Disclosed embodiments of the invention include a method, system, and apparatus to monitor cardiovascular signals such as arterial blood pressure (ABP), pulse oximetry (POX), and intracranial pressure (ICP).

Cardiovascular signals contain parameters of clinical significance that must be estimated, but have a complicated nonlinear relationship to the observed signals. For instance, accurate estimation and tracking of the heart and respiratory frequencies from ABP, POX, and ICP is important for algorithms embedded in patient monitors in the emergency room and intensive care applications. Commercial monitoring systems often include the capability to monitor heart rate and several statistics of pressure signals such as the systolic, diastolic, and mean, but few can reliably estimate other components of pressure waveforms such as the respiratory rate, pulse pressure variation (PPV), harmonic phases, or pulse morphology.
Currently available systems are empirical in nature and do not used an underlying statistical model to estimates and automatically track all the cardiovascular parameters of interest and solve clinically important problems such as: 1) estimation and tracking of heart rate from pressure signals, 2) estimation and tracking of respiratory rate from pressure signals, 3) model-based filtering, artifact removal, and interpolation, 4) cardiovascular signal decomposition, characterization, and tracking of pulse morphology, and 5) PPV estimation on mechanically ventilated subjects during periods of abrupt hemodynamic monitoring
These problems have important clinical significance. For instance, accurate estimation and tracking of PPV is important, since numerous studies have found that PPV is one of the most sensitive and specific predictors of fluid responsiveness and PPV is used to optimize fluid therapy [1-6]. Characterization and tracking of the ICP pulse morphology during intracranial hypertension is also important. Several research studies have indicated ICP morphology changes correlate with a deterioration of the mechanisms that control ICP [7,8,8-11], and great interest exists in developing indices [8,10-14] to characterize and track the pulse morphology in order to understand how such changes in morphology are related to intracranial compliance, cerebral autoregulation (CAR), and outcome. Accurate tracking of the heart rate and respiratory rate from cardiovascular signals without the need for an automatic beat detection algorithm is also important. The ability to track heart rate without performing beat detection is significant since there are currently few publicly available detection algorithms for cardiovascular pressure signals such as ABP, ICP, and POX [15].

Method, system, and apparatus for cardiovascular signal analysis, modeling, and monitoring

Abstract: The system can be used to calculate and monitor useful clinical information such as heart rate, respiratory rate, pulse pressure variation (PPV), harmonic phases, pulse morphology, and for artifact removal. The method uses a statistical state-space model of cardiovascular signals and a generalized Kalman filter (EKF) to simultaneously estimate and track the cardiovascular parameters of interest such as the cardiac fundamental frequency and higher harmonics, respiratory fundamental frequency and higher harmonics, cardiac component harmonic amplitudes and phases, respiratory component harmonic amplitudes and phases, and PPV.

State of Oregon by and through the State Board of Higher Education on Behalf of Portland State University


An ink-jet printer and an apparatus and a method of driving a recording head for an ink-jet printer for suppressing satellite droplets. Two piezoelectric elements are provided for every ink chamber corresponding to each nozzle. Timing of displacement of the piezoelectric elements is adjusted by applying a drive signal for ink droplet ejection to one of the piezoelectric elements and a drive signal for suppressing satellite droplets when a droplet is ejected to the other piezoelectric element. An auxiliary pressure generated by the displacement of the latter piezoelectric element is superimposed on an ejection pressure generated by the displacement of the former piezoelectric element. Trailing of an ink droplet is cut off at an early stage and generation of satellite droplets is suppressed.

