased, the number of the correlators to operate simultaneously is geometrically increased in the mobile station.
This not only increases the hardware complexity, but also brings unsatisfactory results in the performance of the igniter sequence acquisition.
The above references are incorporated by reference herein where appropriate for appropriate teachings of additional or alternative details, features and/or technical background.

High-speed cell searching apparatus and method using DPSK-based distributed sample acquisition


A device for mounting a light source according to the present invention is composed of an electric lamp unit (21) having a baseless electric lamp (7) and a base member (8) and a mounting unit (9) having a cavity for receiving the base member of the electric lamp unit (21). The base member (8) is composed of a cylindrical body having a cavity for receiving a lower part of the baseless electric lamp (7) and supporting a pair of lead wires (7a, 7b) led out of the baseless electric lamp (7) on its outer surface. The mounting unit (9) includes a pair of conductive contact members (10a, 10b) on an inner surface of the cavity, which are connected at their lower ends to connection terminals (12a, 12b) on a printed circuit board (12). The electric lamp unit (21) is fitted into the mounting unit (9) in a removable fashion.

The present invention relates to a device for mounting a light source and more particularly to a mounting device for mounting a baseless electric lamp on a substrate in a removable fashion and a method therefore.
For a meter panel of a motorcar or a display board of various electronic control devices, a light source for display and illumination is generally used. As an example of such a light source, a baseless electric lamp (a small lamp of a crush-sealing type or a bead sealing type) is used as shown in a sectional view of FIG. 8. Namely, as shown in FIG. 8, the baseless electric lamp has a light emission filament 1, which is supported by a pair of lead wires 2a and 2b. Both ends of the lead wires 2a and 2b are sealed in a glass bulb 3. The glass bulb 3 enclosing the light emission filament 1 airtightly, crushes the other ends of the lead wires 2a and 2b at a sealing part 3a with a pincher, and airtightly derives them below from the glass bulb. More specifically, the light emission filament is composed of a coiled tungsten wire having a diameter of several tens xcexcm. The lead wires 2a and 2b supporting the light emission filament at their ends is composed of dumet wire or a nickel-coated dumet wire with a diameter of about 0.2 to 0.5 mm. The glass bulb 3 has an outer diameter of about 2.5 to 10 mm (a thickness of about 0.3 to 0.5 mm) and a length of about 3 to 10 mm.
In place of the pincher to forcibly crush the sealing part 3a, the baseless electric lamp may be formed by the following method. That is, a bead glass for supporting the lead wires 2a and 2b separately is provided at the end of the glass bulb 3 and at least either one of the bead glasses or the glass bulb 3 is fused to seal the lead wires 2a and 2b.
Such a baseless electric lamp is mounted on a socket with a power supply terminal. The socket is then mounted on a printed circuit board for a motorcar meter board, for example, which functions as a display or illumination light source for the motorcar meter board.
FIG. 9 is a cross sectional view showing the baseless electric lamp, which is mounted on a printed circuit board. As shown in the drawing, the sealing part 3a of the baseless electric lamp is inserted into a socket 4 and the lead wires 2a and 2b are led out through a bottom 4a thereof to the other side thereof. The lead wires 2a and 2b led out through to the side of the bottom 4a are then bent respectively along an outer wall 4b of the socket 4. The socket 4 with the baseless electric lamp inserted is mounted on connection terminals (lands) 5a and 5b forming a part of the circuit of a circuit board 5 and is electrically connected as well as is mechanically fixed by solder 6. The lead wires 2a and 2b led out through the bottom 4a to the underside of the bottom 4a and bent along the outer wall 4b of the socket 4 may be guided in a grove (not shown) to form a flat surface.
As described above, the socket 4 receiving the baseless electric lamp electrically connects the electric lamp to the circuit board.
However, there is a problem in the conventional device for mounting a baseless electric lamp on a circuit board described above. Namely, there is generally a need to replace the baseless electric lamp, which is damaged or broken in the assembly course of a meter panel for a motorcar or for a display board of various electron control devices, in the course of conveying and mounting after assembled, or in the course of use after mounted. Since the baseless electric lamp is composed of thin glass bulb and the light emission filament made of a thin wire, which is easily broken with a mechanical shock, cases happen frequently where the damaged or broken baseless electric lamp must be replaced. However, in the conventional device for mounting such kind of the electric lamp, since the lead wires 2a and 2b led out through the bottom 4a of the socket 4 to the underside of it are soldered (6) to the lands 5a and 5b in the circuit board 5, the solder 6 must be fused using a soldering iron to remove the lead wires 2a and 2b from the lands 5a and 5b.
However, such work is not only troublesome but also is apt to damage the whole circuit board. More specifically, soldering and re-soldering at the time of replacing of the baseless electric lamp give a thermal shock on the adjacent electronic parts or generate a short-circuit due to flow of the solder to the neighboring circuit board, thereby making the whole circuit board damaged.
Taking the problem described into consideration, an object of the present invention is to provide a device and a method for mounting an baseless electric lamp, in which the lamp mounted on a substrate is easily replaced.
A device for mounting a light source according to the present invention includes an electric lamp unit composed of a baseless electric lamp and a base member, and a mounting unit having a cavity for receiving the base member of the electric lamp unit.
The baseless electric lamp comprises a light emission filament, a pair of lead wires for supporting the both ends of the filament at their heads and a glass bulb in which the light emission filament and a part of the lead wires are sealed.
The base member comprises a cylindrical body having a cavity for receiving a lower part of said baseless electric lamp and supporting the pair of lead wires led out of the baseless electric lamp on its outer surface,
The mounting unit comprises a pair of conductive contact members on an inner surface of the cavity, which are connected to connection terminals on a printed circuit board at their lower ends.
The lead wires led out of the baseless electric lamp along said outer surface of said base member are made in a sliding contact with said conductive contact members when said electric lamp unit is fitted into said mounting unit.
The electric lamp unit is fitted into said mounting unit in a removable fashion.
Further, the device for mounting a light source according to the present invention includes an electric lamp unit composed of a baseless electric lamp and a base member, a mounting unit having a cavity for receiving the base member of the electric lamp unit, and a printed circuit board having a pair of connection terminals connected to a printed circuit formed on said printed circuit board.
The baseless electric lamp is composed of a light emission filament, a pair of lead wires for supporting the both ends of the filament at their heads and a glass bulb in which the light emission filament and a part of the lead wires are sealed.
The base member is composed of a cylindrical body having a cavity for receiving a lower part of said baseless electric lamp and supporting the pair of lead wires led out from the baseless electric lamp on its outer surface,
The mounting unit is composed of a pair of conductive contact members on an inner surface of the cavity, which are connected to said connection terminals on the printed circuit board at their lower ends,
The lead wires led out of the baseless electric lamp along the outer surface of the base member are made in a sliding contact with the conductive contact members when said electric lamp unit is fitted into the mounting unit.
The electric lamp unit is fitted into the mounting unit in a removable fashion.
A method for mounting a light source device on a circuit board having connection terminals for mounting said light source device on at least one main surface of the circuit board includes a step for fixing a mounting unit on said connection terminals, and a step for mounting an electric lamp unit composed of a baseless electric lamp and a base member on said mounting unit.
The mounting unit has a cavity for receiving the base member of the electric lamp unit.
The baseless electric lamp includes a light emission filament, a pair of lead wires for supporting the both ends of the filament at their heads and a glass bulb in which the light emission filament and a part of the lead wires are sealed.
The base member comprises a cylindrical body having a cavity for receiving a lower part of the baseless electric lamp and supporting the pair of lead wires led out of the baseless electric lamp on its outer surface,
The mounting unit includes a pair of conductive contact members on an inner surface of the cavity, which are connected to connection terminals on a printed circuit board at their lower ends.


