A current source device that cuts off an output current when stopped and obtains a desired output current upon start-up includes a first circuit having a first FET and resistors in series, a second circuit having second and third FETs in series with a point between the second and third FETs and a gate of the third FET connected, a drive circuit supplying a common drive voltage to gates of the first and second FETs, and first and second current source circuits responsive to first and second drive voltages that are gate voltages of the second and third FETs. The first and second current source circuits respectively include first and second current source FETs having the first and second drive voltages as gate voltages, and a start-up circuit changing the first and second drive voltages forcedly when the first and second current source FETs are made conductive.

The present invention relates to a current source device, an oscillator device and a pulse generator used in a semiconductor integrated circuit or the like.
A current source device configured as a basic circuit block is used in a semiconductor integrated circuit. The current source device supplies a predetermined current determined according to circuit constants to other circuit blocks or the like. A circuit example of a conventional current source device 100 is shown in FIG. 1. The current source device 100 comprises a reference voltage generating unit 110, a drive unit 120 and an output unit 130. The reference voltage generating unit 110 generates a reference voltage VREF for determining an output current by dividing a source voltage VCC with resistors. Incidentally, the reference voltage VREF is VREF=VCC·R12/(R11+R12) in the circuit shown in FIG. 1. The reference voltage VREF is supplied to an inversion input terminal of an operational amplifier OP1 of the drive unit 120. An output terminal of the operational amplifier OP1 is connected to the gate of a PMOS transistor P11. The source of the PMOS transistor P11 is connected to the source voltage VCC and the drain thereof is connected to a resistor R13 whose one end is grounded. A potential developed at a connecting point of the drain of the PMOS transistor P11 (first FET) and the resistor R13 is connected to a non-inversion input terminal of the operational amplifier OP1. A PMOS transistor P12 (second FET) is connected to a gate line of the PMOS transistor P11. The source of the PMOS transistor P12 is connected to the source voltage VCC and the drain thereof is connected to its corresponding drain of an NMOS transistor N12 (third FET). Namely, the NMOS transistor N12 is connected in series with the PMOS transistor P12. The gate and drain of the NMOS transistor N12 are short-circuited to each other and the source thereof is grounded. Here, a current Ill that flows through the PMOS transistor P11 can be represented as I11=VREF/R13. On the other hand, if each transistor is used in a saturated region, then a relationship of I12∝I11 is established between the current I11 and a current I12 that flows through the PMOS transistor P12 and the NMOS transistor N12. A voltage VBP developed at a gate line for the PMOS transistors P11 and P12 is used as a gate voltage of a PMOS transistor P13 of the output unit 130, and a voltage VBN developed at a gate line for the NMOS transistor N12 is used as gate voltage of an NMOS transistor N13 of the output unit 130. The source of the PMOS transistor P13 of an output stage is connected to the source voltage VCC and the drain thereof serves as an output terminal OUT1. The source of the NMOS transistor N13 of the output stage is grounded and the drain thereof serves as an output terminal OUT2. With the connection of anther circuit block or the like between the output terminals OUT1 and OUT2 in the current source device 100 having such a configuration, a drive current corresponding to the reference voltage VREF can be supplied to the corresponding circuit block or the like. The current source device referred to above can be used as, for example, a drive current source of an oscillator device having a ring oscillator circuit comprised of inverter circuits of odd-numbered stages. In this case, drive currents are supplied from the current source device every plural inverter circuits constituting the ring oscillator circuit. The current source device can also be used as, for example, a drive current source of a pulse generator including a delay circuit comprised of inverter circuits of plural stages. Even in this case, drive currents are supplied from the current source device every plural inverter circuits constituting the delay circuit.
The above prior art refers to a patent document 1 (Japanese Unexamined Patent Publication No. 2000-78510).
In the above current source device, the condition for its normal operation is that the drive voltages VBP and VBN for driving the PMOS transistor P13 and NMOS transistor N13 of the output stage are respectively set to predetermined potentials. On the other hand, the setting of an output current in a halt state of the current source device to zero might be required depending on specs. In this case, however, it is considered that the drive voltage VBP of the PMOS transistor P13 of the output stage is set to the source voltage VCC to cut off the output current. Further, in this case, it is considered that VBN is set to a ground potential to avoid that the drive voltage VBN of the NMOS transistor N13 of the output stage reaches an indefinite voltage. Thus, there is a need to change the drive voltages VBP and VBN of the transistors of the output stage from the source voltage VCC or ground potential to predetermined potentials when the current source device is started from its halt state. It cannot be however expected that a desired output current is obtained during a period of transition made until VBP and VBN reach a predetermined voltage respectively. Namely, the period during which the required output current cannot be obtained exists immediately after the start-up of the current source device. Thus, in the oscillator device using the current source device as the drive current source as described above, a normal frequency output cannot be expected during a period taken until the output current reaches a predetermined value, after the start-up of the current source device. In the pulse generator using the current source device as the drive current source as mentioned above, a normal pulse output cannot be expected during a period taken until the output current reaches a predetermined value, after the start-up of the current source device.

Current source device, oscillator device and pulse generator


A data loss prevention (DLP) system provides a policy-based mechanism for managing how data is discovered and classified on an endpoint workstation, file server or other device within an enterprise. The technique described herein works in an automated manner by analyzing file system activity as one or more endpoint applications interact with a file system to build a statistical model of which areas of the file system are (or will be deemed to be) active or highly active. Using this information, scanning to those areas by the DLP software is then prioritized appropriately to focus compute resources on scanning and classifying preferably only those files and folders that are necessary to be scanned, i.e., the file system portions in which the user is applying the majority of his or her activity. As a result, the technique limits scanning to only those areas that have meaningful activity (thereby conserving compute resources with respect to files or folders that have not changed), improving scanning efficiency.

Technical Field
This disclosure relates generally to identifying and managing user operations with respect to sensitive information (e.g., intellectual property, personally identifiable information, and the like).
Background of the Related Art
Data Loss Prevention (DLP) systems are well-known in the prior art and operate generally to identify, monitor use of, and to control user operations on, sensitive information within an enterprise computing environment. Typically, DLP systems provide a policy-based mechanism for managing how data is discovered and classified on a user's workstation or file server, also known as an "endpoint." Policies must be distributed to, and enforced on, each endpoint. In an organization comprising a large number of endpoints, the task of creating and managing policies can be onerous. This is particularly true when there are a variety of endpoint configurations, which is the situation that arises due to differing file system layouts from endpoint to endpoint based on operating system and software differences, and/or differences that result from the behaviors and actions of the end users. Creating a single policy (or even multiple such policies) that accurately and efficiently identifies which areas of the file system sensitive information tends to be discovered requires significant input from, and on-going maintenance by, system administrators.
Existing DLP systems typically provide simplistic approaches to solving the issue of how to determine which areas of an endpoint file system should be examined. One brute force approach is to simply scan the entire file system. This approach suffers from large compute resource requirements and long scan times, and it may not be feasible for file systems that contain large amounts of data. For example, a full system scan over a file server with a large amount of data will occupy system resources over a long time period. Users of that file server necessarily will be affected by any impaired performance while the scan is on-going. This problem is even more acute when the scan is carried out over the entire file system but where a large percentage of the data is not actively being accessed (and thus need not be checked).
An alternative approach is to have an administrator attempt to identify a set of known safe directories in the file system that can be then excluded from the DLP policy (and thus the scan). This approach is disadvantageous in that it often requires significant overhead for administrators in managing effectively policies. In addition, this approach naively assumes that each endpoint corresponds to the known configuration, which provides a weakness that can be easily exploited.
While these approaches are valid in some cases and can produce workable systems, they impose significant constraints on the efficiency of the DLP solution.
It is desired to provide enhanced techniques for discovery of sensitive content that addresses the above-described deficiencies.

Method and apparatus for autonomic discovery of sensitive content

International Business Machines Corporation


A novel polyimide having a repeating structure unit expressed by the following general formula (1), a method for manufacturing the same, a gas separation membrane using the novel polyimide and the method for manufacturing the same. The gas separation membrane using this polyimide is excellent in gas permeable performance and separation selectivity for gas, for example, carbon dioxide, methane, etc.. General Formula (1) ##STR1## where R denotes a quadrivalent organic group.