1. Field of the Invention
The present invention relates to an ink-jet printer for ejecting ink droplets through a droplet outlet orifice (a nozzle) and recording an image on paper and an apparatus and a method of driving a recording head for an ink-jet printer.
2. Description of the Related Art
Ink-jet printers for ejecting ink droplets through a droplet outlet orifice communicating with an ink chamber and recording on paper have been widely used. In such an ink-jet printer of related art, a single piezoelectric element is provided for each nozzle. The piezoelectric element is fixed to an oscillation plate forming an external wall of the ink chamber to which ink is fed through an ink duct. The piezoelectric element changes the ink chamber volume by bending in response to a voltage waveform of an applied drive signal so as to generate an ejection pressure. An ink droplet is ejected through the outlet orifice by the ejection pressure.
Since the ejection pressure is generated by changing the ink chamber in such an ink-jet printer as described above, ink ejected through the orifice flies in a columnar shape (in a trailing form). Differences in time and velocity result between the tip and the end of the flying ink droplet.
Consequently, the preceding main ink droplet is accompanied by unwanted minute droplets (called satellite droplets in the following description). Such satellite droplets landing on paper affect the printing result. Although satellite droplets do not have a great effect on the quality of a high-density image recorded with relatively large droplets, the image quality is expected to be significantly reduced by satellite droplets when the image is recorded with small droplets for representing a low-density image or a half-tone image. Satellite droplets generated when small droplets are ejected therefore cause a great problem.
Some methods have been proposed in order to cope with the problem. For example, a method is disclosed in Japanese Patent Application Laid-open Hei 7-76087 (1995) wherein a single piezoelectric element is provided for each nozzle and the velocity of changing ejection voltage applied to the piezoelectric element is switched between two levels for ejecting ink droplets. In the method, as shown in FIG. 1, the ejection voltage is initially increased at first voltage changing velocity xe2x80x98v1xe2x80x99. The ejection voltage is then increased at second voltage changing velocity xe2x80x98v2xe2x80x99 higher than v1. In FIG. 1, the vertical axis indicates voltage. The horizontal axis indicates time. According to the method, the next droplet is ejected to follow the tip of the preceding droplet. The difference in velocity between the tip and the end of the ink column is thereby decreased and satellite droplets are reduced.
Another method is disclosed in Japanese Patent Application Laid-open Sho 59-133067 (1984) wherein a single piezoelectric element is provided for each nozzle and an ink droplet is ejected by applying two independent voltage pulses to the piezoelectric element. In the method, as shown in FIG. 2, first pulse P1 is applied to the piezoelectric element to produce a first pressure fluctuation for starting ink droplet ejection through a nozzle. First pulse P1 is then terminated and second pulse P2 is applied to the piezoelectric element before the ejection of droplet through the nozzle is completed to produce a second pressure fluctuation. In FIG. 2, the vertical axis indicates voltage. The horizontal axis indicates time. According to the method, the ink column ejected through the nozzle ruptures at an early stage and generation of satellite droplets is suppressed.
An ink droplet ejection apparatus is disclosed in Japanese Patent Application Laid-open Sho 51-45931 (1976) wherein two pressure generating means are provided for each nozzle and an ink droplet is ejected by oscillating ink by combining oscillations produced by the two pressure generating means.
In the method disclosed in Japanese Patent Application Laid-open Hei 7-76087 (1995) described above, however, first voltage changing velocity v1 is required to be lower than second voltage changing velocity v2. Consequently, the velocity of an ejected ink droplet is reduced when compared to the case wherein the voltage is changed at high velocity v2 throughout the ejection cycle. A reduction in velocity of an ejected ink droplet results in unstable ejection affecting linearity of the droplet flying route and variations in droplet velocity. As a result, displacements of recorded dots may occur and printing quality may be reduced.
In the method disclosed in Japanese Patent Application Laid-open Sho 59-133067 (1984) described above, second pulse P2 is applied after interval Ti, having terminated first pulse P1. If interval Ti is too long, a trail of an ink column becomes long and satellite droplets may be produced. On the other hand, if interval Ti is too short, the piezoelectric element does not follow the voltage change and the intended operation will not be achieved. This is because the piezoelectric element in general has its intrinsic oscillation characteristic and does not operate at a frequency above the intrinsic oscillation. Although this problem may be solved by fabricating a piezoelectric element having a high intrinsic frequency, this is not realistic since there is a limitation of the intrinsic frequency of the piezoelectric element obtained in practice. In addition, fabricating such a piezoelectric element is accompanied by technical difficulties and manufacturing costs are thereby increased. Furthermore, in the above-mentioned publication, although voltage V1 of first pulse P1 is lower than voltage V2 of second pulse P2, voltage V1 is required to be higher than voltage V2 so that the trailing end of the ink column reaches the tip thereof and becomes integrated with the tip. However, an increase in the voltage applied to the piezoelectric element causes a reduction in the life of the piezoelectric element and the oscillation plate oscillated by the piezoelectric element. A residual oscillation is increased as well and the frequency characteristic may be affected.
The above-mentioned ink droplet ejection apparatus disclosed in Japanese Patent Application Laid-open Sho 51-45931 (1976) is provided for efficiently ejecting ink droplets with a small power input. In order to achieve the object, high-frequency drive signals are each applied to the two pressure generating means and the phase difference between the drive signals and the amplitude are changed so that the oscillations generated by the pressure generating means are successfully combined to oscillate ink. An ink droplet is thereby ejected. That is, the apparatus is not intended for preventing satellite droplets. The method of driving the pressure generating means and the configuration required for preventing satellite droplets are not disclosed, either. No suggestion about such a method or configuration is made in the publication, either.
As thus described, it is difficult to satisfactorily reduce satellite droplets in the related art without reductions in velocity of an ejected droplet, in the apparatus life, in the frequency characteristic and without a limitation of the intrinsic oscillation characteristic of the piezoelectric element.
The related-art ink-jet printers have further problems. FIG. 3 is a schematic diagram of a recording head and a drive circuit thereof in a related-art ink-jet printer. As shown, a recording head 500 includes a nozzle 501 and a piezoelectric element 502 provided in correspondence with the nozzle 501. The piezoelectric element 502 is fixed to a wall of an ink chamber (not shown) to which ink is supplied through an ink duct (not shown). A drive signal 504 of a specific waveform is selectively inputted to the piezoelectric element 502 through an on/off switch 503. That is, the drive signal 504 is only inputted to the piezoelectric element 502 when the switch 503 is turned on. On the application of the drive signal 504, the piezoelectric element 502 is bent in such a direction that the ink chamber volume is reduced. An ink droplet is thereby ejected through the nozzle 501.
For such printers, one of the methods for producing halftone images is varying a droplet size dot by dot. In the drive circuit of the recording head of related art shown in FIG. 3, however, only one type of drive signal 504 is inputted so that merely whether to perform ejection or not is the only operation that is controlled. Consequently, it is impossible to perform control for varying a size of ejected droplet from droplet to droplet although the interval between recorded dots is controlled. It is therefore difficult to faithfully achieve various image representations such as more natural halftone images.
It is an object of the invention to provide an ink-jet printer and an apparatus and a method of driving a recording head for an ink-jet printer for suppressing generation of satellite droplets accompanying an ejected ink droplet while overcoming the problems described above.
An ink-jet printer of the invention comprises: a droplet outlet orifice through which an ink droplet is ejected; an ink chamber for supplying ink to the outlet orifice; a first pressure generating means for generating a pressure for having the ink droplet ejected through the outlet orifice by changing the volume of the ink chamber through displacement; a second pressure generating means for generating a pressure for suppressing generation of minute ink droplets accompanying the ink droplet ejected through the outlet orifice by changing the volume of the ink chamber through displacement; and an ejection control means for controlling a state of the displacements of the first and second pressure generating means.
An apparatus of the invention is provided for driving a recording head for an ink-jet printer including a droplet outlet orifice through which an ink droplet is ejected; an ink chamber for supplying ink to the outlet orifice; a first pressure generating means for generating a pressure for having the ink droplet ejected through the outlet orifice by changing the volume of the ink chamber through displacement; a second pressure generating means for generating a pressure for suppressing generation of minute ink droplets accompanying the ink droplet ejected through the outlet orifice by changing the volume of the ink chamber through displacement. The apparatus comprises: a means for generating drive signals for effecting the displacements of the first and second pressure generating means; and a means for controlling a state of supplying the drive signals to the first and second pressure generating means.
A method of the invention is provided for driving a recording head for an ink-jet printer including a droplet outlet orifice through which an ink droplet is ejected; an ink chamber for supplying ink to the outlet orifice; first and second pressure generating means provided for the outlet orifice. The method comprises the steps of: generating an ejection pressure for having the ink droplet ejected through the outlet orifice by changing the volume of the ink chamber through displacement of the first pressure generating means by applying drive signals for ejection having a specific waveform to the first pressure generating means; and generating an auxiliary pressure for suppressing generation of minute ink droplets accompanying the ink droplet ejected through the outlet orifice by changing the volume of the ink chamber through displacement of the second pressure generating means by applying an auxiliary drive signal having a specific waveform to the second pressure generating means. A state of the generation of the ejection pressure and a state of the generation of the auxiliary pressure are controlled.
According to the ink-jet printer and the apparatus and method of driving a recording head for an ink-jet printer of the invention, the first and second pressure generating means are provided for the outlet orifice. A state of the displacements of the first and second pressure generating means is adjusted. The auxiliary pressure generated by the displacement of the second pressure generating means is superimposed on the ejection pressure generated by the displacement of the first pressure generating means. Trailing of ink droplet is thereby cut off at an early stage.
Another ink-jet printer of the invention comprises: a droplet outlet orifice through which an ink droplet is ejected; an ink chamber, having a wall, for supplying ink to the outlet orifice; a first pressure generating means provided on the wall of the ink chamber for generating a pressure for having the ink droplet ejected through the outlet orifice by changing the volume of the ink chamber through displacement; a second pressure generating means provided on the wall of the ink chamber for generating a pressure for assisting the ejection of the ink droplet through the outlet orifice by changing the volume of the ink chamber through displacement. The first pressure generating means is placed further from the droplet outlet orifice than the second pressure generating means. xe2x80x98Assisting with the ejection of the ink dropletxe2x80x99 means that adjustment is made so that the ink droplet is ejected in an intended state. To be specific, a specific modification is made on the ejection pressure generated by the first pressure generating means so that the ejected droplet has an intended size and velocity or no unwanted droplet is ejected. The same applies to the following description. For example, the second pressure generating means may generate a pressure for suppressing generation of minute ink droplets accompanying the ink droplet ejected.
Another apparatus of the invention is provided for driving a recording head for an ink-jet printer including a droplet outlet orifice through which an ink droplet is ejected; an ink chamber, having a wall, for supplying ink to the outlet orifice; a first pressure generating means provided on the wall of the ink chamber for generating a pressure by changing the volume of the ink chamber through displacement; and a second pressure generating means provided on the wall of the ink chamber for generating a pressure by changing the volume of the ink chamber through displacement. The first pressure generating means is placed further from the droplet outlet orifice than the second pressure generating means. The apparatus comprises: a means for generating a main drive signal for having the first pressure generating means generate a pressure for ejecting the ink droplet through the outlet orifice and an auxiliary drive signal for having the second pressure generating means generate a pressure for assisting the ejection of the ink droplet through the outlet orifice; and a control means for performing control such that the main drive signal and the auxiliary drive signal are each supplied to the first pressure generating means and the second pressure generating means. The auxiliary drive signal may be the signal generating a pressure for suppressing generation of minute ink droplets accompanying the ink droplet.
Another method of the invention is provided for driving a recording head for an ink-jet printer including a droplet outlet orifice through which an ink droplet is ejected; an ink chamber, having a wall, for supplying ink to the outlet orifice; a first pressure generating means provided on the wall of the ink chamber for generating a pressure by changing the volume of the ink chamber through displacement; and a second pressure generating means provided on the wall of the ink chamber for generating a pressure by changing the volume of the ink chamber through displacement. The first pressure generating means is placed further from the droplet outlet orifice than the second pressure generating means. The method comprises the steps of: applying a main drive signal to the first pressure generating means for generating a pressure for ejecting the ink droplet through the outlet orifice; and applying an auxiliary drive signal to the second pressure generating means for generating a pressure for assisting the ejection of the ink droplet through the outlet orifice.
According to the ink-jet printer of the invention, the first pressure generating means is provided on the wall of the ink chamber in the position away from the outlet orifice. The volume of the ink chamber is changed by the displacement of the first pressure generating means and a pressure is generated for having the ink droplet ejected through the orifice. The second pressure generating means is provided on the wall of the ink chamber in the position closer to the outlet orifice the first pressure generating means. The volume of the ink chamber is changed by the displacement of the second pressure generating means and a pressure is generated for assisting the droplet ejection.
According to the apparatus and method of driving a recording head for an ink-jet printer of the invention, the main drive signal is applied to the first pressure generating means provided on the wall of the ink chamber in the position away from the outlet orifice for generating a pressure for ejecting the ink droplet through the orifice. The auxiliary signal is applied to the second pressure generating means provided on the wall of the ink chamber in the position closer to the outlet orifice for generating a pressure for assisting the droplet ejection. The droplet ejection is thereby controlled.
Still another ink-jet printer of the invention comprises: a droplet outlet orifice through which an ink droplet is ejected; a plurality of energy generating means each for generating energy for having the ink droplet ejected through the outlet orifice; and a plurality of selection means each provided for the respective energy generating means for selecting any of a plurality of drive signals for driving the energy generating means and supplying the signal to the respective energy generating means.
Still another apparatus of the invention is provided for driving a recording head for an ink-jet printer including a droplet outlet orifice through which an ink droplet is ejected; and a plurality of energy generating means each for generating energy for having the ink droplet ejected through the outlet orifice. The apparatus comprises: a means for generating a plurality of drive signals for driving the energy generating means; and a plurality of selection means each provided for the respective energy generating means for selecting any of the drive signals and supplying the signal to the respective energy generating means.
Still another method of the invention is provided for driving a recording head for an ink-jet printer including a droplet outlet orifice through which an ink droplet is ejected; and a plurality of energy generating means each for generating energy for having the ink droplet ejected through the outlet orifice. The method comprises the steps of: selecting any of a plurality of drive signals for driving the energy generating means for each of the energy generating means; and supplying the selected drive signal to the respective energy generating means.
According to the ink-jet printer and the apparatus and method of driving a recording head for an ink-jet printer of the invention, one of the drive signals is selected and supplied to each of the plurality of energy generating means. An ink droplet is ejected through the orifice with the drive signal.
Other and further objects, features and advantages of the invention will appear more fully from the following description.

Apparatus and method for driving recording head for ink-jet printer


A device, a method and a program to simplify transcoding of TTS (timestamped transport streams). When transcoding video data in the input TTS, the video processor unit reattaches time stamps in sequence within the applicable frame period of each video frame to each video packet within the applicable video frame after recompression. When transcoding audio data in the input TTS, the audio processor unit reattaches time stamps in sequence within the applicable video frame period of each video frame to each audio packet in the applicable video frame after recompression.