An improved cutter is provided for a plasterboard sheet, used in conjunction with a conventional T-square having a head and an elongated rule extending at a right angle from the head. The improved cutter consists of a mechanism for retaining a utility blade on the elongated rule of the conventional T-square in a proper position. When the head of the conventional T-square slides along one straight edge of the plasterboard sheet, the utility blade will make a score line across the plasterboard sheet, whereby a piece of the plasterboard sheet can then be snapped off.

1. Field of the Invention
The instant invention relates generally to wallboard tools and more specifically it relates to an improved cutter for a plasterboard sheet.
2. Description of the Prior Art
Numerous wallboard tools have been provided in prior art that are adapted to be utilized in wall construction of prefabricated materials, such as gypsum plaster encased in paper or compressed wood fibers and chips, which are a substitute for plaster and wood panels. While these units may be suitable for the particular purpose to which they address, they would not be as suitable for the purposes of the present invention as heretofore described.


A mechanical fluid separator defines an interior chamber for centrifugally separating entrained media from a fluid stream. The mechanical fluid separator has a fluid inlet connecting the interior chamber with a media entrained fluid source. A cone shaped baffle disposed within the mechanical fluid separator defines a conical surface having a concave surface and a convex surface. The conical surface has an annular base side and an annular apex side. The base side terminates in a circumferential rim contacting the annular chamber surface above the fluid inlet and said apex side terminates in an apex annular hole. The fluid stream is centrifugally directed in a first direction about the annular chamber surface and the convex surface of the conical baffle to disentrain the entrained media from the fluid stream. The disentrained fluid stream then passes through a window in the cone shaped baffle and escapes through a fluid outlet.

The present invention relates to a method and apparatus for separating liquid and particulate matter from a gaseous fluid. More particularly, the present invention relates to a method and apparatus for inducing a centrifugal flow in the gaseous fluid, wherein a scrubbing action of the liquid and particulate matter with a scrubbing plane allows separation from the gaseous fluid.
Mechanical fluid separators or "cyclone type" separators are well known in the art for separating liquid and particulate matter from a gaseous fluid or fluid stream. Mechanical fluid separators work well with mixed media, i.e., entrained media such as gas/solid, gas/liquid, or gas/solid/liquid combinations. For brevity, entrained media shall refer to both particulate matter (solid matter) and liquid matter as described herein.
Mechanical fluid separators have found a wide range of uses from reducing dust particles and contaminants in an office environment to removing saw dust, wood Chips, and metal filings in an industrial complex. Fluid separators are generally incorporated into systems which include other process machinery. Fluid separators are thus subject to abundant vibration induced by the other process machinery. It is therefore beneficial for fluid separators to incorporate features which inherently diminish the effect of such vibration. It is also beneficial for the fluid separators to withstand a vibration prone environment while resisting resonant vibration and mechanical stresses. Such features reduce noise and provide greater reliability.
Mechanical fluid separators generally induce a centrifugal flow with the heavier entrained media scrubbing a circumferential wall of the vessel. The heavier media then drain down to a sump through gravity while the gaseous fluid continues about a predetermined path. Since the entrained matter is generally heavier than the gaseous fluid, it is drawn toward the sides of an annular vessel. As the entrained matter scrubs against the sides of the vessel, it becomes separated from the fluid and falls downwardly to a container through the force of gravity. Prior examples of mechanical fluid separators include McNeil, U.S. Pat. No. 3,898,068 and Bielefeldt, U.S. Pat. No. 4,001,121. However, to accomplish the required features, the mechanical fluid separator have incorporated a complicated shape which requires substantial steps during manufacture.


Apparatus for aiding in the showering of bathing of bed patients, which apparatus includes disposable non-porous sheets adapted to be fitted within a basin for collecting shower and bath water after use. The basin is removable from the bathing apparatus frame structure so that it may easily be maneuvered under a bed patient, and then used similar to a stretcher to transport the bed patient from the hospital bed to the apparatus support structure. Water collected during the bathing procedure is directed into a holding tank which includes a water pump and drain hose for draining such shower or bath water into an appropriate lavatory drain.

1. Field of the Invention
This invention relates generally to bathing apparatus for bed patients and more particularly to a portable shower bath apparatus having a disposable catch basin apparatus for collecting shower water used in bathing such bed patients.
2. Description of the Prior Art
Devices for bathing or showering said patients and collecting the water therefrom are not new to this art. For example, U.S. Pat. No. 3,800,336, discloses a portable bed bath having a waterproof sheet attached to a frame to form the bath tub portion. This sheet and frame combination is then positioned above an existing bed surface and supported thereby. Other prior art devices disclosed similar apparatus: a plastic liner that attaches to a bed frame structural member, forming a bath tub over the patient's bed. Other devices incorporate a porous net support member for supporting a bed patient during the shower operation, which permits the shower water to be collected therebelow. Still other devices surround the bed patient in an enclosure, and incorporate a system of spray nozzles within to cleanse the bed patient. All of the prior art devices utilize rather complex mechanisms for supporting the bed patient and/or collecting the shower water after use. In addition, each of the prior art devices disclosed utilizes the "bath tub" repeatedly for each of many patients, giving rise to the possibility of transmitting and/or perpetuating non-sanitary conditions from one bed patient to the next if the "bath tub" is not thoroughly cleaned after each use. Obviously this is a very costly procedure in terms of "non-use" time of a portable shower bath apparatus, and also in terms of labor expended in attempting to thoroughly clean the "bath tub" after each use.
It is therefore an object of the present invention to provide a portable shower bath apparatus for bathing bed-patients, and having a disposable water collecting sheet therein to collect the shower water after use, to prevent the perpetuation of unsanitary conditions.
It is a further object of the present invention to provide a portable shower bath apparatus of simple construction and operation in order to simplify the procedure for bathing and/or showering bed-patients.


Provided is a compound having formula (I): wherein R2 is selected from —C1, —Br and —CN; R1 and R4 are independently selected from H and —F; R631, R632, R641 and R642 are independently selected from —H, —F and substituted or unsubstituted C1-C3 alkyl groups; and R651 and R652 are independently selected from H and substituted or unsubstituted C1-C3 alkyl groups and substituted or unsubstituted phenyl groups; and wherein at least one of R631, R632, R641, R642 and R652 is not —H, or wherein when all of R631, R632, R641, R642 and R652 are —H, R651 is not Me or Et.