Hitherto, as a gas separation membrane, a cellulose acetate membrane has been well known. However, the cellulose acetate membrane is insufficient in chemical resistance, thermal resistance, etc. Therefore, it cannot be said that the cellulose acetate membrane has a practically sufficient performance. Moreover, as a membrane whose thermal resistance property is improved, a polysulfone semipermeable membrane is industrially manufactured, but it also is insufficient in permeation performance. Moreover, a silicone membrane is well known as a selective permeation membrane of oxygen. However, silicone cannot provide a sufficient mechanical strength and be industrially satisfactory.
Recently, researches and developments of a polyimide resin separating membrane excellent in strength, heat resistance and gas selective permeability have been conducted.
Journal Polymer Science Polymer Physics (J.polym. Scie. Polym. Phys., 28, 2291 (1990)) describes an aromatic polyimide membrane having high gas permeability and selectivity, which is made from a phenylenediamine component in which one ortho position amine functional group is replaced by an alkyl group. Moreover, U.S. Pat. No. 4,717,394 and Japanese Patent Application Tokkai No. Sho 63-123420 describe an aromatic polyimide membrane having high gas permeability, which is made from phenylenediamine in which all ortho position amine functional groups are replaced by alkyl groups.
However, a polyimide having higher permeation performance and high separation selectivity and a gas separation membrane using such polyimide are still demanded.

Polyimide, a method for manufacturing the same, a gas separation membrane using the polyimide and a method for manufacturing the same


Lightweight yokes are provided. According to some embodiments, the basic overall appearance of the yoke may be maintained, but the actual material of which it is constructed is changed. According to other embodiments, the yoke is provided with an improved lightweight construction, and, yet other embodiments the yoke may be provided with an improved construction and formed from a preferred material. Yokes may be constructed from cast austempered ductile iron; whereas cast iron has a density, 0.26 lbs/in^3, which is approximately 8% less than steel, 0.283 lbs/in^3, thereby allowing for a reduction in weight over steel. A suitable austempering process is used to produce the austempered metal yoke. Yokes have improved configurations which may require less metal to produce the yoke. Both, the lightweight material and improvements in configuration of the yoke structure may combine to provide a lighter weight yoke.

1. Field of the Invention
This invention relates in general to railcars and, more particularly, to railcar yokes for a coupler system.
2. Brief Description of the Related Art
Railcar couplers are disposed at each end of a railway car to enable joining one end of such railway car to an adjacently disposed end of another railway car. The engageable portion of each of these couplers is known in the railway art as a knuckle. For example, railway freight car coupler knuckles are taught in U.S. Pat. Nos. 4,024,958; 4,206,849; 4,605,133; and 5,582,307.
Typically, adjacent railway cars are joined by heavy shafts extending from each car, known as couplers, and, generally, each coupler is engaged with a yoke housing a shock-absorbing element referred to as the draft gear. The type-E coupler is the standard coupler for railway freight cars. The type-E coupler has standard specifications such that producers making a type-E coupler adhere to a standard specification, so that the standard railway car couplers are completely interchangeable, regardless of the manufacturer. In addition, adherence to a standard also enables couplers from any one manufacturer to be able to be readily joined to couplers from any other domestic manufacturer. The Association of American Railroads ("AAR") has adopted standards for railway couplers. The coupler must include specific geometry and dimensions that allow it to receive a knuckle, and the geometry must be such that the knuckle is allowed to freely operate when coupling and uncoupling railway cars. These dimensions and features of the coupler may be checked for compliance with AAR standards by using gauges, which are applied to the coupler to verify the coupler dimensions or parameters are within an allowable variation or tolerance range.
Couplers have a particular life, and in instances may fail. In many cases when a railcar coupler fails, a replacement coupler must be carried from the locomotive at least some of the length of the train, which may be up to 25, 50 or even 100 railroad cars in length. The repair of a failed coupler can be labor intensive, can sometimes take place in very inclement weather and can cause train delays.
The yoke is a generally elongated structure having two side sections that extend from and join with a tail portion. The side sections are also known and referred to as "straps". The side sections or straps are joined at the opposite end by a head portion where the yoke is joined to the coupler with a securing component, such as a key or pin. The yoke generally has a pocket formed by the straps and a rear wall, and a draft gear is positioned between the straps of the yoke, and between the tail portion and the head portion. The best-known yokes are the E-type and F-type. The E-type yoke is governed by AAR standards that include the AAR S-143 Standard, SY 40AE, Y40 or YS93AE, for a 24⅝ inch gear pocket, although there are some tolerances that the pocket may have, as permitted by the standards. A typical E-type yoke has straps that are 5 inches. The F-type yoke is governed by the S-149 standard and the Y45 standard. Although there are other differences between E-type and F-type yokes, a primary difference is the design and orientation of the pin or key used to join the coupler to the yoke.
Typical yokes contain apertures in the yoke head portion, which also may be known as the key slots or pin bores by which a coupler is joined to the yoke with the installation of a key or pin through the slot or bore to connect the yoke and coupler. Adjacent railcars, when coupled together and in motion, place tension on the yoke and compressive forces are transferred to bearing surfaces at opposed ends of the yoke where the draft gear is housed.
Adjacent freight cars are separated in accordance with standard specifications which includes an allowance for a specified yoke length. In accordance with applicable AAR standards, typically, E-type and F-type yokes, respectively, may have a length of 41⅛″ or 37½″.


The present invention has an object to provide a switching regulator power supply apparatus that realizes a plurality of light emitting amount outputs without increasing a total number of structural components thereof. A switching regulator power supply apparatus according to the present invention includes a switching type power converting circuit; a current detecting circuit for producing a feedback signal in response to a load current; and an SWR control circuit for driving the power converting circuit. In the switching regulator power supply apparatus, the SWR control circuit is provided with a control signal input terminal and a reference voltage circuit capable of outputting a plurality of reference voltages based upon a control signal inputted to the control signal input terminal.

1. Field of the Invention
The present invention relates to a boost type switching regulator for supplying a constant current so as to drive a light emitting diode (referred to as "LED" hereinafter).
2. Description of the Related Art
In various sorts of portable devices employing LEDs as light sources, such as portable telephones, currents to be supplied to the LEDs are required to be controlled at constant values in order to make light emitting amounts, luminance, or chromaticity of the LEDs constant. As power supplies for controlling LED drive currents so as to supply stable and constant currents to loads as described above, boost type switching regulators are utilized.
Switching regulator power supply apparatuses required for driving LEDs produce constant currents which are required in order to produce light emitting amounts, luminance, or chromaticity of the LEDs necessary for users. In most portable devices, the constant currents are fixed. Even when those currents are to be changed, a current required in a fine adjustment is merely changed. Generally, as an example, in a case of switching regulator power supply apparatuses for driving an LED, which are used as LCD panel display back lights of portable telephones and the like, LCD drive currents have been set to such currents capable of obtaining sufficient light emitting amounts required for display operations, and those currents have been set to fixed values.
In the switching regulator power supply apparatus, a constant current for driving the LED is determined by a detecting circuit 5 of FIG. 2. In a normal case, the detecting circuit 5 is constituted by a resistive element and the constant current is set by changing a resistance value of the resistive element. In order to set the light emitting amount of the LED constant as described above, an impedance (resistance value) of the detecting circuit 5 may be connected so as to become a predetermined impedance.
Also, a drive current ILED of the switching regulator power supply apparatus and a resistance value RLED of the detecting circuit 5 are expressed by the following equation.ILED=VREF/RLED
In this case, ILED is a current which is supplied to a load 6, and corresponds to a constant current for driving the LED. VREF is an output voltage value of a reference voltage circuit provided in an SWR control circuit 4. Further, resistance value RLED is an impedance (resistance value) of the detecting circuit 5. The switching regulator power supply apparatus is operated in such a manner that a voltage difference generated by the current (=ILED) flowing through the impedance of the detecting circuit 5 becomes equal to the reference voltage value VREF of the reference voltage circuit provided in the SWR control circuit 4. In other words, a load current is stabilized to become the above-mentioned current ILED by turning on/off a switching transistor by a drive signal whose duty ratio is determined by a feedback signal in response to the load current.
FIG. 3 is a block diagram for showing an SWR control circuit 4 of a conventional switching regulator. The SWR control circuit 4 includes an input terminal 11, a reference voltage circuit 19, an error amplifying circuit 13, a triangular wave oscillating circuit 14, a comparator 15, and a buffer circuit 16. The input terminal 11 is used for inputting a feedback signal from a detecting circuit 5. The reference voltage circuit 19 outputs a reference voltage. The error amplifying circuit 13 amplifies a voltage difference between the reference voltage and the feedback signal. The triangular wave oscillating circuit 14 outputs a triangular wave signal. The comparator 15 compares the triangular wave signal with a signal outputted from the error amplifying circuit 13 to generate an output signal. The buffer circuit 16 converts the output signal of the comparator 15 into a drive signal, which makes it possible to drive a switching transistor Q1 provided in a power converting circuit 3.
The SWR control circuit 4 controls the switching transistor Q1 in such a manner that the feedback signal becomes equal to the reference voltage. The output of the reference voltage circuit is at a predetermined constant voltage level, so a current flowing through the load 6 is controlled to become a constant current based upon a voltage of the detecting circuit 5 and the reference voltage circuit 19 provided in the SWR control circuit 4.
Recently, since there are increasing portable devices which require a plurality of LEDs, the detecting circuit 5 or other such technique which involves connection to a single impedance is not sufficient for setting the light emitting amount of the LED constant, so a detecting circuit having a plurality of impedances corresponding to a plurality of light emitting amount outputs is necessary.
FIG. 4 is a block diagram for showing a conventional boost type switching regulator power supply apparatus for driving an LED, which corresponds to a plurality of light emitting amount outputs (refer to, for example, JP-A-2004-194448). A detecting circuit 7 corresponding to the plurality of light emitting amount outputs includes, when two levels of outputs are required, for example, a first resistive element and a second resistive element both of which are connected in parallel to each other, and a switching transistor. The switching transistor controls with a control signal which is inputted from a terminal 8 for switching output levels. Similarly, when two levels or higher levels of outputs are required, the detecting circuit 7 can be additionally provided with the resistive elements and the switching transistors if necessary.
However, in a case where a switching regulator power supply apparatus for driving an LED, which corresponds to the light emitting amount outputs of a plurality of levels is to be constituted, the resistive elements required for setting the light emitting amounts and the switching transistors controlled by the switching control signals are required. As a result, a total number of elements required for the power supply apparatus is increased, accompanied by an increase of a mounting area thereof, which impedes a reduction of costs and an area saving effect (namely, high density mounting effect).