The present invention relates to transcoding and relates in particular to TTS (timestamped transport stream) transcoding technology.
Time stamps are attached to each packet when sending or storing content data obtained after multiplexing of compressed video data or audio data. Content data containing packets that were all given time stamps are called TTS or timestamped transport streams.
Time stamps are time information for controlling the read timing of the content data. Conventional TTS play devices such as disclosed in Japanese Unexamined Patent Application Publication No. 2008-263404, contain an internal counter that counts the reference clock pulses, compares the time stamp detached from the TTS, with the count value from the counter, and according to those comparison results, controls the timing at which the video data and audio data are output to the decoder.
There are a variety of standards known in the art for compressing video data and include MPEG2 (registered trademark), H.264, VC-1, etc. A decision on whether to compress video data contained within the content data based on one of the standards is made according to the particular application.
In a digital broadcast for example, the video data is often compressed by MPEG2 in applications for transmission systems that transfer content data along transmission paths; and video data is often compressed by H.264 or VC-1 in storage system applications that record the content data onto a recording medium such as a hard disk or optical disk.
Audio data is compressed in the same way according to the content data application based on the different standards.
When recording digital broadcasts for example, content data matching the transmission system application is converted to content data matching the storage system application. In this conversion, the multiplexed video data and audio data are separated from each other, and this video data or audio data or both are then decoded and recompressed by a separate standard, and utilized after remultiplexing.
Conversion is also carried out to reduce the size of the content data for example when copying a large volume of content data to a small capacity recording medium. In this conversion, the multiplexed video data and audio data are separated and this video data or audio data or both are then utilized by decoding, recompressing and then remultiplexing. Recompression may utilize a technique that recompressed the data to a different standard, or a technique that recompresses the data to a higher compression ratio in the same standard.
The process of decoding compressed video data or audio data and then recompressing the data to a separate standard or the same standard at a different compression ratio is called transcoding of the video data or audio data. Japanese Unexamined Patent Application Publication No. 2008-136187 for example disclosed technology for transcoding of MPEG2 video data into H.264 video data.
In the following description in this specification, the process of transcoding and remultiplexing either the audio data or video data or both that are contained in the content data is called content data transcoding or transcode processing.
Audio data and video data are processed separately during transcoding of content data so transcoding of video data and transcoding of audio data, and remultiplexing are usually performed by synchronization from the same clock (pulse).
Transcoding of video data or audio data changes the size and the number of packets in the video data or the audio data. Japanese Unexamined Patent Application Publication No. 2008-131570 discloses a technique for avoiding synchronizing errors (lip synch) during remultiplexing of transcoded video data or audio data when the number of packets has decreased due to smaller packet sizes caused by transcoding of the video data or the audio data. This technique is described while referring to FIG. 2 of Japanese Unexamined Patent Application Publication No. 2008-131570 (FIG. 5 in this specification).
In the technique in Japanese Unexamined Patent Application Publication No. 2008-131570, the TTS that was input is separated into video TTS packets and audio TTS packets, made into TTS packets after the respective transcoding processing to obtain TTS video and TTS audio, and is then remultiplexed.
When transcoding and TTS packetizing the video TTS packets for example, the same time stamp as when the TTS was input is still utilized. That process is described next.
This process detects the first PES (packetized elementary stream) packet from the video TTS, obtains the PES packet along with the collective TTS packet payload, and performs transcoding of the acquired PES packet to obtain the transcoding results. The process continues to still utilize the DTS (decoding time stamp) and PTS (presentation time stamp) within the PES packet header. The transcoding results are then overwritten onto the payload section of the TTS packet that was input. The data size of the post-transcoding is small compared to the pre-transcoding data so besides filling in the remaining areas by padding (P in the drawing), unneeded packets among the TTS packets are replaced with NULL packets (NULL in the figure). The above process in this way acquires the post-transcoding video TTS.
The process also transcodes the audio of the TTS packet in the same way to obtain a transcoded audio TTS. The process then compares the TTS that was input, with the time stamp of the post-transcoded audio and video TTS, and replaces the packet that matches the time stamp with the packet that was trans coded.
This technique retains unchanged both before and after transcoding, the same video and audio TTS packet stamps that were first input to prevent synchronization errors during remultiplexing. Moreover, the video data and audio data can be transcoded and remultiplexed asynchronously with no need to utilize the same clock.

Transcoding device, transcoding method and program thereof


Novel compounds designed to allow interactions with binding sites of GSK-3 and hence are capable of inhibiting GSK-3 activity, via inhibition of substrate binding are disclosed. Further disclosed are pharmaceutical compositions including same and methods of using same in the treatment of GSK-3 mediated conditions.

The present invention relates to novel compounds for inhibiting glycogen synthase kinase-3 (GSK-3) and their use in regulating biological conditions mediated by GSK-3 activity and, more particularly, to the use of these compounds in the treatment of biological conditions such as type II diabetes, neurodegenerative disorders and diseases and affective disorders.
Protein kinases, the enzymes that phosphorylate protein substrates, are key players in the signaling of extracellular events to the cytoplasm and the nucleus, and take part in practically any event relating to the life and death of cells, including mitosis, differentiation and apoptosis. As such, protein kinases have long been favorable drug targets. However, since the activity of protein kinases is crucial to the well being of the cell, while their inhibition oftentimes leads to cell death, their use as drug targets is limited. Although cell death is a desirable effect for anticancer drugs, it is a major drawback for most other therapeutics.
Glycogen synthase kinase-3 (GSK-3), a member of the protein kinases family, is a cytoplasmic proline-directed serine-threonine kinase that is involved in insulin signaling and metabolic regulation, as well as in Wnt signaling and the scheme of cell fate during embryonic development. Two similar isoforms of the enzyme, termed GSK-3α and GSK-3β, have been identified.
GSK-3 has long been considered as a favorable drug target among the protein kinase family since unlike other protein kinases, which are typically activated by signaling pathways, GSK-3 is normally activated in resting cells, and its activity is attenuated by the activation of certain signaling pathways such as those generated by the binding of insulin to its cell-surface receptor. Activation of the insulin receptor leads to the activation of protein kinase B (PKB, also called Akt), which in turn phosphorylates GSK-3, thereby inactivating it. The inhibition of GSK-3 presumably leads to the activation of glycogen synthesis. The intricate insulin-signaling pathway is further complicated by negative-feedback regulation of insulin signaling by GSK-3 itself, which phosphorylates insulin-receptor substrate-1 on serine residues (Eldar-Finkelman et al., 1997).
Therefore, synthetic GSK-3 inhibitors might mimic the action of certain hormones and growth factors, such as insulin, which use the GSK-3 pathway. In certain pathological situations, this scheme might permit the bypassing of a defective receptor, or another faulty component of the signaling machinery, such that the biological signal will take effect even when some upstream players of the signaling cascade are at fault, as in non-insulin-dependent type II diabetes.
The regulation of glycogen catabolism in cells is a critical biological function that involves a complex array of signaling elements, including the hormone insulin. Through a variety of mediators, insulin exerts its regulatory effect by increasing the synthesis of glycogen by glycogen synthase (GS). A key event in insulin action is the phosphorylation of insulin receptor substrates (IRS-1, IRS-2) on multiple-tyrosine residues, which results in simultaneous activation of several signaling components, including PI3 kinase (Myers et al, 1992)). Similarly, the activity of glycogen synthase is suppressed by its phosphorylation. There is a marked decrease in glycogen synthase activity and in glycogen levels in muscle of type II diabetes patients (Shulman et al., 1990).
One of the earliest changes associated with the onset of type II (non-insulin dependent) diabetes is insulin resistance. Insulin resistance is characterized by hyperinsulemia and hyperglycemia. Although the precise molecular mechanism underlying insulin resistance is unknown, defects in downstream components of the insulin signaling pathway are considered to be the cause.
Glycogen synthase kinase-3 (GSK-3) is one of the downstream components of insulin signaling. It was found that high activity of GSK-3 impairs insulin action in intact cells, by phosphorylating the insulin receptor substrate-1 (IRS-1) serine residues (Eldar-Finkelman et al, 1997), and likewise, that increased GSK-3 activity expressed in cells results in suppression of glycogen synthase activity (Eldar-Finkelman et al, 1996). Further studies conducted in this respect uncovered that GSK-3 activity is significantly increased in epididymal fat tissue of diabetic mice (Eldar-Finkelman et al, 1999). Subsequently, increased GSK-3 activity was detected in skeletal muscle of type II diabetes patients (Nickoulina et al, 2000). Additional recent studies further established the role of GSK-3 in glycogen metabolism and insulin signaling (for review see, Eldar-Finkelman, 2002Woodgett, 2001), thereby suggesting that the inhibition of GSK-3 activity may represent a way to increase insulin activity in vivo.
GSK-3 is also considered to be an important player in the pathogenesis of Alzheimer's disease. GSK-3 was identified as one of the kinases that phosphorylate tau, a microtubule-associated protein, which is responsible for the formation of paired helical filaments (PHF), an early characteristic of Alzheimer's disease. Apparently, abnormal hyperphosphorylation of tau is the cause for destabilization of microtubules and PHF formation. Despite the fact that several protein kinases were shown to promote phosphorylation of tau, it was found that only GSK-3 phosphorylation directly affected tau ability to promote microtubule self-assembly (Mandelkow et al., 1992; Mulot et al., 1995). Further evidence for the GSK-3 role in this respect came from studies of cells overexpressing GSK-3 and from transgenic mice that specifically expressed GSK-3 in brain. In both cases GSK-3 led to generation of the PHF like epitope tau (Lucas et al., 2001).
GSK-3 is further linked with Alzheimer's disease by its role in cell apoptosis. The fact that insulin is a survival factor of neurons and initiates its anti-apoptotic action through activation of PI3 kinase and PKB, suggested that GSK-3, which is negatively regulated by these signaling components, promotes neuronal apoptosis. Several studies have indeed confirmed this view, and showed that GSK-3 is critically important in life and death decision. Furthermore, its apoptotic function was shown to be independent of PI3 kinase. Overexpression of GSK-3 in PC12 cells caused apoptosis (Pap et al., 1998). Activation of GSK-3 in cerebellar granule neurons mediated migration and cell death (Tong et al., 2001). In human neuroblastoma SH-SY5Y cells, over expression of GSK-3 facilitated stauroaporine-induced cell apoptosis (Bijur et al., 2000).
The relation between GSK-3 inhibition and the prevention of cells death has been further demonstrated by studies showing that expression of Frat1, a GSK-3β inhibitor, was sufficient to rescue neurons from death induced by inhibition of PI3 kinase (Crowder et al., 2000).
Another implication of GSK-3 was detected in the context of affective disorders, i.e., bipolar disorders and manic depression. This linkage was based on the findings that lithium, a primary mood stabilizer frequently used in bipolar disease, is a strong and specific inhibitor of GSK-3 at the therapeutic concentration range used in clinics (Klein et al., 1996; Stambolic et al., 1996; Phiel et al., 2001). This discovery has led to a series of studies that were undertaken to determine if lithium could mimic loss of GSK-3 activity in cellular processes. Indeed, lithium was shown to cause activation of glycogen synthesis (Cheng et al., 1983), stabilization and accumulation of β-catenin (Stambolic et al., 1996), induction of axis duplication in Xenopus embryo (Klein et al., 1996), and protection of neuronal death (Bijur et al., 2000). Valproic acid, another commonly used mood stabilizer has also been found to be an effective GSK-3 inhibitor (Chen et al., 1999). Altogether, these studies indicated that GSK-3 is a major in vivo target of lithium and valproic acid and thus has important implications in novel therapeutic treatment of affective disorders.
One mechanism by which lithium and other GSK-3 inhibitors may act to treat bipolar disorder is to increase the survival of neurons subjected to aberrantly high levels of excitation induced by the neurotransmitter, glutamate (Nonaka et al., 1998). Glutamate-induced neuronal excitotoxicity is also believed to be a major cause of neurodegeneration associated with acute damage, such as in cerebral ischemia, traumatic brain injury and bacterial infection. Furthermore, it is believed that excessive glutamate signaling is a factor in the chronic neuronal damage seen in diseases such as Alzheimer's, Huntington's, Parkinson's, AIDS associated dementia, amyotrophic lateral sclerosis (AML) and multiple sclerosis (MS) (Thomas, 1995).
Consequently, GSK-3 inhibitors are believed to be a useful treatment in these and other neurodegenerative disorders. Indeed, dysregulation of GSK-3 activity has been recently implicated in several CNS disorders and neurodegenerative diseases, including schizophrenia (Beasley et al., 2001), stroke, and Alzheimer's disease (AD) (Bhat and Budd, 2002; Lucas et al., 2001; Mandelkow et al., 1992).
In view of the wide implication of GSK-3 in various signaling pathways, development of specific inhibitors for GSK-3 is considered both promising and important regarding various therapeutic interventions as well as basic research.
As is mentioned above, some mood stabilizers were found to inhibit GSK-3. However, while the inhibition of GSK-3 both by lithium chloride (LiCl) (PCT International patent application WO 97/41854) and by purine inhibitors (PCT International patent application WO 98/16528) has been reported, these inhibitors are not specific for GSK-3. In fact, it was shown that these drugs affect multiple signaling pathways, and inhibit other cellular targets, such as inositol monophosphatase (IMpase) and histone deacetylases (Berridge et al., 1989).
Similarly, an engineered cAMP response element binding protein (CREB), a known substrate of GSK-3, has been described (Fiol et al, 1994), along with other potential GSK-3 peptide inhibitors (Fiol et al, 1990). However, these substrates also only nominally inhibit GSK-3 activity.
Other GSK-3 inhibitors were recently reported. Two structurally related small molecules SB-216763 and SB-415286 (Glaxo SmithKline Pharmaceutical) that specifically inhibited GSK-3 were developed and were shown to modulate glycogen metabolism and gene transcription as well as to protect against neuronal death induced by reduction in PI3 kinase activity (Cross et al., 2001; Coghlan et al., 2000). Another study indicated that Induribin, the active ingredient of the traditional Chinese medicine for chronic myelocytic leukemia, is a GSK-3 inhibitor. However, Indirubin also inhibits cyclic-dependent protein kinase-2 (CDK-2) (Damiens et al., 2001). These GSK-3 inhibitors are ATP competitive and were identified by high throughput screening of chemical libraries. It is generally accepted that a major drawback of ATP-competitive inhibitors is their limited specificity (Davies et al., 2000).
A general strategy for developing specific peptide and other GSK-3 inhibitors is reported in WO 01/49709 and in U.S. Pat. No. 6,780,625, by the present inventor, which are incorporated by reference as if fully set forth herein. This general strategy is based on defining the structural features of a GSK-3 substrate, and developing GSK-3 inhibitors in accordance with these features. However, while these publications delineate these structural features and teach various short peptides that efficiently inhibit GSK-3 activity, they fail to teach the design and synthesis of small molecules that could serve as GSK-3 inhibitors. WO 2004/052414, by the present inventor, discloses that attaching a hydrophobic moiety to a terminus of a peptide GSK-3 inhibitor enhances its inhibition activity.
However, although peptides are intriguing drug targets, their use is oftentimes limited by, for example, biological instability, immunogenicity, poor capability to cross biological membranes such as cell membranes and the blood brain barrier (BBB), and the like.
There is thus a widely recognized need for, and it would be highly advantageous to have, non-peptidic compounds for inhibiting GSK-3 activity, devoid of the above limitations.