The present invention relates to indoleamine-2,3-dioxygenase (IDO) inhibitors, and in particular IDO inhibitors for use in medicine. The inhibitors of the invention may be used in pharmaceutical compositions, and in particular pharmaceutical compositions for treating a cancer, an inflammatory condition, an infectious disease, a central nervous system disease or disorder and other diseases, conditions and disorders. The invention also relates to methods of manufacture of such inhibitors, and methods of treatment using such inhibitors.
Tryptophan Metabolism—
The kynurenine pathway (KP) is responsible for >95% of the degradation of the essential amino acid tryptophan. The kynurenine pathway for tryptophan metabolism leads to the production of the essential pyridine nucleotide NAD+ and a number of neuroactive metabolites, including kynurenine (KYN), kynurenic acid (KYNA), the neurotoxic free-radical generator 3-hydroxykynurenine (3-HK), anthranilic acid, 3-HAA, picolinic acid (PIC), and the excitatory N-methyl-D-aspartate (NMDA) receptor agonist and neurotoxin, quinolinic acid (QUIN) (see FIG. 1). The remaining 5% of tryptophan is metabolised by tryptophan hydroxylase to 5-hydroxytryptophan and then further to 5-hydroxytryptamine (serotonin) and melatonin.
Both the depletion of tryptophan and accumulation of immunosuppressive tryptophan catabolites act to suppress antigen-specific T-cell and natural killer cell responses and induce the formation of regulatory T cells. Because tryptophan catabolism is induced by inflammatory mediators, notably IFN-γ, it is thought to represent an endogenous mechanism that restricts excessive immune responses, thereby preventing immunopathology. However, there is evidence that in disease states this feedback loop may not be beneficial (reviewed in (Munn and Mellor, 2013).
IDO—
The first step of tryptophan catabolism is catalysed by either TDO or IDO. Both enzymes catalyze the oxidative cleavage of the 2,3 double bond in the indole ring, converting tryptophan to N-formylkynurenine. This is the rate-limiting step in tryptophan catabolism by the kynurenine pathway (Grohmann et al., 2003; Stone and Darlington, 2002). TDO is a homotetramer with each monomer having a molecular mass of 48 kDa, whereas IDO has a molecular mass of 45 kDa and a monomeric structure (Sugimoto et al., 2006; Thackray et al., 2008; Zhang et al., 2007). Despite mediating the same reaction, TDO and IDO are structurally distinct, sharing only 10% homology mainly within the active site (Thackray et al., 2008).
IDO is the predominant tryptophan catabolising enzyme extra hepatically and is found in numerous cells, including macrophages, microglia, neurons and astrocytes (Guillemin et al., 2007; Guillemin et al., 2001; Guillemin et al., 2003; Guillemin et al., 2005). IDO transcription is stringently controlled, responding to specific inflammatory mediators. The mouse and human IDO gene promoters contain multiple sequence elements that confer responsiveness to type I (IFN-α/β) and, more potently, type II (IFN-γ) interferons (Chang et al., 2011; Dai and Gupta, 1990; Hassanain et al., 1993; Mellor et al., 2003). Various cell types, including certain myeloid-lineage cells (monocyte-derived macrophages and DCs), fibroblasts, endothelial cells and some tumour-cell lines, express IDO after exposure to IFN-γ (Burke et al., 1995; Hwu et al., 2000; Mellor et al., 2003; Munn et al., 1999; Varga et al., 1996). However, the control of IDO transcription is complex and cell-type specific. IDO activity is found constitutively at the maternal-fetal interface, expressed by human extravillous trophoblast cells (Kudo and Boyd, 2000). Outside of the placenta, functional IDO expression was reported to be highest in the mouse epididymis, gut (distal ileum and colon), lymph nodes, spleen, thymus and lungs (Takikawa et al., 1986).
Another recent variant enzyme of IDO has been shown to catalyse the same enzymatic step: indoleamine-2,3-dioxygenase 2 (IDO2). However, its physiological relevance remains unclear due to its very low activity, the presence of common polymorphisms that inactivate its enzymatic activity in approximately half of all Caucasians and Asians, and the presence of multiple splice variants (Lob et al., 2008; Meininger et al., 2011; Metz et al., 2007).
IDO-deficient mice are at a gross level phenotypical normal (Mellor et al., 2003), however, they are slightly more prone to induction of autoimmunity and stimulation of the innate immune system. IDO−/− knockout mice also display enhanced inflammatory-mediated colon carcinogenesis and exhibit resistance to inflammation-driven lung and skin cancers (Chang et al., 2011; Yan et al., 2010).
Immuno-Modulation:
Tryptophan Depletion and Kynurenine Accumulation-Immunoregulation by tryptophan metabolism modulates the immune system by depletion of the TDO/IDO substrate (tryptophan) in the microenvironment and the accumulation of products such as kynurenine.
Effector T cells are particularly susceptible to low tryptophan concentrations, therefore, depletion of the essential amino acid tryptophan from the local microenvironment resulting in effector T-cell anergy and apoptosis. The depletion of tryptophan is detected by the general control non-derepressible-2 kinase (GCN2) (Munn et al., 2005). The activation of GCN2 triggers a stress-response program that results in cell-cycle arrest, differentiation, adaptation or apoptosis. T cells lacking GCN2 in mice are not susceptible to IDO-mediated anergy by myeloid cells, including dendritic cells in tumor-draining lymph nodes (Munn et al., 2005).
Tryptophan metabolites such as kynurenine, kynurenic acid, 3-hydroxykynurenine, and 3-hydroxy-anthranilic acid suppress T-cell function and are capable of inducing T-cell apoptosis. Recent studies have shown that the aryl hydrocarbon receptor (AHR) is a direct target of kynurenine (Mezrich et al., 2010; Nguyen et al., 2010; Opitz et al., 2011). The AHR is a basic helix-loop-helix Per-Amt-Sim (PAS) family transcription factor. As kynurenine accumulates in a tumour, KYN binds the AHR, translocates to the nucleus and activates transcription of target genes regulated by dioxin-responsive elements (DREs). In T-helper-cells kynurenine results in the generation of regulatory T cells (Treg).
Pharmacological inhibitors of IDO have utility in a wide range of indications, including infectious diseases, cancer, neurological conditions and many other diseases.
Infectious Diseases and Inflammation—
Infection by bacteria, parasites, or viruses induces a strong IFN-γ-dependent inflammatory response. IDO can dampen protective host immunity, thus indirectly leading to increased pathogen burdens. For example, IDO activity attenuates Toxoplasma gondii replication in the lung, and the inflammatory damage is significantly decreased by the administration of the IDO inhibitor 1MT after infection (Murakami et al., 2012). Also, in mice infected with murine leukaemia virus (MuLV), IDO was found to be highly expressed, and ablation of IDO enhanced control of viral replication and increased survival (Hoshi et al., 2010). In a model of influenza infection, the immunosuppressive effects of IDO could predispose lungs to secondary bacterial infection (van der Sluijs., et al 2006). In Chagas Disease, which is caused by the Trypanosoma cruzi parasite, kynurenine is increased in patients and correlates with disease severity (Maranon et al., 2013). Therefore, IDO inhibitors could be used to improve the outcomes of patients with a wide variety of infectious diseases and inflammatory conditions.
IDO and Immunity to Gut Bacteria—
IDO plays a role in regulating mucosal immunity to the intestinal microbiota. IDO has been shown to regulate commensal induced antibody production in the gut; IDO-deficient mice had elevated baseline levels of immunoglobulin A (IgA) and immunoglobulin G (IgG) in the serum and increased IgA in intestinal secretions. Due to elevated antibody production, IDO deficient mice were more resistant to intestinal colonization by the gram-negative enteric bacterial pathogen Citrobacter rodentium than WT mice. IDO-deficient mice also displayed enhanced resistance to the colitis caused by infection with C. rodentium (Harrington et al., 2008).
Therefore, pharmacological targeting of IDO activity may represent a new approach to manipulating intestinal immunity and controlling the pathology caused by enteric pathogens including colitis (Harrington et al., 2008).
HIV Infection—
Patients infected with HIV have chronically reduced levels of plasma tryptophan and increased levels of kynurenine, and increased IDO expression (Fuchs et al., 1990 and Zangerle et al., 2002).
In HIV patients the upregulation of IDO acts to suppress immune responses to HIV antigens contributing to the immune evasion of the virus. HIV triggers high levels of IDO expression when it infects human macrophages in vitro (Grant et al., 2000), and simian immunodeficiency virus (SIV) infection of the brain in vivo induces IDO expression by cells of the macrophage lineage (Burudi et al., 2002).
The pathogenesis of HIV is characterized by CD4+ T cell depletion and chronic T cell activation, leading ultimately to AIDS (Douek et al., 2009). CD4+ T helper (TH) cells provide protective immunity and immune regulation through different immune cell functional subsets, including TH1, TH2, T regulatory (Treg), and TH17 cells. Progressive HIV is associated with the loss of TH17 cells and a reciprocal increase in the fraction of the immunosuppressive Treg cells. The loss of TH17/Treg balance is associated with induction of IDO by myeloid antigen-presenting dendritic cells (Favre et al., 2010). In vitro, the loss of TH17/Treg balance is mediated directly by the proximal tryptophan catabolite from IDO metabolism, 3-hydroxyanthranilic acid. Therefore in progressive HIV, induction of IDO contributes to the inversion of the TH17/Treg balance and maintenance of a chronic inflammatory state (Favre et al., 2010). Therefore, IDO inhibitors could have utility in addressing the TH17/Treg balance in HIV.
Sepsis-Induced Hypotension—
Systemic inflammation such as sepsis is characterized by arterial hypotension and systemic inflammatory response syndrome (Riedemann et al., 2003). The associated increase in circulating pro-inflammatory cytokines, including interferon-γ (IFN-γ), leads to the unchecked production of effector molecules such as reactive oxygen and nitrogen species that themselves can contribute to pathology (Riedemann et al., 2003).
The metabolism of tryptophan to kynurenine by IDO expressed in endothelial cells contributes to arterial vessel relaxation and the control of blood pressure (Wang et al., 2010). Infection of mice with malarial parasites (Plasmodium berghei), and experimental induction of endotoxemia, caused endothelial expression of IDO, resulting in decreased plasma tryptophan, increased kynurenine, and hypotension. Pharmacological inhibition of IDO increased blood pressure in systemically inflamed mice, but not in mice deficient for IDO or interferon-γ, which is required for IDO induction. Arterial relaxation by kynurenine was mediated by activation of the adenylate and soluble guanylate cyclase pathways. (Wang et al., 2010). Therefore, inhibitors of IDO could have utility in treating sepsis-induced hypotension.