A feed-forward predistortion circuit to provide improved linear response in optic modulators. The circuit includes a non-linear element, an amplifier/delay means and a power combiner. The non-linear element generates a first signal sin(X), where (X) is the input signal. The amplifier/delay means generates a second signal 2(X). The first and second signals are combined in the power combiner to produce a modulating signal 2(X)-sin(X) which is fed to an optic modulator. The modulating signal 2(X)-sin(X) compensates for the transfer function of the optic modulator which has a transfer function sin(X), thereby producing a linear output.

A trend in optical communication systems is to integrate functions traditionally performed by discrete optical components onto an integrated optic ("IO") device. These functions include polarizing, filtering, modulating, etc. One such IO device, having utility in the communications field, is operative to modulate an optical signal. Such an IO device is typically fabricated from a substrate of lithium niobate, LiNbO.sub.3, or lithium tantalate, LiTaO.sub.3, and has a waveguide formed on a major surface to provide parallel optic pathways. Examples of such a device, commonly referred to as an optic modulator, include a Mach-Zehnder modulator and a Balanced-Bridge interferometer.
A Mach-Zehnder includes input and output Y-junctions, parallel waveguide arms, and electro-optic modulators. An input optic signal such as a laser beam is split at the input Y-junction in the waveguide into two equal components. Each component travels in a corresponding arm of the waveguide before being recombined at the output Y-junction. To modulate the optic signals in the Mach-Zehnder, one or more electro-optic modulators comprising electrodes are formed on the waveguide surface in the vicinity of the arms. A time varying voltage, e.g., a radio frequency ("RF") signal, applied to the electrodes produces an electric field in the IO device substrate.
The basic operating principle of all optic modulators is the same. In accordance with the well-known electro-optic effect, an electrical field produced by an electrical input ("modulating") signal effectively changes the relative indices of refraction and thus changes the optic path lengths of the waveguide arms. Modulation of an optic input signal occurs since the relative phase of the optic signals in the arms varies according to the instantaneous amplitude of the time varying modulating signal driving the electrodes. The varying phase results in a varying amplitude of the intensity of the optic signal at the output of the modulator.
Since a modulator operates on light interference principles, its transfer function is a sine curve, i.e., sin(X). Consequently, a modulator generates undesirable harmonics when driven by a modulating signal such as an RF signal. When the modulator is driven symmetrically about the optical half intensity point of the sine curve, i.e., the approximately linear region of the curve, fundamental and odd harmonics predominate in the modulator's output. The amplitudes of the higher harmonics increase as the modulating voltage is increased. Thus, the modulator's output deviates noticeably from that which would be obtained with a perfectly linear device. See Donaldson, A. et al., "Linearity Considerations in High Performance Amplitude Modulators", IEEE Colloquium on `Analogue Optical Communications`, Digest No. 156, pp. 4/1-5, December 1989.
Such harmonic intermodulation distortion due to odd harmonics is a problem in a multichannel optical communication system, e.g., cable television ("CATV"), where an RF signal is used to modulate an optical signal. A CATV system may have 80 channels multiplexed for transmission in a frequency range of 50-600 MHz. The large number of closely spaced carriers places strict requirements on the linearity of system elements in order to reduce undesired harmonic intermodulation distortion.
Typical amplitude modulation ("AM") transmission requirements for second and third order harmonics are -65 dBc relative to the fundamental. The inherent sine response of an optic modulator does not provide the requisite linearity. One means of lessening the effect of harmonic intermodulation distortion is to decrease the carrier modulation depth, known as the optical modulation index ("OMI"). However, this is an inefficient use of the optical power. This reduction in OMI has been taught by Donaldson. Attempts at linearizing the modulator's response have been made so as to reduce the amplitude of the higher order distortions. Such restriction reduces the transmitted signal strength. Thus, to improve the signal to noise ratio it is necessary to increase the transmitted optic power, which requires a more expensive optic source.
It is known in the art to use directional couplers, alone or in combination with Mach-Zehnders, to reduce harmonic intermodulation distortion. Such schemes employ exponential or other trigonometric terms to reduce the second and third order terms. See Lin, Z. -Q. et al., "Waveguide Modulators with Extended Linear Dynamic Range--A Theoretical Prediction", IEEE Photonics Technology Letters, Vol. 2, No. 12, pp. 884-886, December 1990; Liu, P. -L. et al., "In Search of a Linear Electrooptic Amplitude Modulator", IEEE Photonics Technology Letters, Vol. 3, No. 2, pp. 144-146, February 1991. However, creating a parallel optic structure requires complex phase and amplitude adjustment schemes. Further, coherent addition of correction terms requires the difficult task of maintaining the optic phase alignment of one or more parallel branches.
Optic linearization schemes are known in which two parallel Mach-Zehnders achieve incoherent combination of light intensities. See, e.g. Lin, Z. -Q. et al., "Reduction of Intermodulation Distortion of Interferometric Optical Modulators Through Incoherent Mixing of Optical Waves", Electronics Letters, 1990, Vol. 26, No. 23, pp. 1980-1982. However, such a scheme may be limited to a narrow frequency range and a small optic signal transmission distance due to wavelength dispersion of the transmitted optic signal.
Commonly-owned, co-pending U.S. patent application Ser. No. 07/803,818, filed Dec. 9, 1991, now U.S. Pat. No. 5,168,534 entitled CASCADE OPTIC MODULATOR ARRANGEMENT discloses a cascade linearization circuit to reduce harmonic intermodulation distortion. In the cascade circuit, two optic modulators, such as Mach-Zehnders, are connected in series. A signal fed to the optic input of the first Mach-Zehnder is modulated by an electro-optic modulator. The resulting modulated optic signal is fed to the optic input of a second Mach-Zehnder and is modulated by the electro-optic modulator of the second Mach-Zehnder. The phase offset of both modulators, and the contrast of one modulator, are adjusted to minimize both second and third order harmonics. However, the cascade arrangement requires phase and gain accuracy to be tightly constrained. Further, the arrangement is costly because two modulators are required.
It is also known in the art to use predistortion to compensate for the optic modulator's non-linear transfer function. Predistortion refers to a technique of distorting a modulating signal equally in phase but opposite in amplitude to the transfer function of the optic modulator before feeding the modulating signal to the optic modulator. Thus, the predistortion effectively cancels the distortion inherent to the optic modulator. Prior art predistortion circuits employ a simple diode network to directly approximate the transfer function arcsin(X). Arcsin(X) is used since the transfer function of the optic modulator is sin(X), i.e., sin[arcsin(X)]=X. However, such prior art systems have severe limitations. Such systems drift and operate over relatively narrow bandwidth. Further, high impedance and current biasing sources are needed.

Apparatus for linearization of optic modulators using a feed-forward predistortion circuit


A camera includes a pulse transmitter for transmitting at a transmit time through an aperture and along an optical path to a target a coherent electromagnetic ranging pulse at a first wavelength range outside the visible spectrum. In some embodiments, the camera includes a reflected pulse detector for receiving a reflected electromagnetic pulse reflected by the target back along the optical path and through the aperture at a detect time subsequent to the transmit time. In some embodiments, the camera includes a shutter positioned for shielding the pulse detector from at least transmit time to an intermediate time between the transmit time and the detect time. In some embodiments, the shutter includes a layer of semiconductor material placed in the optical path at a point between the target and the detector.