Tel Aviv University Future Technology Development L.P.


A clock housing is arranged to include a front wall having a window directed therethrough, within the clock housing is arranged adjacent first and second endless belts having first and second respective self-reversing step motors arranged to direct opaque portions of the respective first and second belts along the window for indication of respective hours and minutes, with the belts reversing to present respective second colorations of the respective first and second belts upon reversing of the step motors.

1. Field of the Invention
The field of invention relates to clock apparatus, and more particularly pertains to a new and improved clock apparatus wherein the same is arranged to indicate hours and minutes employing endless belts to simulate bar graph type simulation.
2. Description of the Prior Art
Clock apparatus of various types are indicated in the prior art such as indicated in the U.S. Pat. Nos. 4,026,102; 4,847,785; 5,105,396; and 4,739,319.
The instant invention attempts to address deficiencies of the prior art by providing for a structure arranged for ease of construction as well as use, wherein preprogrammed self-reversing step motors are arranged to direct opaque portions of a belt in adjacency to a transparent window, wherein opposed sides of the windows are arranged in gradations to indicate respective hours and minutes relative to a calendar day.


A method of cleaning a substrate includes receiving a substrate and applying a stress-free cleaning process to the top surface of the substrate. The substrate includes a top surface that is substantially free of device dependent planarity nonuniformities and device independent planarity nonuniformities. The top surface also includes a first material and a device structure formed in the first material, the device structure being formed from a second material. The device structure has a device surface exposed. The device surface has a first surface roughness. A system for stress-free cleaning a substrate is also described.

1. Field of the Invention
The present invention relates generally to dual damascene semiconductor manufacturing processes, and more particularly, to methods and systems for planarizing features and layers in a semiconductor manufacturing process.
2. Description of the Related Art
Dual damascene manufacturing processes are becoming more common in semiconductor manufacturing. In a typical dual damascene manufacturing process, one or more conductive materials are deposited in previously patterned trenches and vias formed in a semiconductor substrate or films formed on the semiconductor substrate to form the desired electrical circuit interconnects. An excess or overburden portion of the conductive material is often formed. The overburden portion of the conductive material is unnecessary and undesirable and must be removed both to produce a damascene feature and to provide a planar surface for subsequent processing. Often, the overburden portion is formed unevenly having low areas and raised areas that correspond to the patterned trenches and vias formed in the underlying layer.
The overburden portion of the conductive material is typically removed from the semiconductor substrate through chemical mechanical polishing (CMP) and electro-chemical polishing (ECP) (e.g., etching) processes and combinations of CMP and ECP processes. Each of these processes has significant shortfalls. By way of example, ECP typically has a relatively low throughput, poor uniformity and inability to effectively remove non-conductive material.
CMP is a physical contact process which typically leaves conductive residues, or causes corrosion of the various materials, or result in non-uniform removal, and the inability to suitably planarize interconnect and interlevel dielectric (ILD) top surface. CMP can also cause stress related damage (e.g., interlayer delamination, peeling) to remaining interconnect and ILD structures. The CMP-caused stress damage is further exacerbated by the very poor inter-layer adhesion characteristics of the more-recently used materials (e.g., low-k dielectric materials). Reducing the physical force of the CMP process to reduce the physical stress can often result in unacceptably low throughput rates and other poor process performance parameters.
FIG. 1A shows a typical semiconductor substrate 100. A typical CMP process has been applied to the semiconductor substrate 100 to substantially remove an overburden layer and to expose an underlying layer 104. Layer 104 includes features (e.g., vias, trenches, etc.) that were formed in a previous manufacturing process. A portion of the overburden layer remains in the form of a non-uniformity 102 on the surface of the semiconductor substrate 100. The non-uniformity 102 has a thickness of greater than about 500 angstroms in a thickest portion. Multiple elevations 102A–102E of the non-uniformity 102 are illustrated. By way of example, the region encompassed by elevation 102A can represent where the non-uniformity 102 has a thickness of about less than 100 angstroms. Similarly, the region encompassed by elevation 102B can represent where the non-uniformity 102 has a thickness of between about 100 and about 200 angstroms. The region encompassed by elevation 102C can represent where the non-uniformity 102 has a thickness of between about 200 and about 300 angstroms. The region encompassed by elevation 102D can represent where the non-uniformity 102 has a thickness of between about 300 and about 400 angstroms. The region encompassed by elevation 102E can represent where the non-uniformity 102 has a thickness of between about 400 and about 500 angstroms. The region encompassed by elevation 102F can represent where the non-uniformity 102 has a thickness of greater than about 500 angstroms.
The typical CMP process includes applying a moving a polishing pad to the surface of the semiconductor substrate 100. Friction is generated between the polishing pad and the materials in surface of the semiconductor substrate 100. The friction removes a portion of the materials in the surface of the semiconductor substrate 100. Each material on the surface of the semiconductor substrate 100 has a different coefficient of friction with the polishing pad. By way of example, the surface of the semiconductor substrate 100 can include oxide (e.g., silicon oxide) and copper materials. The oxide has a first coefficient of friction with the polishing pad and the copper has a second coefficient of friction with the polishing pad. The first coefficient of friction is typically different (i.e., higher or lower) than the second coefficient of friction.
Where a difference in the first and second coefficients of friction occur, stresses can be imparted into the semiconductor substrate 100. At a point or area where the two different coefficients of friction meet, the stresses can be substantially concentrated. By way of example, as a typical CMP process polishes through a copper layer to expose an underlying oxide layer, the stresses become concentrated at the areas where the differences in coefficients of friction occur (i.e., where the copper layer and the oxide layers meet).
Referring again to FIG. 1A above, as the polishing pad polishes across a first material (i.e., the exposed underlying layer 104) to a second material (i.e., the non-uniformity 102) the coefficient of friction varies. As a result, the polishing process can concentrate considerable stresses into the semiconductor substrate 100 where the non-uniformity is thinnest (e.g., region 102A). Region 102A can have relatively large areas. As a result, the stresses can be imparted to a relatively large portion of the semiconductor substrate 100. These stresses can be substantially parallel (i.e., horizontal) stress vectors that are substantially parallel with the surface of the substrate 100. These stresses can also be substantially vertical stress vectors that are substantially perpendicular with the surface of the semiconductor substrate 100.
FIG. 1B shows a detailed, cross-sectional view of the semiconductor substrate 100. As shown in FIG. 1A, the non-uniformity 102 becomes relatively thin (e.g., toward the outer edges) such as in region 102A, the non-uniformity becomes increasing susceptible to damage caused by the vertical and horizontal stresses. By way of example, if the polishing pad is moving in the direction 120 relative to the surface of the substrate, then the thin, edge region 102A of the non-uniformity 102 can be peeled away from the underlying layer 104 by the horizontal stresses caused by the difference in a first coefficient of friction between the underlying layer 104 and the polishing pad and a second coefficient of friction between the non-uniformity 102 and the polishing pad. As the non-uniformity 102 is pulled away from the underlying layer 104, a feature 112 that is attached to the non-uniformity 102 can be pulled or stressed in a vertical direction. By way of example, the feature 112 can be a via that is filled with a conductive material (e.g., copper, aluminum, etc) to provide a contact to a device 114 in an underlying layer 116. As the conductive material is pulled vertically from the via 112, the contact area with the device 114 is substantially reduced.
FIG. 1C shows yet another example of damage 132 that can be caused by typical CMP processes. Due to the difference between the first coefficient of friction (e.g., between the layer 104 and the polishing pad) and a third coefficient of friction between the conductive material in the via 112, the layer 104 can be pulled away from the conductive material in the via 112. FIG. 1D shows another detailed view of the damage 132 that can be caused by typical CMP processes. As shown in FIG. 1D, the conductive material in the via 112 is slightly dished, relative to the layer 104. As a result, an edge 134 of the layer 104 is exposed. The edge 134 can further concentrate the stresses on the edge so as to cause the edge of the layer 104 to be pulled away from the conductive material in the via 112.
As a result of the layer 104 being pulled away from the conductive material in the via 112, a void 132 is formed between the conductive material in the via 112 and the layer 104. The void 132 can cause countless problems (e.g., corrosion, misalignment, etc.) in the subsequent manufacturing processes. The void 132 can also substantially reduce the reliability of the contact to the device 114. As shown in FIGS. 1A–C above, the stresses imparted to the top layers 102 and 104 by the typical CMP processes can damage features 112, 114 one or more layers below.
In view of the foregoing, there is a need for an improved planarizing system and method to uniformly and substantially remove overburden material while minimizing physical stresses to the remaining features. The improved planarizing system and method should be suitable for use in semiconductor manufacturing and should be applicable to processes such as a dual damascene process or other semiconductor manufacturing processes.