CNS Disorders—
In the central nervous system both fates of TRP which act as a precursor to kynurenine and serotonin are pathways of interest and importance. Metabolites produced by the kynurenine pathway have been implicated to play a role in the pathomechanism of neuroinflammatory and neurodegenerative disorder (summarised in FIG. 2). The first stable intermediate from the kynurenine pathway is KYN. Subsequently, several neuroactive intermediates are generated. They include kynurenic acid (KYNA), 3-hydroxykynurenine (3-HK), and quinolinic acid (QUIN), 3-HK and QUIN are neurotoxic by distinct mechanisms; 3-HK is a potent free-radical generator (Hiraku et al., 1995; Ishii et al., 1992; Thevandavakkam et al., 2010), whereas QUIN is an excitotoxic N-methyl-D-aspartate (NMDA) receptor agonist (Schwarcz et al., 1983; Stone and Perkins, 1981). KYNA, on the other hand, has neuroprotective properties as an antagonist of excitatory amino acid receptors and a free-radical scavenger (Carpenedo et al., 2001; Foster et al., 1984; Goda et al., 1999; Vecsei and Beal, 1990). Changes in the concentration levels of kynurenines can shift the balance to pathological conditions. The ability to influence the metabolism towards the neuroprotective branch of the kynurenine pathway, i.e. towards kynurenic acid (KYNA) synthesis, may be one option in preventing neurodegenerative diseases.
In the CNS, the kynurenine pathway is present to varying extents in most cell types. Infiltrating macrophages, activated microglia and neurons have the complete repertoire of kynurenine pathway enzymes (Guillemin et al., 2000; Lim et al., 2007).
Given the role of IDO in the pathogenesis of several CNS disorders, IDO inhibitors could be used to improve the outcomes of patients with a wide variety of CNS diseases and neurodegeneration.
Amyotrophic Lateral Sclerosis—
Amyotrophic lateral sclerosis (ALS), or Lou Gehrig's disease, is a progressive and fatal neurodegenerative disease targeting the motor system. ALS results in the selective attacking and destruction of motor neurons in the motor cortex, brainstem and spinal cord.
Although multiple mechanisms are likely to contribute to ALS, the kynurenine pathway activated during neuroinflammation is emerging as a contributing factor. Initial inflammation may inflict a nonlethal injury to motor neurons of individuals with a susceptible genetic constitution, in turn triggering a progressive inflammatory process which activates microglia to produce neurotoxic kynurenine metabolites that further destroy motor neurons.
In the brain and spinal cord of ALS patients large numbers of activated microglia, reactive astrocytes, T cells and infiltrating macrophages have been observed (Graves et al., 2004; Henkel et al., 2004). These cells release inflammatory and neurotoxic mediators, among others IFN-γ, the most potent inducer of IDO (McGeer and McGeer 2002). The neuronal and microglial expression of IDO is increased in ALS motor cortex and spinal cord (Chen et al., 2010). It has been proposed that the release of immune activating agents activates the rate-limiting enzyme of the KP, IDO, which generates metabolites such as the neurotoxin QUIN. Therefore, inhibition of IDO would reduce the synthesis of neurotoxic QUIN, which has been clearly implicated in the pathogenesis of ALS.
Huntington's Disease—
Huntington's disease (HD) is a genetic autosomal dominant neurodegenerative disorder caused by expansion of the CAG repeats in the huntingtin (htt) gene. Patients affected by HD display progressive motor dysfunctions characterized by abnormality of voluntary and involuntary movements (choreoathetosis) and psychiatric and cognitive disturbances. In-life monitoring of metabolites with in the KYN pathway provide one of the few biomarkers that correlates with the number of CAG repeats and hence the severity of the disorder (Forrest et al., 2010). Post mortem very high levels of QUIN are found located in areas of neurodegeneration, while striatal glutamatergic neurones, on which QUIN acts as an excitotoxin, are a principal class lost in the disease.
Alzheimer's Disease—
Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterised by neuronal loss and dementia. The histopathology of the disease is manifested by the accumulation of intracellular β-amyloid (Aβ) and subsequent formation of neuritic plaques as well as the presence of neurofibrillary tangles in specific brain regions associated with learning and memory. The pathological mechanisms underlying this disease are still controversial, however, there is growing evidence implicating KP metabolites in the development and progression of AD.
It has been shown that Aβ (1-42) can activate primary cultured microglia and induce IDO expression (Guillemin et al., 2003; Walker et al., 2006). Furthermore, IDO overexpression and increased production of QUIN have been observed in microglia associated with the amyloid plaques in the brain of AD patients (Guillemin et al., 2005). QUIN has been shown to lead to tau hyperphosphorylation in human cortical neurons (Rahman et al., 2009). Thus, overexpression of IDO and over-activation of the KP in microglia are implicated in the pathogenesis of AD.
Psychiatric Disorders and Pain—
Most tryptophan is processed through the kynurenine pathway. A small proportion of tryptophan is processed to 5-HT and hence to melatonin, both of which are also substrates for IDO. It has long been known that amongst other effects acute tryptophan depletion can trigger a depressive episode and produces a profound change in mood even in healthy individuals. These observations link well with the clinical benefits of serotonergic drugs both to enhance mood and stimulate neurogenesis.
The co-morbidity of depressive symptoms and implication of the kynurenine pathway in inflammation also implicate a role in the treatment of chronic pain (Stone and Darlington 2013).
Schizophrenic patients exhibit elevated KYN levels both in CSF and brain tissue, particularly the frontal cortex. This has been associated with the "hypofrontality" observed in schizophrenia. Indeed rodents treated with neuroleptics show a marked reduction in frontal KYN levels. These changes have been associated with reduced KMO and 3HAO. Evidence includes an association between a KMO polymorphism, elevated CSF KYN and schizophrenia (Holtze et. al., 2012). Taken together there is potential for manipulations in this pathway to be both pro-cognate and neuroleptic.
Pain and depression are frequently comorbid disorders. It has been shown that IDO1 plays a key role in this comorbidity. Recent studies have shown that IDO activity is linked to (a) decreased serotonin content and depression (Dantzer et al., 2008; Sullivan et al., 1992) and (b) increased kynurenine content and neuroplastic changes through the effect of its derivatives such as quinolinic acid on glutamate receptors (Heyes et al., 1992).
In rats chronic pain induced depressive behaviour and IDO upregulation in the bilateral hippocampus. Upregulation of IDO resulted in the increased kynurenine/tryptophan ratio and decreased serotonin/tryptophan ratio in the bilateral hippocampus. Furthermore, IDO gene knockout or pharmacological inhibition of hippocampal IDO activity attenuated both nociceptive and depressive behaviour (Kim et al., 2012).
Since proinflammatory cytokines have been implicated in the pathophysiology of both pain and depression, the regulation of brain IDO by proinflammatory cytokines serves as a critical mechanistic link in the comorbid relationship between pain and depression through the regulation of tryptophan metabolism.
Multiple Sclerosis—
Multiple sclerosis (MS) is an autoimmune disease characterized by inflammatory lesions in the white matter of the nervous system, consisting of a specific immune response to the myelin sheet resulting in inflammation and axonal loss (Trapp et al., 1999; Owens, 2003).
Accumulation of neurotoxic kynurenine metabolites caused by the activation of the immune system is implicated in the pathogenesis of MS. QUIN was found to be selectively elevated in the spinal cords of rats with EAE, an autoimmune animal model of MS (Flanagan et al., 1995). The origin of the increased QUIN in EAE was suggested to be the macrophages. QUIN is an initiator of lipid peroxidation and high local levels of QUIN near myelin may contribute to the demyelination in EAE and possibly MS.
Interferon beta 1b (IFN-β1b) induces KP metabolism in macrophages at concentrations comparable to those found in the sera of IFN-b treated patients, this which may be a limiting factor in its efficacy in the treatment of MS (Guillemin et al., 2001). After IFN-β administration, increased kynurenine levels and kynurenine/tryptophan ratio were found in the plasma of MS patients receiving IFN-b injection compared to healthy subjects indicating an induction of IDO by IFN-β (Amirkhani et al., 2005). IFN-β1b, leads to production of QUIN at concentrations sufficient to disturb the ability of neuronal dendrites to integrate incoming signals and kill oligodendrocytes (Cammer 2001). In IFN-β1b-treated patients concomitant blockade of the KP with an IDO inhibitor may improve its efficacy of IFN-β1b.
Parkinson's Disease—
Parkinson's disease (PD) is a common neurodegenerative disorder characterised by loss of dopaminergic neurons and localized neuroinflammation.
Parkinson's disease is associated with chronic activation of microglia (Gao and Hong, 2008). Microglia activation release neurotoxic substances including reactive oxygen species (ROS) and proinflammatory cytokines such as IFN-γ (Block et al., 2007), a potent activator of KP via induction of IDO expression. KP in activated microglia leads to upregulation of 3HK and QUIN, 3HK is toxic primarily as a result of conversion to ROS (Okuda et al., 1998). The combined effects of ROS and NMDA receptor-mediated excitotoxicity by QUIN contribute to the dysfunction of neurons and their death (Braidy et al., 2009; Stone and Perkins, 1981). However, picolinic acid (PIC) produced through KP activation in neurons, has the ability to protect neurons against QUIN-induced neurotoxicity, being NMDA agonist (Jhamandas et al., 1990). Microglia can become overactivated, by proinflammatory mediators and stimuli from dying neurons and cause perpetuating cycle of further microglia activation microgliosis. Excessive microgliosis will cause neurotoxicity to neighbouring neurons and resulting in neuronal death, contributing to progression of Parkinson's disease. (Zinger et al 2011)
Therefore, PD is associated with an imbalance between the two main branches of the KP within the brain. KYNA synthesis by astrocytes is decreased and concomitantly, QUIN production by microglia is increased.