Technical Field
This disclosure relates generally to adjusting the focal distance of a camera in response to the range to a camera target.
Description of the Related Art
The advent of small, mobile multipurpose devices such as smartphones and tablet or pad devices has resulted in a need for better photography results from high-resolution, small form factor cameras for integration in the devices.
Some small form factor cameras for integration in the devices may incorporate focus mechanisms that may attempt to sense and react to distances from small form factor cameras to camera targets by adjusting location of the optical lens on the X and/or Y axis in an attempt to compensate for changes in the distances to the targets from small form factor cameras. Some small form factor cameras may incorporate an autofocus (AF) mechanism whereby the object focal distance can be adjusted to focus an object plane in front of the camera at an image plane to be captured by the image sensor. In some such autofocus mechanisms, the optical lens is moved as a single rigid body along the optical axis (referred to as the Z axis) of the camera to refocus the camera.
The inability to accurately determine the range from small form factor cameras for integration in the devices to camera targets has heretofore limited the effectiveness of small form factor cameras for integration in the devices.


A temperature conditioning apparatus for the human body includes a vest or other clothing unitary with a thermoelectric or Stirling cycle heat pump worn by the user. The unit is powered by a battery source worn on the user's belt or other part of his or her body, or by an externally-mounted electrical energy source, for example, in a vehicle. The vest has front and rear panels with an air flow layer and permeable inside layer that accept and release conditioned air to the user. The vest may be used with body armor or other protective layers, that is, the vest may be worn underneath body armor or body armor may be built into the vest, or the vest may be used without body armor to cool the user in an exceptionally hot environment such as a non-air conditioned space in hot weather.

1. Background of the Invention
The present invention relates generally to apparatus for selectively heating or cooling the human body trunk which is adapted to be worn under outer protective equipment or clothing items such as a so-called bulletproof vest or jacket, fireman or firefighter garb, bio/chemical protective suit, or the like.
2. Description of Related Art
In many situations an individual may find it necessary or highly desirable to wear protective gear such as a bulletproof vest for a policeman or fire protection gear for a fireman, for example. Such gear, although highly useful and even life protecting, is uncomfortable when worn for a length of time especially during warm or humid weather.
It is therefore a desideratum to provide a means and method of supplementing protective gear with cooling/heating equipment that alleviates uncomfortable aspects of wearing the gear resulting from an increase or decrease in the wearer's temperature while wearing the gear.

Temperature conditioning apparatus for the trunk of a human body


The present invention is prosthetic tooth replacement including a dental crown portion and a joining portion adapted to fixedly attach to a dental implant. Further, present invention also comprises the combination of a prosthetic tooth replacement and a dental implant. Additionally, the present includes a method for making an oral surgical guide stint by vacuum forming a thermoplastic material over a model of an implant target area. Finally, the present invention includes a method of inserting the combination of the prosthetic tooth replacement and implant into the jaw of a patient.

Dental implants are well known devices used in dental surgery to restore patients' lost, broken or decayed teeth. The essential function of a dental implant is to act as an anchor to hold in place a prosthetic device such as a fixed or removable denture appliance or single prosthetic tooth. Implants attain stability by being embedded in the patient's jawbone, thereby giving a firm foundation to the prosthetic device that protrudes above a patient's gum line.
Implants seen in the prior art have several disadvantages. First, to bring an implant procedure to completion requires several patient visits. Usually five to seven or more visits are necessary as well as possible referrals to specialists. The implant procedure itself requires surgery with flap and sutures leading to both significant patient discomfort, temporary restrictions on the types of food patients are permitted to eat, and a four to twelve month time period before the entire procedure is completed. In addition, there is a 10–15% failure rate. Failure of the procedure requires the use of alternative procedures over and above the failed implant surgery. Finally, the complete implant procedure, including the prosthetic device, can entail a high cost often out of the range of the average patient.
Typical of implants found in the prior art are those disclosed in U.S. Pat. Nos. 6,217,331 and 6,394,809 as well as United States Patent Application No. 2002/0142266, all to Rogers, et al. This series discloses a dental implant supporting a single prosthetic crown. The implant is described as having a threaded portion with a self-tapping region which allows insertion into the jawbone of a patient. The gingival portion is flared with a threaded bore that accepts a prosthetic device that extends above the gum line. The size of these implants mandate a waiting period of approximately 3–6 months before the prosthetic device is installed after the implant is first placed into the patient's jaw. This hold period allows ossification of the bone material around the inserted implant to ensure it is sufficiently secured in the bone structure. During this time, a flap is sewn over the implant to prevent infection during the ossification process. The required hold period delays the final installation of the dental prosthesis while the surgery can contribute to significant patient discomfort.
A similar implant is disclosed in United States Patent Application No. 2003/0068599 to Balfour, et al. The implant disclosed in the '599 application includes scalloped buccal and lingual portions that allow for tissue attachment to create a natural appearing gum line. However, the size of the implant disclosed in the '599 application necessitates the use of an insertion procedure that incorporates an extended waiting period to ensure sufficient ossification around the implant occurs.
Vigolo, et al. discloses the use of implants having a diameter in the range of 2.9 mm as supports for prosthetic crowns. [See The Journal of Prosthetic Dentistry, 84(1):50–54 (July 2000) which is hereby incorporated by reference in its entirety.] However, use of implants of this size still require a two month waiting period before a prosthesis can be attached to the implant. Similarly, U.S. Pat. No. 4,313,696 to Kasama, et al., which is hereby incorporated by reference in its entirety, discloses an implant supporting a single prosthetic crown. However, the '696 patent discloses that a period of wound healing must occur after the implant is placed in a patient's jaw. In addition, the device disclosed in the '696 patent includes an elastomeric cushion placed between the prosthetic crown and the implant.
The use of mini dental implants (MDIs) has been disclosed in U.S. Pat. No. 5,749,732 to Sendax, which patent is hereby incorporated by reference in its entirety. The '732 patent discloses an implant having a length of in the range of 17–19 mm, a threaded shaft diameter of about 1.8 mm with the threaded area having an unthreaded chord shaped section. Integral in the MDI of the '732 patent is an abutment end to which a dental prosthesis can be attached. The '732 patent discloses the use of the MDI to anchor a denture appliance holding a plurality of prosthetic teeth and requiring either a second MDI or another anchor such as a natural tooth to hold the denture. Also disclosed in the '732 patent is an implantation procedure for the MDI that eliminates the need for a surgical incision, flap and sutures, and the consequent ossification period before installing the dental prosthesis. However, the advantage of MDIs in enabling fast, relatively pain free insertion of dental prostheses is somewhat negated by their confinement to use with dentures supporting a plurality of artificial crowns and the need to use at least two anchors to support the denture.
Therefore, there exists in the field a need for a dental implant that can be used to securely support single dental crown prosthesis and that can be secured in a patient's jawbone using a procedure that reduces the time to complete installation of the prosthesis and patient discomfort and pain.

System of dental restoration of single stage dental implants and loading with a preformed crown restoration


The application describes a dispenser for manual discharge of a single dose of a flowable substance, comprising a casing (1) which has a nozzle (2) and a pair of shoulders (3) aside the nozzle. The nozzle (2) has a piston member (5) extending inwardly from an outlet opening (9), the piston member having at least one discharge channel. A container (10) of the substance to be discharged is mounted on the piston member (5), and a seal (12) is arranged across the container (10) to seal in all the substances to be discharged. The piston member (5) has a piercing member (8) which extends towards the seal (12), whereby on pressing the container (10) on to the piston member (5) the seal (12) is pierced to allow the contents of the container (10) to be expelled along the discharge channel and out through the outlet opening (9).