Methods and systems for a stress-free cleaning a surface of a substrate


Modafinil is effective in improving symptoms of attention deficit hyperactivity disorder and symptoms of multiple sclerosis fatigue. The administration of modafinil is also shown to activate the tuberomamillary neurons of the posterior hypothalamus, and thus exhibits activity in an area of the brain associated with normal wakefulness functions.

1. Field of the Invention
The present invention is related to the fields of neuropharmacological agents, including agents that are useful in the treatment of attention deficit hyperactivity disorder and multiple sclerosis associated fatigue.
2. Description of Related Art
Attention-deficit/hyperactivity disorder (ADHD) is a chronic neuropsychiatric disorder in children that is characterized by developmentally inappropriate hyperactivity, impulsivity, and inattention. ADHD is estimated to affect 3%-5% of school-age children. Historically ADHD was thought not to continue beyond adolescence; however, current research suggests that ADHD persists into adulthood in 10% to 60% of childhood-onset cases. ADHD persistence is associated with a high incidence of academic and occupational dysfunction, as well as a high incidence of psychiatric comorbidity (e.g., conduct, major depressive, and anxiety disorders). It is estimated that approximately 1% to 3% of adults have symptoms of ADHD. Adults with ADHD have a pattern of demographic, psychosocial, psychiatric, and cognitive features that mirrors well-documented findings among children with the disorder. This further supports the validity of the diagnosis for adults. The core ADHD symptoms in adults include a frequent and persistent pattern of inattention/distractibility and/or hyperactivity-impulsivity. The most common symptoms exhibited in ADHD adults are marked inattention, poor concentration, easy distractibility, day dreaming, forgetfulness and a frequent shift in activities. ADHD adults also report marked impulsivity, intrusiveness, low frustration/stress tolerance, temper tantrums, irritability, and extreme impatience. Less commonly reported symptoms in adults include hyperactivity, which may be confined to fidgeting, or an inward feeling of jitteriness or restlessness. In addition to the core ADHD symptoms, adults with ADHD often exhibit associated clinical characteristics such as boredom, social inappropriateness, and chronic conflicts in social situations. These features may be responsible for the high incidence of: (1) separation and divorce and (2) poor academic performance and occupational achievement that exist despite adequate intellectual abilities. In addition, adults with ADHD have a high incidence of substance abuse disorders.
While the pathogenesis of ADHD remains unclear, alterations in the dopaminergic and noradrenergic functions appear to be the neurochemical basis for the disorder. Brain positron emission tomography in adults with ADHD have revealed alterations in glucose metabolism in areas of the cerebral cortex that are involved with attention and motor activity, like the frontal lobe. The most common treatment for both adult and pediatric ADHD is stimulants (e.g., dextroamphetamine, methylphenidate, and pemoline). Stimulants are thought to work by increasing the amount of dopamine available in the synapses of the neuron. The stimulants appear to do this in multiple cerebral anatomical locations. Other therapies that have been used include: antidepressants (e.g., tricyclic antidepressants such as imipramine and desipramine; novel antidepressants such as buproorion and venlafaxine), antihypertensives (e.g., clonidine and guanfacine), monoamine oxidase inhibitors ([MAO""s], e.g., selegiline), amino acids (e.g., levodopa, phenylalanine, and L-tyrosine), and combined pharmacotherapies (e.g., concurrent use of a serotonin-selective reuptake inhibitor and a stimulant medication; or a stimulant and catelcholaminergic antidepressant regimen) (Bhandary et al., Psychiatric Annals 27:545-555, 1997; Wilens et al., J. Clin. Psychopharmacol. 15:270-279, 1995; Finkel, The Neurologist 3:31-44, 1997; Miller and Catellanos, Pediatrics in Review 19:373-384, 1998).
While stimulants are the most commonly used treatments, approximately 30%-50% of adults with ADHD do not respond positively to the stimulants, have unacceptable side effects or have concurrent depressive or anxiety disorders that stimulant medications may exacerbate or be ineffective in treating. The long-term adverse effects and their use in high-risk substance abuse subgroups of ADHD remain unstudied and are of concern; thus, there is still a need for nonstimulant pharmacotherapy for ADHD.
Another condition for which there is a long felt need for a non-stimulant pharmacological therapy is the fatigue associated with multiple sclerosis (MS). Multiple sclerosis is one of the most common disabling neurologic diseases of young adults in the United States, where an estimated 400,000 persons have the disease. Although MS can cause a variety of disabling neurological impairments such as blindness, paralysis, incoordination, and bowel or bladder dysfunction, a less apparent symptom that can also be severely disabling is fatigue. In one study involving 656 patients with MS, 78% complained of fatigue, 60% experienced it every day, and 22% suffered disruption of their daily activities (Freal et al., Arch. Phys. Med. Rehabil. 65:135, 1984). The National Multiple Sclerosis Society evaluated 839 patients who had only minor neurologic impairment despite having had MS for longer than 10 years, and fatigue was the most commonly reported symptom in this group of mildly affected patients (Jones, New York: National Multiple Sclerosis Society, Health Services Research Report, 1991). In another study 40% of MS patients listed fatigue as the most serious symptom of their disease (Murray, Can. J. Neurol. Sci. 12:251, 1985). Fatigue is reported to be the cause of at least temporary disability in up to 75% of patients with MS; and the British MS Society found fatigue to be the most important symptom leading to unemployment in this group (Rolak, Curr. Neurol. 9:109, 1989). In the United States, the prevalence of disability related to MS fatigue is underscored by its inclusion as a criterion for disability allowance under guidelines set forth by the Social Security Administration.
The mechanism of MS fatigue is poorly understood. It has been attributed to nerve conduction abnormalities within the central nervous system and increased energy demands caused by neurologic disability. Several characteristics of MS fatigue are interference with physical functioning and activities of daily living, aggravation by heat, and worsening at the end of the day (Krupp et al., Arch. Neurol. 45:435, 1988). Medications that are prescribed for the treatment of MS fatigue include amantadine, pemoline, and other stimulants. Amantadine has been demonstrated to benefit MS fatigue in 79% of patients in a double blind, randomized study, but its mechanism of beneficial action is not known (Krupp et al., Neurology 45:1956, 1995). Although amantadine has been demonstrated in a rigorous fashion to benefit MS fatigue, the benefit is partial for most patients and there are still significant numbers of patients who report no benefit. The same study failed to show a beneficial effect for pemoline, which is often used in the treatment of MS fatigue. There is a strong need, therefore, for a safe and effective treatment for this debilitating condition.
The present disclosure provides a novel use for modafinil in treatment of attention deficit hyperactivity disorder (ADHD) and in ameliorating the symptoms of fatigue due to multiple sclerosis (MS).
Studies forming the basis of the present disclosure demonstrate that, unexpectedly, administration of wake-promoting doses of modafinil to rats results in selective increases in activity of the tuberomamillary nucleus (TMN) of the posterior hypothalamus. Modafinil administration reduced the activity of the neurons in the ventrolateropreoptic area (VLPO) of the hypothalamus which are known to inhibit the activity during sleep of wake-promoting histaminergic neurons in the TMN. Activation of this histaminergic pathway by modafinil results in cortical activation and wakefulness. Thus, it appears that the physiologic basis for the wake-promoting actions of modafinil involves disinhibition of histaminergic neurons of the TMN by inhibitory actions on the VLPO. This represents the first pharmacologic agent known to produce wakefulness by selective activation of the TMN and was unexpected based on the previous publications in the field.
Based on these mechanistic studies, modafinil has a significantly different activity than the stimulants in common use for ADHD and MS fatigue. These are quite different drugs, as it is herein disclosed that modafinil promotes wakefulness by selective activation of hypothalamic nuclei involved in normal wakefulness, and in contrast, commonly used psychostimulants, such as amphetamines, act largely by enhancing dopaminergic input to the cortex and other brain regions by facilitating neurotransmission of dopaminergic neurons in the mesolimbic, tuberoinfundibular and nigrostriatal systems. Of these major dopaminergic pathways, the mesolimbic system originating in the ventral tegmentum may be most directly involved in cortical activation while the tuberoinfundibular and nigrostriatal systems are involved in pituitary and motor function, respectively. Simultaneous facilitation of these pathways by amphetamines results in the well-characterized cortical stimulation and hyperactivity associated with amphetamine administration. In contrast to the hypothalamic systems involved in normal wakefulness, facilitation of dopaminergic neurotransmission appears to induce a state of wakefulness that is abnormal in that it is associated with alterations in mood and perceptions of well-being as well as increases in motor activity.
Because of the surprising discovery of activation of the tuberomamillary neurons of the posterior hypothalamus by modafinil, as disclosed herein, novel uses for modafinil are revealed and such uses are an aspect of the present invention. For example, it is an aspect of the present invention that modafinil is a novel therapeutic agent that would provide important benefits for patients suffering from ADHD. Because modafinil activates the hypothalamus, and further because an inhibitory histaminergic neural pathway from the hypothalamus synapses on inhibitory gamma-aminobutyric acid (GABA) frontal lobe interneurons, the activation of the hypothalamus may contribute to subsequent pyramidal cell activation and provides a mechanism for the usefulness of modafinil in ADHD. In addition, activation of the TMN can also result in enhanced cortical action by direct histerminergic excitation. In other words, activation of the TMN neurons is excitory either directly or indirectly to the cortex. Insufficient activity at the frontal cortex has been implicated in the etiology of ADHD (Castellanos, F. X., Clinical Pediatrics, 381-393 (1997); Swanson, J., et al., Current Opinion in Neurobiology, 8:263-271 (1998); Barkley, R. A., Scientific American, 66-71 (1998)).
An aspect of the present disclosure may be described therefore as a method of treating attention deficit hyperactivity disorder, where the treatment includes administering to a subject suffering from or susceptible to the development of attention deficit hyperactivity disorder a composition that includes a modafinil compound in an amount effective to improve or prevent symptoms of attention deficit hyperactivity disorder in said subject.
An additional aspect of the present disclosure is a method of treating fatigue associated with multiple sclerosis including administering to a subject suffering from multiple sclerosis fatigue a composition that contains a modafinil compound in an amount effective to improve or prevent symptoms of multiple sclerosis fatigue in the subject. As used herein xe2x80x9cfatiguexe2x80x9d includes loss of power, or capacity to respond to stimulation. As such, modafinil is shown herein to be effective as a treatment for alleviating tiredness, or sleepiness associated with multiple sclerosis and also as a method of promoting wakefulness in multiple sclerosis patients.
A further aspect of the disclosure is a method of treating a subject suffering from the symptoms of attention deficit hyperactivity disorder or multiple sclerosis fatigue that includes administering to the subject a pharmaceutical composition that includes a modafinil compound in an amount effective to stimulate activity in the tuberomamillary neurons of the brain of the subject.
Yet a further aspect of the disclosure is a pharmaceutical composition in unit dose form, for use in treating attention deficit hyperactivity disorder in a subject susceptible to the development of or suffering from attention deficit hyperactivity disorder, which includes an amount of a modafinil compound such that one or more unit doses thereof are effective to stabilize or improve the symptoms of attention deficit hyperactivity disorder in the subject upon periodic administration.
An aspect of the present disclosure is also a pharmaceutical composition in unit dose form, for use in treating fatigue in a multiple sclerosis patient, where the composition includes an amount of a modafinil compound such that one or more unit doses thereof are effective to stabilize or improve the symptoms of multiple sclerosis fatigue in the patient upon periodic administration.