HIV—
HIV patients, particularly those with HIV-linked dementia (Kandanearatchi & Brew 2012), often have significantly elevated KYN levels in CSF. These levels are directly related to the development of neurocognitive decline and often the presence of sever psychotic symptoms (Stone & Darlington 2013).
Cancer—
It is clear that tumours can induce tolerance to their own antigens. Tryptophan catabolism in cancer is increasingly being recognized as an important micro-environmental factor that suppresses antitumor immune responses. Depletion of tryptophan and accumulation of immunosuppressive tryptophan catabolites such as kynurenine create an immunosuppressive milieu in tumours and in tumour-draining lymph nodes by inducing T-cell anergy and apoptosis. Such immunosuppression in the tumour microenvironment may help cancers evade the immune response and enhance tumorigenicity (reviewed in Adam et al., 2012).
Recently, IDO has been implicated in tumour progression. IDO has been found to be overexpressed in various cancers. IDO mediates immunosuppressive effects through the metabolization of Trp to kynurenine, triggering downstream signalling through GCN2, mTOR and AHR that can affect differentiation and proliferation of T cells. Also, expression of IDO by activated dendritic cells can serve to activate regulatory T cells (Tregs) and inhibit tumor-specific effector CD8+ T cells, thereby constituting a mechanism by which the immune system can restrict excessive lymphocyte reactivity (reviewed in Platten et al., 2012).
IDO—
Increased expression of IDO has been shown to be an independent prognostic variable for reduced survival in patients with acute myeloid leukemia (AML), small-cell lung, melanoma, ovarian, colorectal, pancreatic, and endometrial cancers (Okamoto et al., 2005; Ino et al., 2006). Indeed, sera from cancer patients have higher kynurenine/tryptophan ratios than sera from normal volunteers (Liu et al., 2010; Weinlich et al., 2007; Huang et al., 2002). The level of IDO expression was also shown to correlate with the number of tumour infiltrating lymphocytes in colorectal carcinoma patients (Brandacher et al., 2006).
In preclinical models, transfection of immunogenic tumour cells with recombinant IDO prevented their rejection in mice (Uyttenhove et al., 2003). While, ablation of IDO expression led to a decrease in the incidence and growth of 7,12-dimethylbenz(a)anthracene-induced premalignant skin papillomas (Muller et al., 2008). Moreover. IDO inhibition slows tumour growth and restores anti-tumour immunity (Koblish et al., 2010) and IDO inhibition synergises with cytotoxic agents, vaccines and cytokines to induce potent anti-tumour activity (Uyttenhove et al., 2003; Muller et al., 2005; Zeng et al., 2009).
Inhibition of IDO will dramatically lower kynurenine levels, relieving the brake on the immune system allowing it to attack and eliminate tumours. While there is evidence that an IDO inhibitor would be useful as a stand-alone agent, inhibitors of this type would be particularly effective when used in combination with other cancer immunotherapies. In fact, upregulation of IDO expression has been identified as a mechanism by which tumours gain resistance to the CTLA-4 blocking antibody ipilimumab. Ipilimumab blocks the co-stimulatory molecule CTLA-4, causing tumour-specific T cells to remain in an activated state. IDO knockout mice treated with anti-CTLA-4 antibody demonstrate a striking delay in B16 melanoma tumor growth and increased overall survival when compared with wild-type mice. Also, CTLA-4 blockade strongly synergizes with IDO inhibitors to mediate tumour rejection. Similar data was also reported for IDO inhibitors in combination with anti-PD1 and anti-PDL-1 antibodies (Holmgaard et al., 2013).
Agents that will influence an immunosuppressive environment may also be relevant to chimeric antigen receptor T cell therapy (CAR-T) therapies to enhance efficacy and patient responses.
Other Diseases—
Although these effects are defensive strategies to cope with infection and inflammation, they may have unintended consequences because kynurenines formed during IDO mediated degradation of tryptophan can chemically modify proteins and have been shown to be cytotoxic (Morita et al., 2001; Okuda et al., 1998). In coronary heart disease, inflammation and immune activation are associated with increased blood levels of kynurenine (Wirleitner et al., 2003) possibly via interferon-γ-mediated activation of IDO. In experimental chronic renal failure, activation of IDO leads to increased blood levels of kynurenines (Tankiewicz et al., 2003), and in uremic patients kynurenine-modified proteins are present in urine (Sala et al., 2004). Further, renal IDO expression may be deleterious during inflammation, because it enhances tubular cell injury.
General anaesthesia unfortunately mimics many of these effects inducing stress and inflammatory processes. Post anaesthesia cognitive dysfunction has often been correlated with these sequelae. Recently these deficits have been shown to be correlated with changes in kynurenine pathway markers, but not cytokines, following cardiac surgery and in recovering stroke patients (Stone and Darlington 2013).
Cataracts—
A cataract is a clouding of the lens inside the eye that leads to a decrease in vision. Recent studies suggest that kynurenines might chemically alter protein structure in the human lens leading to cataract formation. In the human lens IDO activity is present mainly in the anterior epithelium (Takikawa et al., 1999). Several kynurenines, such as kynurenine (KYN), 3-hydroxykynurenine (3OHKYN), and 3-hydroxykynurenine glucoside (3OHKG) have been detected in the lens; where they were thought to protect the retina by absorbing UV light and therefore are commonly referred to as UV filters. However, several recent studies show that kynurenines are prone to deamination and oxidation to form α,β-unsaturated ketones that chemically react and modify lens proteins (Taylor et al., 2002). Kynurenine mediated modification could contribute to the lens protein modifications during aging and cataractogenesis. They may also reduce the chaperone function of α-crystallin, which is necessary for maintaining lens transparency.
Transgenic mouse lines that overexpress human IDO in the lens developed bilateral cataracts within 3 months of birth. It was demonstrated that IDO-mediated production of kynurenines results in defects in fibre cell differentiation and their apoptosis (Mailankot et al., 2009). Therefore inhibition of IDO may slow the progression of cataract formation.
Endometriosis—
Endometriosis, the presence of endometrium outside the uterine cavity, is a common gynaecological disorder, causing abdominal pain, dyspareunia and infertility. IDO expression was found to be higher in eutopic endometrium from women with endometriosis by microarray analysis (Burney et al., 2007 and Aghajanova et al., 2011). Furthermore, IDO was shown to enhance the survival and invasiveness of endometrial stromal cells (Mei et al., 2013). Therefore, an IDO inhibitor could be used as a treatment for endometriosis.
Contraception and Abortion—
The process of implantation of an embryo requires mechanisms that prevent allograft rejection; and tolerance to the fetal allograft represents an important mechanism for maintaining a pregnancy. Cells expressing IDO in the foeto-maternal interface protect the allogeneic foetus from lethal rejection by maternal immune responses. Inhibition of IDO by exposure of pregnant mice to 1-methyl-tryptophan induced a T cell-mediated rejection of allogeneic concepti, whereas syngeneic concepti were not affected; this suggests that IDO expression at the foetal-maternal interface is necessary to prevent rejection of the foetal allograft (Munn et al., 1998). Accumulating evidence indicates that IDO production and normal function at the foetal-maternal interface may play a prominent role in pregnancy tolerance (Durr and Kindler., 2013). Therefore, an IDO inhibitor could be used as a contraceptive or abortive agent.
On the above basis, the inventors have determined that a strong rationale exists for the therapeutic utility of drugs which block the activity of IDO, in treating the above-mentioned diseases, conditions and disorders.
Having regard to the above, it is an aim of the present invention to provide IDO inhibitors, and in particular IDO inhibitors for use in medicine. It is a further aim to provide pharmaceutical compositions comprising such inhibitors, and in particular to provide compounds and pharmaceutical compositions for treating a cancer, an inflammatory condition, an infectious disease, a central nervous system disease or disorder and other diseases, conditions and disorders. It is also an aim to provide methods of synthesis of the compounds.
WO 2012/084971 discloses indole amide compounds with substitution patterns which are different to those presently envisaged. These compounds are disclosed as being direct antibacterial agents. IDO inhibition is not mentioned, and there is no disclosure that the compounds have IDO inhibitory activity, or a pharmacology associated with an IDO mechanism.
WO 94/19321 and WO 2014/009794 each disclose compounds for treating HIV. The most similar compounds are indole amides with substitution patterns which are different to those presently envisaged. In WO 94/19321 the compounds are indicated to be direct reverse transcriptase inhibitors, whilst in WO 2014/009794 they are indicated to be direct anti-virals. IDO inhibition is not mentioned, and there is no disclosure that the compounds have IDO inhibitory activity, or a pharmacology associated with an IDO mechanism.
WO 2008/002674 and WO 03/035621 disclose protein kinase and phosphatase inhibitors, which may be employed inter alia in the treatment of cancer. Some such compounds are indole amides with substitution patterns different to those investigated by the present inventors. IDO inhibition is not mentioned, and there is no disclosure that the compounds have IDO inhibitory activity, or a pharmacology associated with an IDO mechanism, i.e. the ablation of tryptophan depletion/kynurenine production, with the associated increase in T-cell proliferation and tumour immune response.
Previously, Dolusic et al. have tested indole compounds to determine their IDO inhibitory activity (European Journal of Medicinal Chemistry 46 (2011) 3058-3065; Bioorganic and Medicinal Chemistry, Vol. 19(4), 2011, pp 1550-1561). That study determined that certain indole compounds with ketone substituents at the 2-position might be useful IDO inhibitors. However, the activity of such compounds was found to be marginal at best. It was concluded that an amide compound of the type the inventors have investigated was not an effective inhibitor as compared with the ketone compounds. However, the inventors have now determined that Dolusic et al. were mistaken about such amide compounds in that certain variants are highly active.