The invention relates to a unit-dose discharging device of the type in which a single cylinder containing one dose of a flowable substance to be discharged is moved manually relative to a piston in order to expel the contents of the cylinder through a nozzle opening in the piston. This device is particularly adapted for intranasal adminstration of a predetermined dose of a pharmaceutical substance in liquid form. The device is suited for the intranasal administration of the drug sumatriptan for use in the treatment of conditions associated with cephalic pain, such as cluster headache, chronic paroxysmal hemicrania, headache associated with vascular disorders, headache associated with substances or their withdrawal, tension headache, and in particular migraine.
U.S. Pat. No. 4946069--equivalent to European Patent Publication No. 0311863--describes this type of device. The device has a hollow casing with a nozzle extending from one end, the other end of the casing being open. A piston extends towards the body of the casing from the nozzle and a cylinder containing a dose of the substance to be discharged is mounted on the piston. The piston has at least one discharge channel along its length communicating with the nozzle outlet. On both sides of the nozzle, the casing has rounded shoulders on which two fingers of the user's hand can rest. The device is thus generally oval in plan view. Two opposite sides of the casing have recesses so that the thumb of the user's hand can extend across the shorter dimension of the casing, in contact with the cylinder.
Thus, to use the device, the user simply holds it in one hand with the nozzle at one nasal cavity and presses the container with his or her thumb. Since the volume of the container is known, since the container is filled with a predetermined amount of the substance, and since the pump stroke of the cylinder is defined by the device, a unit dose of the pharmaceutical substance can be reliably and easily administered. The device is disposable after use.
Although the device is relatively simply constructed and is easy to use, a disadvantage does arise from the simple construction. The disadvantage is that, since the discharge channel or channels through the piston communicate with the outside environment, the contents of the cylinder are not entirely closed off from the outside. There is therefore a possibility of loss of the contents of the cylinder over time through evaporation. There is also the problem of contamination, for example microbiological contamination, which is a particular disadvantage where pharmaceuticals are being dispensed. Thus, the device would also require hermetically sealed packaging, e.g. double foil blister packaging, which can make the pack large and cumbersome for the user to carry.
A solution to the problem of the open cylinder of the known device has been briefly mentioned by the proprietors of the above mentioned U.S. Pat. No. 4946069, namely Ing. Erich Pfeiffer GmbH & Co. KG, in U.S. Pat. No. 4921142--equivalent to European Patent Publication No. 218840. In these publications there is mentioned the possibility of the discharge channel being sealed by a membrane which is broken by the pressure inside the container when it is pushed onto the piston. In the equivalent German publication, DE-OS-3631341, there is also described the possibility of the membrane being broken by a penetrating element fitted in the container. However, since the seal is formed on the piston of the discharging device there remains the disadvantage that the container which holds the substance to be discharged can remain unsealed for a period of time before it is fitted onto the device. The potential for contamination of the contents of the container thus still remains.
Pfeiffer propose another solution in European Patent Publication No. 0388651. In this publication there is disclosed a device in which the cylinder has a central pin extending from its base along the central axis, the pin having a diameter slightly less than that of the central discharge channel of the piston. The pin, however, has a hollow flared end which, at least in theory, seals against the mouth of the discharge opening of the piston. Upon actuation by the user, the pin is forced into the discharge channel and the flared end is deformed inwardly, thereby allowing the contents of the cylinder to flow along the channel and out through the nozzle. In practice, it may be difficult to achieve a reliable seal with this arrangement, and the problem with respect to evaporation around the piston flanges is not wholly overcome. Again the container is not sealed for a time before it is fitted onto the discharge device.
In European Patent Publication No. 452728 (Coster) there is described similar type of discharge device which, like the above mentioned Pfeiffer proposal, has a membrane seal. The membrane is fitted immediately behind the nozzle opening and has a pre-formed slit which opens under a predetermined pressure.
A slightly different form of the device is described in European Patent Publication No. 407276 --(Valois) equivalent to Canadian Patent No. 2020425. In this device, the substance to be discharged is contained within the body of the device and is expelled by the user pressing a piston into the device. The substance, typically a powder, may be sealed off from the piston by means of a tearable partition and the piston can be formed with a penetrating member. Movement of the piston firstly increases pressure behind the partition and then the partition is broken by the penetrating member, the compressed air expelling the powder.
In a different art, syringes are known which have a membrane sealing the syringe barrel and a double ended discharge needle. In use, pressure on the plunger of the syringe moves the membrane towards the rear end of the needle, which then punctures the membrane, and further movement of the plunger discharges the contents
U.S. Pat. No. 4017007 (Ciba-Geigy) describes a dispenser which includes a single dose container having a compressed air inlet opening and a closable discharge orifice. The container can either be mounted on a piston pump separately or the container and the pump can be combined in an integral container pump assembly. The valve means includes a breakable diaphragm which is located at the junction of the inlet opening of the container and the compressed air outlet of the pump. A pin is mounted on the forward face of the piston of the pump. During compression, when the front face of the piston reaches the end of its stroke, the diaphragm is ruptured by the pin and the compressed air surges into the interior of the container to thereby expel the product out through the discharge orifice.
International Patent Publications Nos. WO91/12197 and WO91/12198 (CP Packaging) describe unit dose assemblies consisting of compressible tubes, sealed by a thin wall, and closed by caps. In both cases, the cap has an inner spike and when the cap is pushed onto the tube the thin wall is punctured to allow the contents to be dispersed. In the first case, the contents are dispersed through the spike, which is hollow, onto an applicator pad on the cap. In the second case, the cap is removed to allow the contents of the tube to be expelled.
European Patent Publication No. 282338 (Unidec) discloses a liquid dispenser comprising a compressible container and an applicator with an internal spike. When the container is compressed, a membrane which seals the container is forced onto the spike by means of the pressure inside the container. The contents are then expelled through the applicator.

Single dose dispenser having a piercing member


Knitting fabric take-down devices, located in front and back of and facing each other across a knitting fabric passageway formed under a needle bed gap between at least a pair of front and back needle beds of a flat knitting machine, for taking down a knitting fabric. Each of the knitting fabric take-down device includes a front knitting fabric take-down mechanism for capturing only a front part of the knitting fabric in the knitting fabric passageway and taking it down; a back knitting fabric take-down mechanism for capturing only a back part of the knitting fabric and taking it down; and a take-down force adjusting mechanism for adjusting a take-down force of each of the knitting fabric take-down mechanism. The front and back knitting fabric take-down mechanism each comprises a plurality of take-down members which are arranged along a longitudinal direction of the needle beds and are each adapted to be sequentially or individually actuated to take down the knitting fabric in the knitting fabric take-down operation.

(1) Field of the Invention
The present invention relates to a knitting fabric take-down device located under a needle bed gap between front and back needle beds of a flat knitting machine and also relates to a knitting fabric take-down device for taking down a double-wall-in-section knitting fabric having a front knitting fabric wall and a back knitting fabric wall, like a tubular knitting fabric, by use of the flat knitting machine.
(2) Description of the Prior Art
Generally, a flat knitting machine has at least a pair of spaced apart, opposite, front and back needle beds and knitting fabric take-down devices, located under the needle bed gap between the needle beds, for taking down a knitting fabric knitted with needles on the needle beds. A general type of knitting fabric take-down device for taking down a knitted fabric, especially for taking it down uniformly over a whole width of the knitting fabric, to deal with a formation knitting and a stereoscopic knitting is disclosed in, for example, Japanese Patent Publication No. Sho 57(1982)-55815.
With the device disclosed by the abovesaid prior art, a plurality of driving flaps (hereinafter it is referred to as "take-down members") are arranged in parallel at one side of the knitting fabric take-down devices facing each other across a knitting fabric passageway under the needle bed gap, and knitting fabric contacting surfaces are arranged at the other side, facing the driving flaps (take-down members) across the knitting fabric passageway. The knitting fabric is held between the take-down members and the knitting fabric contacting surfaces. The take-down members, which act as a holding portion subjected to a spring preload to be swingable within a limited range around a pivot shaft extending in a vertical direction of the needle beds, are selectively operated by a raising and lowering device so that when the take-down members are lowered, the knitted fabric can be pulled out downward along the knitting fabric contacting surfaces, and held between the free edges of the take-down members and the knitting fabric contacting surfaces.
This type of device has an advantage of enabling the knitted fabric to be flexibly taken down by controlling the drive of the respective take-down members, with the result that even a stereoscopic knitting fabric can be surely taken down in a desired uniform state along its entire knitting width.
However, in this conventional type take-down device, since the take-down members are always subjected to the preload from the springs, they are pressed against the knitting fabric contacting surfaces, whether or not the knitting fabric exists between the take-down members and the knitting fabric contacting surfaces. This structure by which the take-down members are forced to be always in the above positions can present problems when the knitting fabric is moved transversely in racking operations of the needle beds or transference operations of knitted loops or when holes are formed in specified locations of the knitting fabric.
Also, Japanese Laid-Open Patent Application No. Hei 2(1990)-210046 discloses a knitting machine with a knitting-out device movable up and down along a knitting fabric passageway, and it is capable of capturing the first knitting part of the knitting fabric and transferring the same to the take-down device arranged thereunder. However, this known knitting machine can present a problem in that it is difficult to provide a passageway for the knitting-out device.
Recently, a producing method, what is called a non-sewn knit, has attracted attention, in which sleeves or front and back bodies of a knitted clothing such as a sweater are knitted together at their side edges in a knitting width direction, so as to be formed into a tubular form with a double wall in section, thereby omitting the sewing process after knitting and obtaining a fully stretchable knitting clothing.
However, the front side body and the back side body knitted into a tubular body are not necessarily symmetric about the form and the number of courses of loops, for the reasons that the front and back knitted fabrics must be taken down according to their form and number of courses of loops. With this conventional type take-down device designed to sandwich the knitting fabric between front and back, there was a disadvantage that the knitting fabric could not be taken down adequately.