As disclosed herein and as used in the compositions and methods of the present invention, a modafinil compound may include a racemic mixture, and may be in an acid form, such as a metabolic acid of modafinil or a benzhydrylsulfinylacetic acid, a sulfone form, a hydroxylated form, a conjugated form such as a modafinil compound conjugated to a protein, a polysaccharide, a glucuronide or a sulfate, or a polymorphic form, it may include compounds containing isosteric replacements of the phenyl groups of modafinil, and polymorphic species or analogs of modafinil, or derivatives of cogeners and prodrugs, particularly those preparations that stimulate activity in the TMN when administered to a mammal. In preferred embodiments, the modafinil compound is modafinil. Prodrugs are known in the art as compounds that are converted to the active agent (modafinil) in the body of a subject.
Compositions and methods as disclosed herein are preferably useful in the treatment of mammalian subjects, and more particularly in humans. Because MS and ADHD are known to afflict both adults and juveniles or children, the methods and compositions disclosed herein are directed to those population groups. While effective doses may be given in mg/day for human oral administration, it is understood that the dose, unless otherwise stated, may be directed to the treatment of a human adult and that a dose for a child is adjusted appropriately.
It is an object of the present invention to provide methods of treatment that include effective doses of a modafinil compound for the treatment of ADHD and MS fatigue, and that an effective amount is preferably from about 1 to about 400 mg per daily dose. It is known in the art, for example, that a dose of from about 200 mg/day to about 400 mg/day is an effective wake-promoting dose, and that such a dose is contemplated to be useful in treatment of ADHD and MS fatigue. It is also known that a dose of about 100 mg/day is at the lower threshold of wake-promoting doses, but that such a dose is contemplated to be useful for the treating ADHD and MS fatigue. Studies reported elsewhere have also shown beneficial activity of modafinil at sub-wakefulness-promoting doses, particularly in the improvement of cognitive function. As such, it is an aspect of the present disclosure that an effective amount of a modafinil compound for use in the methods disclosed herein may include from about 1 mg/day to about 400 mg/day, or from about 100 to about 400 mg per daily dose, or from about 200 to about 400 mg per daily dose, or even 200 mg per daily dose. It is also understood that doses within those ranges, but not explicitly stated, such as 30 mg, 50 mg, 75 mg, etc. are encompassed by the stated ranges, as are amounts slightly outside the stated range limits.
In the preferred embodiments, a composition including a modafinil compound is formulated for oral administration, and is more preferred to be formulated as a tablet for oral administration. The formulation of modafinil containing tablets is known in the art as described below, and such tablets may preferably contain various inert ingredients such as lactose, corn starch, magnesium silicate, croscarmellose sodium, povidone, magnesium stearate, or talc in any combination thereof.
An aspect of the present disclosure may also be described as a therapeutic package for dispensing to, or for use in dispensing to, a mammal being treated for attention deficit hyperactivity disorder or multiple sclerosis fatigue, where the package includes (1) one or more unit doses, each such unit dose containing an amount of a modafinil compound such that said one or more unit doses thereof are effective to stabilize or improve a symptom of attention deficit hyperactivity disorder or multiple sclerosis fatigue in the mammal upon periodic administration and the unit doses being administered periodically, and (2) a finished pharmaceutical container therefor, said container containing (a) said unit dose or unit doses and (b) labeling directing the use of the package in the treatment of said mammal. In preferred embodiments the package is adapted for oral administration.
Although the compositions and methods disclosed herein have been described in light of certain preferred embodiments, it is understood that the modafinil compounds described herein may be orally administered with an inert diluent or an assimilable edible carrier, for example. The compositions may also be enclosed in hard or soft shell gelatin capsule, compressed into tablets, or incorporated directly with the food of the diet. For oral therapeutic administration, the active compounds such as modafinil may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like, although tablets are the generally preferred method of administering modafinil. Such compositions and preparations should contain at least 0.1% of active compound. The percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 60% of the weight of the unit.
The tablets, troches, pills, capsules and the like may also contain any of the following: a binder, as gum tragacanth, acacia, cornstarch, or gelatin; excipients, such as dicalcium phosphate; a disintegrating agent, such as corn starch, potato starch, alginic acid and the like; a lubricant, such as magnesium stearate; and a sweetening agent, such as sucrose, lactose or saccharin may be added or a flavoring agent, such as peppermint, oil of wintergreen, or cherry flavoring, for example. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets, pills, or capsules may be coated with shellac, sugar or both. A syrup or elixir may contain the active compounds sucrose as a sweetening agent methyl and propylparabens as preservatives, a dye and flavoring, such as cherry or orange flavor. Of course, any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed. In addition, the active compounds may be incorporated into sustained-release preparation and formulations.
In certain embodiments, the disclosed compositions may be formulated to be administered by use of a skin patch, or transdermal delivery system. The administration of the modafinil compositions described herein transdermally may be accomplished by any of a number of systems known in the art. Examples of systems that may be adapted for use with the compositions described herein include those systems of transdermal administration described in U.S. Pat. No. 4,816,252; U.S. Pat. No. 5,122,382; U.S. Pat. No. 5,198,223; U.S. Pat. No. 5,023,084; U.S. Pat. No. 4,906,169; U.S. Pat. No. 5,145,682; U.S. Pat. No. 4,624,665; U.S. Pat. No. 4,687,481; U.S. Pat. No. 4,834,978; and U.S. Pat. No. 4,810,499 (all incorporated herein by reference.
These methods typically include an adhesive matrix or drug reservoir system and may include a skin permeation enhancement agent such as ethanol, polyethylene glycol 200 dilaurate, isopropyl myristate, glycerol trioleate, linolenic acid saturated ethanol, glycerol monooleate, glycerol monolaurate, n-decyl alcohol, capric acid, and certain saturated and unsaturated fatty acids, and their esters, alcohols, monoglycerides, acetate, diethanolamides and N,N-dimethylamides (See for examples, U.S. Pat. No. 4,906,169).
The present invention further relates to a method for identifying a compound that stimulates activity in the TMN of the posterior hypothalamus. This method involves the use of standard screening techniques applied to the novel discovery as set out hereinabove. Accordingly, there is provided by the present invention compounds identified by this method and uses therefor as drugs wherein stimulation in the TMN of the posterior hypothalamus will have a salutary effect on the wellbeing of the animal or patient being treated.
Modafinil is an agent with activity in the central nervous system, and has been developed as a treatment for excessive daytime sleepiness associated with narcolepsy. The primary pharmacological activity of modafinil, like amphetamine-like agents, is to promote wakefulness. Modafinil promotes wakefulness in rats (Touret, et al., Neuroscience Letters, 189:43-46 (1995); Edgar and Seidel, J. Pharmacol. Exp. Ther., 283:757-69 (1997)), cats (Lin et al., Brain Research, 591:319-326 (1992)), canines (Shelton et al., Sleep 18(10):817-826, (1995)) and non-human primates (DS-93-023, pp 180-181; Hemant et al., Psychopharmacology, 103:28-32 (1991)), as well as in models mimicking clinical situations, such as sleep apnea (English bulldog sleep disordered breathing model) (Panckeri et al, 1996) and narcolepsy (narcoleptic canine) (Shelton et al., Sleep 18(10):817-826, (1995)). Modafinil has also been demonstrated to be a useful agent in the treatment of Parkinson""s disease (U.S. Pat. No. 5,180,745); in the protection of cerebral tissue from ischemia (U.S. Pat. No. 5,391,576); in the treatment of urinary and fecal incontinence (U.S. Pat. No. 5,401,776); and in the treatment of sleep apneas of central origin (U.S. Pat. No. 5,612,378). U.S. Pat. No. 5,618,845 describes modafinil preparations of a defined particle size less than about 200 microns that is more potent and safer than preparations containing a substantial proportion of larger particles.
Various neuroanatomical pathways have been investigated for their role in inducing and maintaining wakefulness, and some of the work has pointed to the potential role of the tuberomamillary nucleus (TMN) (Sherrin et al., Science 271:216-219, 1996). A study by Lin et al., (Proceedings of the National Academy of Science, USA 93:14128-14133, 1996) demonstrated selective activation of the anterior hypothalamus by modafinil, and the authors of that study also demonstrated that administration of modafinil to cats at a wake-promoting dose failed to cause activation of the TMN of the posterior hypothalamus. A similar study of wake-promoting doses of modafinil administered to rats (Engber et al., Neuroscience, 87:905-911 (1998)) also demonstrated that modafinil-induced wakefulness was not associated with activation of the TMN. Thus, while activation of the TMN has been implicated in normal wakefulness, the studies of these researchers has clearly taught that TMN activation was not involved in modafinil-induced wakefulness.
The present invention arises in part from the discovery that modafinil, when administered at wakefulness-promoting doses, does result in a stimulation of activity in the TMN of the posterior hypothalamus. Modafinil administration in rats reduced the activity of the neurons in the ventrolateropreoptic area (VLPO) of the hypothalamus, which are known to inhibit the activity of wake-promoting histaminergic neurons in the TMN during sleep. Activation of this histaminergic pathway by modafinil results in cortical activation and wakefulness. Thus, it appears that the physiologic basis for the wake-promoting actions of modafinil involves disinhibition of histaminergic neurons of the TMN by inhibitory actions on the VLPO. This represents the first pharmacologic agent known to produce wakefulness by activation of the TMN. Furthermore, because modafinil activates the hypothalamus, and because an inhibitory histaminergic neural pathway from the hypothalamus synapses on inhibitory gamma-aminobutyric acid (GABA) frontal lobe interneurons, the present inventors contemplate that the activation of the hypothalamus contributes to subsequent pyramidal cell activation and provides a mechanism for the usefulness of modafinil in ADHD, and in MS fatigue (Swanson, J., et al., Current Opinion in Neurobiology, 8:263-271 (1998); Roelke, U., et al., Neurobiology, 48:1566-1571 (1997)).
Prior to any invention disclosed or claimed herein, modafinil was known in the art in the form of a therapeutic package, marketed under the name Provigil(copyright). Provigil(copyright) is a pharmaceutical product manufactured by Cephalon, Inc. of West Chester, Pa. and is also marketed by Cephalon, Inc. Provigil(copyright) is supplied as tablets containing 100 mg or 200 mg modafinil. In commercial use, modafinil-containing therapeutic packages in the prior art were labeled and otherwise indicated for use in narcolepsy patients.
Accordingly, known in the prior art were therapeutic packages providing one or more unit doses of modafinil as an active ingredient thereof, supplied in a finished pharmaceutical container that contain said unit doses, and further contained or comprised labeling directing the use of said package in the treatment of a human disease or condition as described above. In the provided literature accompanying a pharmaceutical container are instructions that the daily dosage of modafinil is 200 mg/day given as a single dose in the morning. Although 400 mg/day was well tolerated in clinical trials, 200 mg/day is the optimum wakefulness promoting dose in adult humans.
All of the compositions and methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and/or methods and in the steps or in the sequence of steps of the methods described herein without departing from the concept, spirit and scope of the invention. More specifically, it will be apparent that certain agents which are both chemically and physiologically related may be substituted for the agents described herein while the same or similar results would be achieved. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims.