Substituted 1H-indole-2-carboxamide compounds as indoleamine-2,3-dioxygenase inhibitors


A release film for label stock and the like having:. (a) a cavitated layer of a thermoplastic polymer matrix material within which is located a strata of voids, positioned at least substantially within at least a substantial number of each of the voids is at least one spherical void-initiating solid particle which is phase-distinct and incompatible with the matrix material, the void space occupied by the particle being substantially less than the volume of the void, with one generally cross-sectional dimension of the particle at least approximating a corresponding cross-sectional dimension of the void; the population of the voids being such as to cause a degree of opacity of less than 70% light transmission; PA1 at least one surface of the layer free of any coating tending to mask the surface affects of cavitation; and PA1 (b) opposite to this surface, a coating of a release material of a type having a tendency to partially transfer to any contacting surface.

The present invention relates to a release film, a major utility of which is to protect and carry label stock until the label is put into use on an appropriate surface.
For many years labels have been prepared with a pressure sensitive adhesive applied to one side thereof. Obviously some means had to be provided to protect the adhesive surface in advance of applying the label to the ultimate surface to be labeled. A technique has evolved over the years by which the pressure sensitive adhesive surface is protected by bringing the adhesive surface into contact with a release layer which has little tendency to aggressively adhere to the pressure sensitive adhesive surface. Thus, a second film having a release surface is brought into contact with the pressure sensitive surface carried by the label and thus protects the pressure sensitive adhesive until the label is to be applied to its ultimate surface.
Release films can be manufactured separately from the label face stock. The release film is manufactured and then convolutely wound into roll stock, which is thereafter unwound and slit during the manufacture of release film of a particular width dimension suited for a particular label dimension. Often times the release film roll stock manufacturer sells the roll film to a different commercial entity which performs one or more of the follow-on steps leading to the ultimate release film-label combination for end use on a particular surface or product.
A problem which manifests itself during the manufacture of release film is the transfer of areas of release material to the back surface of the film. This transfer leads to printing problems during completion of the release film-label stock combination. After the release film is mated with adhesively backed label stock, the label surface is printed with the appropriate label indicia. This printing operation is a step which often occurs after the release liner and label stock has been mated and convolutely wound. If during winding and unwinding of the release film, release material is inadvertently transferred to the back surface of the release film, this unwanted transfer can, in turn, be transferred to the surface to be printed and the printing ink will not adhere to such surfaces. This condition, at this point in the operation, results in a costly rejection of the release film-label combination.
It is an object of the present invention is to present a release film, which will not transfer release material to any part of a label surface intended to be printed.