Knitting fabric take-down device of flat knitting machine


A system, method, and computer program product for tracking user participation in a shared media session. A shared media session is connected to, where the shared media session includes a plurality of participants. A first identity is determined for a first participant with a first confidence level. The first participant is identified as the first identity if the first confidence level is above a first threshold. An amount of participation is tracked for the first identity. The amount of participation by the first identity is displayed on an electronic calendar for the shared media session to the plurality of participants.

The present invention relates to tracking user participation in a shared media session. Meetings between employees, partners, or any individuals working together are an important component to any successful business organization. As such, tracking the behavior of individuals during such meetings has become increasingly important.
In large corporations, employees can spend much of their day on conference calls or in other types of media inspired meetings. As such, it would be beneficial to determine which meetings hold high value for a given employee, or for the corporation as a whole.

This patent is subject to a terminal disclaimer.

Tracking participation in a shared media session


Pharmaceutical compositions comprising 1-(3,4-dimethoxyphenyl)-4-methyl-5-ethyl-7-methoxy-8-hydroxy-5H-2,3-benzodiazepine; or a pharmaceutically acceptable salt thereof. The compositions are used for treating, preventing or delaying the onset of disorders mediated by LTB4, TXA2 or adenosine.

2,3-Benzodiazepines
Certain 2,3-benzodiazepines have been explored extensively for their potent CNS modulating activity. Compounds such as tofisopam (Grandaxin®)(structure shown below, with the atom numbering system indicated), girisopam, and norisopam have demonstrated substantial anxiolytic and antipsychotic activity.

Tofisopam has been shown in humans to have an activity profile that is significantly different from that of widely used 1,4-benzodiazepine (BZ) anxiolytics such as diazepam (Valium®) and chlordiazepepoxide (Librium®). The 1,4-benzodiazepines, in addition to having sedative-hypnotic activity, also possess muscle relaxant and anticonvulsant properties that, though therapeutically useful in some disease states, are nonetheless potentially untoward side effects. Thus the 1,4-benzodiazepines, though safe when administered alone, may be dangerous in combination with other CNS drugs, including alcohol.
Tofisopam, in contrast, is a non-sedative anxiolytic that has no appreciable sedative, muscle relaxant or anticonvulsant properties (Horvath et al., Progress in Neurobiology, 60 (2000), 309-342). In clinical studies, tofisopam improved rather than impaired psychomotor performance and showed no interaction with ethanol (Id.). These observations comport with data that show that tofisopam does not interact with central BZ receptors and binds only weakly to peripheral BZ receptors.
Other 2,3-benzodiazepines that are structurally similar to tofisopam have been investigated and shown to have varying activity profiles. For example, GYKI-52466 and GYKI-53655 (structures shown below) act as noncompetitive glutamate antagonists at the AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) site, and have demonstrated neuroprotective, muscle relaxant and anticonvulsant activity (Id.). Another group of 2,3-benzodiazepines that have been investigated are represented by the compound GYKI-52895, and show activity as selective dopamine uptake inhibitors with potential use in antidepressant and anti-Parkinsonism therapy.

Tofisopam is a racemic mixture of (R)- and (S)-enantiomers. This is due to the asymmetric carbon, i.e., a carbon with four different groups attached, at the 5-position of the benzodiazepine ring.
The molecular structure and conformational properties of tofisopam have been determined by NMR, CD and x-ray crystallography (Visy et al., Chirality 1:271-275 (1989)). The 2,3-diazepine ring exists as two conformers. The major conformers, (+)R and (−)S have the 5-ethyl group in a quasi-equatorial position, while in the minor conformers, (−)R and (+)S, the 5-ethyl group is positioned quasi-axially. Thus, racemic tofisopam may exist as four molecular species, i.e., two enantiomers, each of which exists in two conformations. The sign of the optical rotation is reversed upon inversion of the diazepine ring from one conformer to the other. In crystal form, tofisopam exists only as the major conformations, with dextrorotatory tofisopam being of the (R) absolute configuration. (Toth et al., J. Heterocyclic Chem., 20:709-713 (1983); Fogassy et al., Bioorganic Heterocycles, Van der Plas, H. C., Ötvös, L, Simongi, M., eds. Budapest Amsterdam: Akademia; Kiado-Elsevier, 229:233 (1984)).
Differential binding of the (+) and (−) conformers of 2,3-benzodiazepines generally, has been reported for tofisopam in binding studies with human albumin (Simongi et al. Biochem. Pharm., 32(12), 1917-1920, 1983). The (+) and (−) conformers of tofisopam have also been reported as existing in an equilibrium (Zsila et al., Journal of Liquid Chromatography & Related Technologies, 22(5), 713-719, 1999; and references therein).
The optically pure (R)-enantiomer of tofisopam (R)-1-(3,4-dimethoxyphenyl)-4-methyl-5-ethyl-7,8-dimethoxy-5H-2,3-benzodiazepine) has been isolated and shown to possess the nonsedative anxiolytic activity of the racemic mixture. See U.S. Pat. No. 6,080,736; the entire disclosure of which is incorporated herein by reference.
Metabolism of Tofisopam
Tofisopam is metabolized in human, rat, dog, monkey and rabbit to one or more of six major metabolites, depending on the host species:
Compound #Compound Name11-(3,4-dimethoxyphenyl)-4-methyl-5-ethyl-7-hydroxy-8-methoxy-5H-2,3-benzodiazepine21-(3,4-dimethoxyphenyl)-4-methyl-5-ethyl-7-methoxy-8-hydroxy-5H-2,3-benzodiazepine31-(3-methoxy-4-hydroxyphenyl)-4-methyl-5-ethyl-7,8-dimethoxy-5H-2,3-benzodiazepine41-(3-hydroxy-4-methoxyphenyl)-4-methyl-5-ethyl-7,8-dimethoxy-5H-2,3-benzodiazepine51-(3-methoxy-4-hydroxyphenyl)-4-methyl-5-ethyl-7-hydroxy-8-methoxy-5H-2,3-benzodiazepine61-(3-hydroxy-4-methoxyphenyl)-4-methyl-5-ethyl-7-hydroxy-8-methoxy-5H-2,3-benzodiazepineSee Tomori et al., Journal of Chromatography, 241 (1982), p. 89-99.
Of the compounds named above, Compounds 1, 3 and 5 have been identified as metabolites in humans. These compounds have been synthesized and tested in certain pharmacological assays. C. Ito, "Behavioral Pharmacological Study on the Structure Activity Relationship of Benzodiazepine Derivatives: With Particular Reference to the Activity of 2,3-Benzodiazepine," J. Tokyo Med. College, 39:369-384 (1981)._In an assay of inhibition of aggression in mice, Compound 1 and 3 showed 0% inhibition of aggression and Compound 5 showed a 28.6% inhibition of aggression. In an assay of muricide (mouse killing behavior) in rats, Compound 3 exhibited 0% inhibition of muricide while Compounds 1 and 5 each exhibited a 20% inhibition of muricide. In assays testing for anti-noradrenergic effects, Compound 1 exhibited no effect, while Compounds 3 and 5 demonstrated measurable activity.
Compounds 1, 3, 5 and 6 are also disclosed in U.S. Pat. No. 4,322,346, the entire disclosure of which is incorporated herein by reference. Compound 3 is reported therein to demonstrate narcosis-potentiating activity in mice.
Leukotriene B4 (LTB4)
Leukotrienes, along with prostaglandins and thromboxanes, are products of arachidonic acid metabolism. LTB4 is produced by leukocytes, particularly macrophage and monocytes upon activation by immune complexes, phagocytosis or other stimuli. LTB4 is a potent chemotactic agent that stimulates neutrophil and macrophage migration (chemotaxis) to sites of inflammation. The structure of LTB4 is shown below.