Compositions including modafinil for treatment of attention deficit hyperactivity disorder and multiple sclerosis fatigue


The snow making tower of the present invention includes a vertical ground support pole having its bottom end anchored in the ground surface on a ski slope and a tower support sleeve is coaxially received over the upper end of this ground support pole for free axial rotation on the support pole. An elongated pipe snow making tower with snow making nozzles adjacent its upper end and water and air inlets at its lower end is secured adjacent its lower end to the tower support sleeve at a vertical incline. The elongated pipe tower, together with the support sleeve, are permitted to freely coaxially rotate on the ground support pole. A vertical wind vane is secured to the tower for turning the tower with the tower support sleeve on the ground support pole with prevailing ambient wind applied to the wind vane so that the vertical incline of the tower always points down wind.

This invention relates generally to the art of fluid sprinkling and more particularly to snow making towers for ski slopes.
The present invention pertains to improvements in snow making towers of the type disclosed in my U.S. Pat. No. 5,360,163, issued Nov. 1, 1994, for ADJUSTABLE SNOW MAKING TOWER. This patent discloses an adjustable snow making tower which includes a vertical ground support pole that is anchored into the ground and has a tower support pole coaxially received on this ground support pole for support of a snow tower for horizontal rotation on the ground support pole vertical axis.
While this described adjustable snow making tower is extremely easy and versatile in articulation for adjusting the snow tower to different ambient temperature and wind conditions, nevertheless, it must always be actually physically attended to to make any such modifications.
This type of snow making tower is generally referred to as an adjustable lean-out tower, and it is a principal object of the present invention to provide such a snow making tower which automatically adjusts itself appropriately for prevailing wind conditions so that maximum quality snow is manufactured and appropriately distributed on the ski slopes for changing wind conditions.
If the lean-out type tower is adjusted so that the prevailing wind is directed into the face of the tower, or against the direction of incline of the tower, the wind will cause the snow being manufactured to blow back against the base of the tower where it has no benefit for the underlying ski slopes and can possibly cause unwanted accumulation of ice on the tower structure.

Snow making tower with wind vane positioning


A variable gain amplifier circuit 1 includes an amplifier A1, an amplifier A2, an inductor L1, and an inductor L2. The amplifier A1 has a predetermined gain and is connected at a terminal to a circuit output section. The amplifier A2 has a different gain from the amplifier A1 and is connected at a terminal to the circuit output section. The inductor L1 is connected at an end to a circuit input section and at the other end to the input terminal of the amplifier A1. The inductor L2 is connected at an end to ground and at the other end to the input terminal of the amplifier A2. The inductors L1 and L2 form a transformer T. The configuration restricts input impedance variations which are dependent on the signal path taken by an input signal Vin. The input impedance and the signal source impedance remain matched. Impedance matching is preformed with the signal source with variable gain.