Release film with reduced transferable silicone material


A novel dispensing apparatus and method for dispensing objects responsive to magnetic attraction retained thereon is provided comprising a strap and a permanent magnet in the form of a ring attached to the strap whereby objects responsive to magnetic attraction may be retained thereon for dispensing.

This invention relates generally to the art of dispensing and, more particularly, to the art of dispensing magnetically attracted objects.
It is known within the prior art to use magnetic devices for nailing. It is also known within the prior art to attach pin cushions to the wrist of a user and to retain pins in the cushion. Such a use of a pin cushion, however, suffers from the disadvantage of having to individually place the pins in the cushion in order to have the cushion retain them. Also, only items such as pins, small and pointed, can usually be retained on such a cushion.
There has to date, however, been no completely satisfactory apparatus or method for quickly and easily grasping, retaining and dispensing such objects.


Method and apparatus for providing provisioning parameters to a mobile device. A short messaging service message is used to send bootstrap data sufficient to establish communication between an Internet Protocol-based server and a mobile device. The mobile device then establishes such communication and the provisioning parameters from the Internet Protocol-based server.

1. Field
The present invention relates to wireless communication systems generally and specifically, to methods and apparatus for provisioning a mobile device in a wireless communication system using a short messaging service to establish communication to an Internet Protocol (IP) based server.
2. Background
To establish communication with a mobile device, the system first provides provisioning parameters to the mobile device. The provisioning parameters assist the mobile device in communications within and as part of the system. The provisioning parameters are typically provided by the service provider at a point of purchase, such as a cellular service center, or accessed from the service provider using circuit switching communications. Often the subscriber is instructed on a sequence of key strokes to send to the service provider; the service provider in response sends the provisioning parameters as a wireless transmission.
The initial transfer of provisioning parameters may be transmitted to the mobile device using the Wireless Application Protocol, referred to as WAP. The WAP is an application environment and set of communication protocols for wireless devices designed specifically for access to the Internet and higher telephony functions. Devices supporting WAP incur additional cost and complexity.
There is a need, therefore, for a low-cost method for providing provisioning parameters to a mobile device which do not support WAP applications or browser.

Provisioning a mobile device in a wireless communication system


Small-volume oral transmucosal dosage forms or NanoTabs® comprising a predetermined amount of a pharmaceutically active drug are provided. Exemplary applications include use of the NanoTabs® to administer a drug for the treatment of acute, post-operative or breakthrough pain.

Currently, standard treatment regimens for oral administration of medications for treatment of a number of conditions have clear limitations with regard to both efficacy and toxicity. Routes of administration, formulations and dosage control among other attributes contribute to these limitations.
Reproducible and effective drug delivery technology represents an area of active research and controlled drug delivery systems offer numerous advantages relative to conventional dosage forms, which include improved efficacy, reduced toxicity, as well as improved patient compliance and convenience. This is particularly relevant to the treatment of pain, more specifically: acute, intermittent and breakthrough pain.
Medications based on a variety of routes of administration and the development of new and improved dosage forms for the treatment of a large number of medical conditions, such as pain, is an ongoing process. There remains a need to develop safer drug dosage forms without the fluctuation in efficacious levels that are seen with medications using current commercially available dosage forms. Currently available treatment regimes for treatment of pain often fail to provide patients with sufficient or consistent therapeutic effect, often due to a slow, erratic onset of action and the difficulty in adjusting and controlling doses such that the medical condition is not treated effectively.
U.S. Pat. Nos. 6,974,590, 6,764,696, 6,641,838, 6,585,997, 6,509,036, 6,391,335, 6,350,470, 6,200,604 and US Patent Publication Nos. 20050176790, 20050142197 and 20050142198 describe pharmaceutical combinations of active compounds such as fentanyl and congeners thereof in combination with an effervescent agent used as a penetration enhancer to influence the permeability of the active compound across the buccal, sublingual, and gingival mucosa.
U.S. Pat. Nos. 6,761,910 and 6,759,059 and U.S. Patent Publication No. 20040213855 disclose pharmaceutical compositions for the treatment of acute disorders such as pain by sublingual administration of an essentially water-free, ordered mixture of microparticles with at least one pharmaceutically active agent adhered to the surfaces of the carrier particles by way of a bioadhesion and/or mucoadhesion promoting agent. U.S. Pat. No. 6,759,059 discloses compositions and methods for sublingual administration of fentanyl or a pharmaceutically acceptable salt thereof using a tablet which is approximately 100 mg in size.
U.S. Pat. No. 5,800,832 and U.S. Pat. No. 6,159,498 (Tapolsky, et al.), and U.S. Patent Publication Nos. 20030194420 and 20050013845 disclose a water soluble, biodegradable drug delivery device, e.g., a bilayer film disk having an adhesive layer and a backing layer, both water-soluble, which adheres to mucosal surfaces.
U.S. Pat. Nos. 6,682,716; 6,855,310; 7,070,762 and 7,070,764 and (Rabinowitz, et al.), disclose delivery of an analgesic via the inhalation route using a method which comprises: a) heating a thin layer of analgesic drug on a solid support to form a vapor; and, b) passing air through the heated vapor to produce aerosol particles.
U.S. Pat. No. 6,252,981 (Zhang et al.) discloses oral mucosal drug delivery as an alternative method of systemic drug delivery formulation and method for oral transmucosal delivery of a pharmaceutical. The invention provides a drug formulation comprising a solid pharmaceutical agent in solid solution with a dissolution agent in solid form, yielding a solid solution. The solid solution formulation may be further combined with buffers and other excipients as needed in order to facilitate the drug's manufacturing, storage, administration and delivery through oral mucosal tissue. The formulation can be used with a variety of oral transmucosal delivery dosage forms, such as a tablet, lozenge, lozenge on a stick, chewing gum, and buccal or mucosal patch. See, also Zhang et al, Clin Pharmacokinet. 2002; 41(9):661-80.
A number of transmucosal dosage forms for treatment of pain are presently in clinical development, examples of which include a buccal morphine spray and a buccal fentanyl spray (Generex Biotechnology) and an oral, fast-dissolving tablet of fentanyl for sublingual administration (Rapinyl™; Endo Pharmaceuticals). Two transmucosal fentanyl preparations which currently are commercially available are a fentanyl buccal tablet (FENTORA™; Cephalon) and ACTIQ® (Cephalon), an oral transmucosal form of fentanyl citrate administered as a lollipop, both are only indicated for the management of breakthrough cancer pain in patients who are already receiving and who are tolerant to opioid therapy for their underlying persistent cancer pain.
Although various oral drug delivery systems and dosage forms have been described for the treatment of various medical disorders and conditions, there remains a need for improved dosage forms, formulations and treatment regimens for use in the treatment of such medical disorders and conditions, e.g., for treatment of acute and breakthrough pain.
High bioavailability is critical for efficacious treatment with a variety of drugs including opioids, since higher doses of the drug must be packaged in the commercial dosage form to counter the generally poor bioavailability. An example is oxymorphone (Opana®) which has a bioavailability of 10% and therefore must be packaged with nine-fold more drug for the oral tablet versus the equivalent IV dosage form. Especially problematic are drug systems that have large amounts of residual drug left after full usage of the product. An example is IonSys™, which is an inefficient drug delivery system (transdermal) that requires three times the amount of drug packaged into the transdermal patch than is maximally delivered to the patient during regular usage. These inefficient systems, whether oral pills or patches, can be easily abused by injecting the drug intravenously and obtaining full bioavailability of the excess drug. If a given dosage form administered by the intended route of administration provides close to full bioavailability, then abusing the drug by intravenous injection does not provide for increased bioavailability and therefore this formulation may mitigate drug abuse and diversion.
There remains a need for improved dosage forms for oral drug delivery which provide more rapid and consistent onset of action, more consistent plasma concentrations and higher and more consistent bioavailability than currently available dosage forms. The present invention addresses this need.