The known pathophysiological responses of LTB4 include: induction of potent neutrophil chemotactic activity, promotion of adhesion of polymorphonuclear leukocytes (PMN) to vasculature, increase in vascular permeability, stimulation of the release of lysosomal enzymes, by PMN. The pro-inflammatory action of LTB4 has been demonstrated in vivo, wherein topical LTB4 on human skin promotes the infiltration of PMN and other inflammatory cells. Intradermal injection of LTB4 induces accumulation of neutrophils at the injection site. Intravenous injection of LTB4 causes rapid but transient neutropenia (Kingsbury et al., J. Med. Chem., 1993, 36, 3308-3320; and references cited therein).
In addition, the presence of physiologically relevant LTB4 concentration at inflammatory sites has been associated with, for example, disease states such as psoriasis, asthma and active gout; in colonic mucosa associated with inflammatory bowel disease; in synovial fluid from patients with active rheumatoid arthritis; and in reperfusion injury. All of these observations together support the involvement of LTB4 in human inflammatory disease (Kingsbury et al, and Griffeths et al., Proc. Natl. Acad. Sci. Vol. 92, pp517-521, January 1995; and references cited therein.).
Inflammatory Disorders
Crohn's disease and ulcerative colitis, collectively referred to as inflammatory bowel disease (IBD), are chronic recurrent inflammatory diseases of unclear etiology, affecting the small intestine and colon. Inflammatory bowel disease (IBD) can involve either or both the small and large bowel. These disorders fall into the category of "idiopathic" inflammatory bowel disease because the etiology for them is unknown.
Pathologic findings are generally not specific, although they may suggest a particular form of IBD. "Active" IBD is characterized by acute inflammation. "Chronic" IBD is characterized by architectural changes of crypt distortion and scarring. The term "crypt" refers to a deep pit that protrudes down into the connective tissue surrounding the small intestine. Crypt abscesses (active IBD characterized by the presence of neutrophils in crypt lumens) can occur in many forms of IBD, not just ulcerative colitis. Under normal conditions the epithelium at the base of the crypt is the site of stem cell proliferation and the differentiated cells move upwards and are shed 3-5 days later at the tips of the villi. This normal process, necessary for proper bowel function, is interrupted by IBD
Ulcerative colitis (UC) involves the colon as a diffuse mucosal disease with distal predominance. The rectum is virtually always involved, and additional portions of colon may be involved extending proximally from the rectum in a continuous pattern. Most often ulcerative colitis occurs in young people 15 to 40 years of age. Ulcerative colitis occurs only in the inner lining of the colon (large intestine) or rectum. When it is localized in the rectum, it is called "proctitis."
Crohn's Disease is a chronic inflammatory disease that has periods of remission (time when person feels well) and relapse (when a person feels ill). Crohn's disease is an inflammation and ulceration process that occurs in the deep layers of the intestinal wall. The most common areas affected are the lower part of the small intestine, called the ileum, and the first part of the colon. This type of Crohn's disease is called ileocolitis. Crohn's disease can infrequently affect any part of the upper gastrointestinal tract. Aphthous ulcers, which are similar to cold sores, are common. Ulcers can also occur in the esophagus, stomach and duodenum.
Therapy for IBD has historically included administration of corticosteroids. However drawbacks of long term corticosteroid therapy include masking (or induction) of intestinal perforation, osteonecrosis and metabolic bone disease. Additional problems relate to development of corticosteroid dependency (Habnauer, New England Journal of Medicine, 334(13), p 841-848, 1996). Aminosalicylates such as sulfasalazine and mesalamine have been used to treat mild or moderately active ulcerative colitis and Crohn's Disease, and to maintain remission (Id at 843). Immunomodulatory drugs such as azathioprine and mercaptopurine have been used in long term treatment for patients with IBD. Common complications with both of these drugs include pancreatitis, which occurs with an incidence of 3-15% of patients, and bone marrow suppression, which requires regular monitoring. More potent immunosuppressive drugs such as cyclosporine and methotrexate have been employed, but toxicity of these drugs limits their use to specific situations of refractory disease states. Other therapeutic approaches include antibiotic therapy and nutritional therapy. Often, therapy involves a combination of the above-described drug therapies in addition to surgical resection of the bowel.
There is no cure for IBD. Ultimately, the chronic and progressive nature of IBD demands a long-term treatment that maximizes the local antiinflammatory effect while minimizing the global systemic effect on the immune system.
Chronic inflammatory disorders such as Crohn's Disease typically demonstrate periods of remission between intervals when the inflammatory is active and requires acute treatment. This is an example of a circumstance wherein it is known beforehand that an individual will develop, or is likely to develop an inflammatory disorder.
Another chronic inflammatory condition believed to be mediated by LTB4 is psoriasis. Psoriasis is a chronic, recurrent, papulosquamous plaque on areas of trauma such as the elbow, knee or scalp, though it may appear elsewhere on the skin. Psoriasis may coexist with lupus erythematosis in some individuals. Current treatments include topical administration of psoralens. "Psoralens" refers to a group of substances found in many different plants, especially psoralea corylifolia. Psoralens interact with nucleic acids and are also used as research tools. Psoriasis is also treated by long-wave ultraviolet radiation. Neither treatment cures or prevents recurrence of psoriasis symptoms.
Another chronic inflammatory disorder believed to be mediated by LTB4 is rheumatoid arthritis, which is an autoimmune disease of the joints. Rheumatoid arthritis is characterized by the following criteria 1-7, wherein criteria 1-4 are present for more than 6 weeks: (1) morning stiffness in and around joints lasting at least one hour before maximum improvement; (2) soft tissue swelling (arthritis) of three or more joints observed by a physician; (3) swelling (arthritis) of the proximal interphalangeal, metacarpal phalangeal, or wrist joints; (4) symmetric swelling; (5) rheumatoid nodules, i.e., a granulomatous lesion characterized by central necrosis encircled by a palisade of monocytes and an exterior mantle of lymphocytic infiltrate. These lesions present as subcutaneous nodules, especially at pressure points such as the elbow in individuals with rheumatoid arthritis or other rheumatoid disorders; (6) presence of rheumatoid factors, i.e., an autoantibody in the serum of individuals with rheumatoid arthritis; and (7) roentgenographic erosions, i.e., joint lesions visible on an X-ray.
Rheumatoid arthritis is a chronic disorder for which there is no known cure. The major goals of treatment of rheumatoid arthritis are to reduce pain and discomfort, prevent deformities and loss of joint function, and maintain a productive and active life. Inflammation must be suppressed and mechanical and structural abnormalities corrected or compensated by assistive devices. Treatment options include reduction of joint stress, physical and occupational therapy, drug therapy, and surgical intervention.
There are three general classes of drugs commonly used in the treatment of rheumatoid arthritis: non-steroidal anti-inflammatory agents (NSAID's), corticosteroids, and remittive agents or disease modifying anti-rheumatic drugs (DMARD's). NSAID's and corticosteroids have a short onset of action while DMARD's can take several weeks or months to demonstrate a clinical effect. DMARD's include leflunomide (Arava™), etanercept (Enbrel™), infliximab (Remicade™), antimalarials, methotrexate, gold salts, sulfasalazine, d-penicillamine, cyclosporin A, cyclophosphamide and azathioprine. Because cartilage damage and bony erosions frequently occur within the first two years, rheumatologists now move more aggressively to a DMARD agent.
Treatment of rheumatoid arthritis by chronic administration of a corticosteroid involves the same side effect profile as discussed regarding IBD above. Chronic administration of NSAID's also produces side effects. The most common toxicity of NSAID's is gastrointestinal disturbance. Because prostaglandins play a role in the regulation of renal blood flow and maintenance of glomerular filtration, NSAID's can impair renal function in certain patients. Weight gain and cushingoid appearance is a frequent problem and source of patient complaints. Recent studies have raised concern over the increased cardiovascular risk and accelerated osteoporosis associated with low dose prednisone particularly at doses above 10 mg daily.
Gout is another inflammatory disorder believed to be mediated by LTB4. Gout is characterized by a disturbance of uric-acid metabolism occurring chiefly in males. Gout is characterized by painful inflammation of the joints, especially of the feet and hands, and arthritic attacks resulting from elevated levels of uric acid in the blood and the deposition of urate crystals around the joints. The condition can become chronic and result in deformity.
Gout can present another circumstance wherein it is known beforehand that an individual will or is likely to develop an inflammatory disorder. In the instance of patients undergoing radiotherapy or chemotherapy, the individual may experience a dramatic rise in serum uric acid levels associated with lysis of the tumor mass. Such large increases in uric acid can deposit urate crystals in synovial fluid of joints thereby causing the inflammatory disorder, gout. When such a rise in serum uric acid levels is known to be likely, prophylaxis with an LTB4 antagonist can act to prevent the inflammatory condition of gout.