Wireless receivers are in popular use for data communications in, for example, the 2.4 GHz and 5 GHz bands in compliance with the IEEE 802.11a, IEEE 802.11b, and IEEE 802.11g standards. Mobile phones provide good examples. The wireless receiver amplifies an incoming wireless signal with an amplifier circuit tuned to a predetermined wireless frequency. The amplifier circuit in the wireless receiver is typically capable of receiving weak signals of about −90 dBm.
The incoming signal has a strength which is variable with the distance between the receiver and the transmitter where the signal originates. For example, if the transmitter is located close to the receiver, the signal level as received on the antenna is about −5 dBm. The necessary input signal can become weaker than unwanted signals in nearby channels.
The amplifier circuit is required to provide a flat signal characteristics profile and high linearity over a wide range of input signal frequencies. Specifically, the amplifier circuit desirably amplifies low level input signals (−90 dBm to −60 dBm) at high gain with low noise and high level input signals (−60 dBm or higher) at high gain and high linearity.
Generally, these requirements are met by a variable gain amplifier circuit which allows for a variable gain setting. Receivers incorporating a variable gain amplifier circuit detect input signal strength and automatically change the gain of the variable gain amplifier circuit.
Conventional variable gain amplifier circuit come in various forms which will be now described in reference to FIG. 11 to FIG. 17.
U.S. Pat. No. 6,600,371 (published Jul. 29, 2003) discloses the conventional circuit shown in FIG. 11. The illustrated circuit is a quad amplifier containing four transistors Q112, Q113, Q112′, and Q113′. The four transistors amplify signals from major signal paths while controlling gains. A gain setting is made through control voltage.
FIG. 12 shows an exemplary conventional circuit. The illustrated conventional circuit is a wireless signal transmitter/receiver. The circuit provides a Gilbert cascode stage containing an input transistor Q121 with an emitter feedback as well as transistors Q122 and Q123. The Gilbert cascode stage processes signals either to or from the output section Vout. This means that the Gilbert cascode stage controls the amount of signal traversing from input Vin to output Vout, by adjusting the controlling voltages Vc1 and Vc2.
U.S. Pat. No. 6,566,963 (published May 20, 2003) discloses the circuit shown in FIG. 13. The conventional circuit has two amplifier stages. Specifically, in the conventional circuit, the first amplifier stage involving a transistor Q131 connects to the second amplifier stage (transistors Q132, Q133, and Q134) via a transformer 131.
FIG. 14 shows another conventional circuit example. The illustrated conventional circuit has two signal paths. A first signal path consists of transistors Q141, Q142, and Q143 an has high gain. A second signal path consists of Q144 and has low gain and high linearity in signal conversion. Along the first signal path, the gain can be varied by the transistors Q142, Q143. As to the second signal path, the transistor Q144 is a common base configuration. The resistor R141 helps to improve the linearity of the transistor Q144.
The conventional circuit shown in FIG. 15 is disclosed in "A 2.5-GHz BiCMOS transceiver for wireless LAN's" by R. G. Meyer et al., IEEE Journal of Solid-State Circuits, Vol. 32, No. 12, pp. 2097–2104, December 1997. Like the one in FIG. 14, this conventional circuit has two signal paths. A first signal path consists of a transistor Q154 and has high gain. A second signal path consists of transistors Q151, M152 and has low gain. Both transistors Q151, M152 act as an emitter follower. When the first signal path is used to amplify an input signal, the transistor Q154 acts on the signal. On the other hand, when the second signal path is used to amplify an input signal, the transistors Q151, M152 act on the signal; the transistor Q154 is turned off.
The conventional circuit shown in FIG. 16 is disclosed in "A direct-conversion receiver for 900 MHz (ISM Band) spread-spectrum digital cordless telephone" by C. D. Hull et al., IEEE Journal of Solid-State Circuits, Vol. 31, No. 1a2, pp. 1955–1963, December 1996. Like the one in FIG. 12, the illustrated conventional circuit relies on transistors Q164, Q167 for variable gain. The degree of linearity of the circuit is determined by the characteristics of the transistor Q164.
The conventional circuit shown in FIG. 17 is disclosed in Published Japanese translation of PCT application 2002-506304 (Tokuhyo 2002-506304; published Feb. 26, 2002). The illustrated circuit can vary its gain because of a change of bias current Ibias to digital.
These conventional circuits however have a narrow dynamic range, variable input impedance dependent on the gain setting, and other problems.
The conventional circuit in FIG. 11 has another problem that a balanced unbalanced device (balun) is needed to couple the input signal from an antenna to the amplifier stage. Another problem is that resistor and transistor parameters among others must be altered to suit the operating wireless frequency.
The conventional circuits shown in FIGS. 12, 13, 16 shows a narrow dynamic range when the input signal has large amplitude, which can be a problem.
The FIG. 14 conventional circuit has other problems: The circuit does not show a constant input impedance when the signal paths are switched. The resistor R141 adds to the noise factor. The input signal inverts in polarity depending on the operating signal path. Concretely, in the FIG. 14 circuit, the transistor Q141 is an inverting amplifier. The input signal inverts its polarity when it passes through the transistors Q141, Q142. In contrast, the transistor Q144 is a common base configuration; the input signal does not invert its polarity when it goes through the path involving the transistor Q144.
As for the FIG. 15 conventional circuit, the input impedance does not match the signal source impedance. An external matching network is needed for the impedance matching, which adds to the component count. Another problem is found where the input signal has different polarities between the two signal paths, because the transistor Q154 is an inverting amplifier, and the transistor M152 is a non-inverting amplifier. Also, the parasitic capacitance due to the presence of the transistors M151, M152 can degrade noise factor.
In the FIG. 17 conventional circuit, the input impedance, which is a function of the bias current Ibias, is dependent on the gain setting and varies greatly. Therefore, the input impedance does not match the signal source impedance.


An electromagnetic launcher is provided for accelerating a projectile from a breech end to a muzzle end. The launcher includes a container, a rail contained therein and a support. The container includes an inner surface along an axial direction. The rail is contained within the inner surface and includes a load surface to support the projectile and an interface surface. The support is disposed between the interface surface and the inner surface. The rail and the support provide a value to an expression for critical velocity

The invention relates generally to electromagnetic launcher rails, and more particularly to such methods and configurations that preferably can improve durability and performance of rails for launching a projectile at high speed.
An electromagnetic launcher utilizes electromagnetic force to propel an electrically conductive payload. Electrically conductive rails may be disposed in a longitudinal launch direction from breech to muzzle ends. Electric current flowing through the rails induces a magnetic field. This field produces a mutual repulsion force between the rails and accelerates the payload along at least one of the rails.
An armature pushes the projectile for release through the muzzle. Physical and design constraints present limitations as to launch speeds and rail ability to perform after firing multiple loads without failure.

Rails for electromagnetic hypervelocity launcher

Abstract: V      cr        =                            2                                EIk                                    ρ                                                              A                      ,where E is Young's modulus for the rail, I is moment of inertia for the rail, k is foundation modulus for the support, ρ is density for the rail and A is the cross-sectional area of the rail. The launcher is configured such that the critical velocity increases along the axial direction towards the muzzle. In particular, a material term √E/ρ of the rail increases along the axial direction, such for the rail being made from a first material being proximate to the breech and a second material being proximate to the muzzle, such that the material term √E/ρ of the second material being greater than that of the first material. Alternatively, the rail is made into a first shape being proximate to the breech and a second shape being proximate to the muzzle, such that a shape term √I/A of the second shape is greater than that of the first shape.

United States of America as represented by the Secretary of the Navy


A delay locked loop block receives external clocks to generate first internal clocks including a reference clock. An internal delay unit delays the first internal clocks to output second internal clocks, which are fed back to the delay locked loop block. The delay locked loop block adjusts delay time of the delay unit according to a phase difference between each second internal clock and the reference clock so that the second internal clocks are delay locked. A duty cycle correcting block corrects a duty cycle of each second internal clock and outputs a duty cycle corrected clock. An error determining unit compares a phase of each second internal clock with one another and, based on the comparison, feeds back a feedback clock including one of the duty cycle corrected clock or the second internal clock to the delay locked loop block.

The present invention relates to a delayed locked loop, and more particularly, to a delayed locked loop circuit with duty cycle correction and a method of controlling the same.
In general, clocks that are used in systems or circuits are used as references to match operating timings. The clocks may also be used to ensure a high-speed operation without the occurrence of any error. When a clock that is input from the outside of a semiconductor circuit is used in the semiconductor circuit, clock skew, that is, a time delay occurs due to an internal circuit. A delay locked loop circuit is used to correct the time delay, such that an internal clock and the external clock have the same phases as each other.
Further, when the semiconductor circuit operates, the clocks need to be delay locked. However, it is also important to maintain a duty ratio of a rising period and a falling period of each of the clocks to 50:50. Therefore, general delay locked loop circuits to which duty cycle correction circuits are added are being currently used in semiconductor circuit technology.
Meanwhile, the delay locked loop circuit with duty cycle correction according to the related art may cause a duty correction error according to a change in process, voltage, and temperature (hereinafter, simply referred to as "PVT").
That is, after a rising clock RCLK in synchronization with a rising edge of the external clock and a falling clock FCLK in synchronization with a falling edge of the external clock are delay locked, a phase delay may occur due to the change in PVT.
The duty correction is performed by comparing a phase of the rising clock RCLK with a phase of the falling clock FCLK and adjusting the width of a rising period or a falling period of each of the two clocks. When the amount of phase delay of the rising clock RCLK is different from that of the falling clock FCLK, the phase of the rising clock RCLK is not corrected. FIG. 1 is a diagram illustrating an early stage in which a duty correction error occurs. As in a duty cycle corrected clock DCC_OUT as shown in FIG. 1A, an error occurs when the duty ratio of the rising period and the falling period is not 50:50.
The duty cycle corrected clock DCC_OUT is fed back to the delay locked loop circuit and subjected to delay locked signal processing. Then, in the duty cycle correction circuit, the processed duty cycle corrected clock DCC_OUT is subjected to the duty cycle correction. These operations are repeatedly performed.
Since the delay locked signal processing operation and the duty cycle correction are repeated, the skew occurring when the duty correction error occurs, that is, a phase distortion component is accumulated. As a result, as in FIG. 1B, an abnormal signal in which a high-level period and a low-level period are not normally repeated is output.
As described above, the delay locked loop circuit with duty cycle correction according to the related art causes a duty cycle correction error due to a phase delay occurring according to a change in PVT. This causes a failure in the operation of the semiconductor circuit that uses the delay locked loop circuit.

Delay locked loop circuit with duty cycle correction and method of controlling the same