This patent is subject to a terminal disclaimer.


A computer-implemented method for configuring a hardware verification system is presented. The method includes receiving a first data representative of a first design including a first sequential element configured to be evaluated in accordance with a first signal. The method further includes transforming the first data into a second data representative of a second design. The second data includes a third data associated with a second sequential element including functionality of the first sequential element and a fourth data associated with a first logic circuit. The evaluation of the second sequential element at cycle i of the hardware verification system is performed in accordance with the first logic circuit and a value of the first signal as computed during cycle i−1 of the hardware verification system when the second data is compiled for programming into the hardware verification system, where i is an integer number.

The present disclosure relates generally to testing a circuit design, and more specifically to testing such circuit using a programmable emulation tool having improved performance.
Integrated circuit (IC) designers commonly describe their designs in hardware description language (HDL) such as Verilog, VHDL, SystemC, and the like. In IC design, hardware emulation may refer to the process of replicating behavior of one or more pieces of hardware, hereinafter also referred to as a design under test (DUT), with another piece of hardware, such as a special-purpose emulation system. An emulation model is usually generated in accordance with a hardware description language source code representing the design under test. The emulation model is compiled into a format used to program the emulation system. Running the emulation system that has been programmed enables debugging and functional verification of the design under test. Overall progress of the emulation is usually controlled by a master clock signal generated on the emulator hardware.
With recent advances in technology, circuit designs are becoming more and more complex. Therefore, there is a need in the art for improving performance of hardware emulation systems, reducing overhead while mapping the design to programmable hardware in the emulation systems, and reducing verification time.

Overlaying of clock and data propagation in emulation


An image display apparatus splits a barrier panel, which forms a plurality of light-transmitting areas and a plurality of light-blocking areas on each pixel, into a plurality of areas, and individually correcting locations of the light-transmitting areas and the light-blocking areas on the basis of viewing location information of a viewer with respect to a display panel, thereby realizing a stereoscopic image on an entire area of the display panel even if the viewing location of the viewer is varied.

Field of the Invention
The present invention relates to an image display apparatus, and more particularly, to an image display apparatus that displays a non-glasses type stereoscopic image.
Discussion of the Related Art
Recently, as realistic images are becoming more in demand, stereoscopic image display devices that display 3D (three-dimensional) images as well as 2D (two-dimensional) images are being developed.
2D-image display devices have been greatly advanced in terms of a quality of a display image such as resolution and viewing angle, but have a limitation in that 2D-image display devices cannot display depth information of an image because they are displaying 2D images.
On the other hand, a stereoscopic image display devices display stereoscopic images instead of 2D-planar images, and thus fully transfer original 3D information to a user. Therefore, in comparison with the existing 2D-image display devices, stereoscopic image display devices display far more vivid and realistic stereoscopic images.
Stereoscopic image display devices are largely categorized into glasses type stereoscopic image display devices using 3D glasses and non-glasses type stereoscopic image display devices using no 3D glasses. The non-glasses type stereoscopic image display devices are the same as the glasses type stereoscopic image display devices in the sense that the non-glasses type stereoscopic image display devices provide a three-dimensionality of an image to a viewer by using a binocular parallax. However, since the non-glasses type stereoscopic image display devices do not require wearing the 3D glasses, the non-glasses type stereoscopic image display devices are more advantageous than the glasses type stereoscopic image display devices. The non-glasses type stereoscopic image display devices may be categorized into a lenticular type and a barrier type, wherein the non-glasses type stereoscopic image display device of the lenticular type splits a left-eye image and a right-eye image from each other by using a cylindrical lens array, and the non-glasses type stereoscopic image display device of the barrier type splits a left-eye image and a right-eye image from each other by using a barrier.
FIG. 1 is a diagram illustrating a general barrier type stereoscopic image display apparatus.
Referring to FIG. 1, the general barrier type stereoscopic image display apparatus includes a display panel 10 displaying images by splitting a left-eye image L1 and a right-eye image RI from each other, and a barrier panel 20 formed to have light-transmitting areas 22 and light-blocking areas 24, which are repeatedly arranged, and arranged on an entire surface of the display panel 10.
A viewer views images displayed on the display panel 10 through the light-transmitting areas 22 of the barrier panel 20, wherein a left eye LE and a right eye RE of the viewer see different areas of the display panel 10 through the same light-transmitting area 22. Accordingly, the viewer views the left-eye image LI and the right-eye image RI, which are displayed to adjoin each other through the light-transmitting areas 22, thereby feeling three-dimensionality.
The stereoscopic image display apparatus described as above is advantageous in that switching of a 2D display mode or a 3D display mode may be performed in accordance with the status of the light-transmitting areas 22 and the light-blocking areas 24, which are formed on the barrier panel 20. The stereoscopic image display apparatus is recently applied to televisions, monitors, notebook computers, netbook computers, tablet computers, and mobile devices owing to the advantage.
However, in the general stereoscopic image display device, since the light-transmitting areas 22 and the light-blocking areas 24 are fixedly formed on the barrier panel 20, if a viewing location (or distance) of the viewer is varied, the location of the viewer is not matched with the light-transmitting areas 22 in some area of the display panel 10. For this reason, a problem occurs in that stereoscopic images are not realized in some area of the display panel 10.