Radiation-induced gastrointestinal inflammation is another inflammatory disorder believed to be mediated by LTB4. Radiation works by damaging cancer cells, but unfortunately can damage non-diseased tissue as well, causing a typical inflammatory reaction in response. Therapeutic radiation is thus generally applied to a defined area of the subject's body which contains abnormal proliferative tissue in order to maximize the dose absorbed by the abnormal tissue and minimize the dose absorbed by the nearby normal tissue. However, it is difficult (if not impossible) to selectively administer therapeutic ionizing radiation to the abnormal tissue. Thus, normal tissue proximate to the abnormal tissue is also exposed to potentially damaging doses of ionizing radiation throughout the course of treatment. Moreover, some treatments that require exposure of the subject's entire body to the radiation, in a procedure called "total body irradiation", or "TBI." The efficacy of radiotherapeutic techniques in destroying abnormal proliferative cells is therefore necessarily balanced by the associated cytotoxic effects on nearby normal cells.
After or during a course of radiotherapy, LTB4-mediated inflammatory processes may be triggered, causing damage to the bowel, and leading to sloughing of the cells of the inner lining of the GI tract. Radiation-induced gastrointestinal inflammation can present another circumstance wherein it is known beforehand that an individual will or is likely to develop an inflammatory disorder. In the instance of patients undergoing radiotherapy, the inflammation, damage and sloughing of the gastrointestinal tract is a predictable side effect of the radiotherapy.
New antiinflammatory agents are needed which are useful in the treatment of inflammatory disorders such as IBD, rheumatoid arthritis, gout, psoriasis and radiation-induced gastrointestinal inflammation. In particular, agents are needed that are appropriate for chronic long-term use in treatment. In addition, agents are needed that are useful in the prevention of LTB4-mediated inflammatory disorders that occur secondary to observable events such as ionizing radiation therapy.
Thromboxane A2
Thromboxane A2 (TXA2), like LTB4, is a product of the arachidonic acid metabolic pathway. TXA2 induces a variety of differential cellular responses including platelet aggregation, contraction of vascular and bronchial smooth muscle cells (SMC), potentiation of hypertrophic and mitogenic responses in vascular SMC and endothelial cells.
TXA2 is considered to be an important mediator of asthma because it can induce contraction of airway smooth muscle, and because it has been implicated in airway hyperresponsiveness in animal models wherein increased airway reactivity was induced by allergens, platelet-activating factor (PAF), LTC4, LTD4, LTB4, bradykinin, endothelin, endotoxin and ozone. (See J. Dogne et al., Expert Opin. Investig. Drugs (2002), 11(2), and references cited therein, the entire disclosures of which are incorporated herein by reference.)
TXA2 has also been implicated in the pathophysiology of radicular pain induced by hemeated nucleus pulposis. A study in a rat model examined the role of TXA2 (and LTB4) in the hyperalgesia induced by application of nucleus pulposus to the lumbar nerve root in the rat. A TXA2 synthetase inhibitor, injected into the epidural space, decreased mechanical hyperalgesia at both three and seven days after epidural injection. There were no significant differences in sensitivity to noxious thermal stimuli following application of the nucleus pulposus or an epidural injection. Epidural injection of TXA2 synthetase inhibitor may attenuate the painful radiculopathy due to lumbar disc herniation.
TXA2 has further been implicated as an in vivo mediator of fibroblast growth factor (FGF)-stimulated angiogenesis. See, T. Daniel et al., Cancer Research, 59, 4574-4577, Sep. 15, 1999, the entire disclosure of which is incorporated herein by reference. Thromboxane synthase inhibitors have further been shown to inhibit metastasis of lung carcinoma in a mouse model, thus demonstrating the involvement of TXA2 in angiogenesis and tumor metastasis. See, D. Nie et al., Biochem. Biophys. Res. Commun., 2000, 267(1), p. 245-251, the entire disclosure of which is incorporated herein by reference.
TXA2 is also believed to possess anticoagulant activity. See Schenk et al., "Antiplatelet and anticoagulant effects of "HN-11 500," a selective thromboxane receptor antagonist," Thromb. Res. 2001 Jul. 15; 103(2):79-91.
Anticoagulant has potential therapeutic value in chronic inflammation according to a model associating chronic inflammatory disorders with a coagulation protein defect is termed immune system activation of coagulation (ISAC). The model proposes that a majority of individuals diagnosed with certain chronic inflammatory illnesses may, based on clinical criteria, be potentially defined as or involve AntiPhospholipid Antibody Syndrome (APS)-with the endothelial cell (EC) as the disease target. These patients have a hypercoagulable, state demonstrated by increased markers of coagulation activation and increased blood viscosity due to the generation of Soluble Fibrin Monomer (SFM). The CFS/FM process and related processes may be triggered by a variety of pathogens (CMV, HHV6, Mycoplasma, Chlamydia pneumonia, etc.), or some vaccines, resulting in pathogen-mediated immune activation that induces antibodies which cross react with EC protective proteins B2GPI & Annexin V. These antibodies dislodge the protective proteins from EC surfaces, exposing PhosphatidylSerine (PS) on the EC surfaces in capillary beds.
Pathogens induce inflammatory responses which include cytokine modulation of EC to down regulate the antithrombotic environment (ThromboModulin, tPA) in favor of prothrombotic expression of Tissue Factor (TF). TF and PS exposure allows binding of the coagulation tenase and prothombinase complexes to EC surfaces. This results in thrombin generation leading to SFM formation. SFM dimerizes easily, increasing blood viscosity and precipitating out on EC surfaces as fibrin(oid) deposition, creating local ischemia and pathology, blocking nutrient and oxygen delivery in the microcirculation. A blood clot does not form because there is not enough of a thrombin burst to activate Factor XIII to cross link the fibrin into a clot.
A hereditary defect in a coagulation regulatory protein; such as protein C, protein S. Factor VL, prothrombin gene mutation, Heparin Cofactor II, tPA, PAI-1, Lp(a), or elevated Factor II, X, XII, or homacysteine is predispositional in greater than 75% of patients. Because this hypercoagulability does not result in an immediate thrombosis (100% occlusion), but rather in fibrin deposition (50-95%), it has been suggested that an appropriate name for this antiphospholipid antibody process would be Immune System Activation of Coagulation (ISAC) syndrome.
The ISAC model provides an explanation for the therapeutic benefits reported with low dose anticoagulant therapy (heparin or warfarin) in some of these patients. Diagnoses with published associations include: Chronic Fatigue. Syndrome/Fibromyalgia (CFS/FM), Infertility (Recurrent Fetal Loss and Fetal Wastage Syndromes), Osteonecrosis of the Jaw, Multiple Sclerosis (MS), Depression and Autism. Diagnoses under investigation include: Crohn's Disease and Inflammatory Bowel Disease (IBD), Late Lyme Disease, Sjogren's Syndrome (SS), Transient Ischemic Attack (TIA), Attention Deficit Disorder (ADD) and Parkinson's Disease. See Berg et al., "Chronic Fatigue Syndrome &/or Fibromyalgia as a variation of antiphospholipid antibody syndrome (APS): An explanatory model and approach to laboratory diagnosis," Blood Coagulation and Fibrinolysis, 1999, 10:435-438.
New TXA2 agents are needed which may be useful in the treatment of TXA2-mediated disorders such as asthma, pain, tumors in which angiogenesis associated with the tumor is mediated by TXA2, and in chronic inflammatory illnesses such as, for example Chronic Fatigue Syndrome/Fibromyalgia, IBD, Crohn's Disease, late Lyme disease and IBD.
Adenosine
Adenosine is a multi-purpose signal molecule that regulates a variety of cellular functions and is released under conditions of physiological stress. The actions of adenosine are mediated through four receptor subtypes (A1, A2A, A2B and A3).
Adenosine acts at the A1 receptor subtype to cause decreases in heart rate, force of contraction, and responsiveness to adrenaline, and at the A2A receptor subtype to cause dilation of coronary arteries to enhance blood flow to the heart. In the central nervous system (CNS), adenosine, released during episodes of epilepsy or as a consequence of hypoxia or stroke, acts at the A1 receptor subtype to exert a neuroprotective action by decreasing electrical excitability, inhibiting the release of excitatory amino acids (EAA) and acts at the A2A receptor subtype to increase cerebral blood flow.
In the kidney, A1 receptors located on preglomerular vessels and in the tubule are involved in the regulation of glomerular filtration. Whole body fluid balance is strongly dependent on the ability of the kidney to maintain stable glomerular filtration. Several antagonists to A1 receptors have been developed. These agents generate excess fluid (diuresis) and sodium (natriuresis) excretion in control animals and animal models of fluid retention, as well as in normal and oedematous humans. In both animals and humans, these effects are generally achieved without major changes in glomerular filtration. Animal studies have confirmed the location of A1 receptors in relevant tissue sites in the kidney. More highly selective antagonists for A1 receptors are regularly developed, improving their use in fluid retaining disorders. See Welch W J, "Adenosine type 1 receptor antagonists in fluid retaining disorders," Expert Opin Investig Drugs 2002 November; 11(11):1553-62.
Adenosine, whether endogenously released or added exogenously, is a potent antiinflammatory agent. Adenosine mediates its antiinflammatory effects via interaction with specific receptors (A1, A2a, A2b and A3) on the surface of inflammatory cells. Receptor-specific analogs of adenosine have been shown to increase the rate at which wounds heal. Am J Pathol 2002 June; 160(6):2009-18.
Adenosine promotes wound healing and mediates angiogenesis in response to tissue injury via occupancy of A2A receptors. See Montesinos et al., "Adenosine promotes wound healing and mediates angiogenesis in response to tissue injury via occupancy of A2A receptors," Am. J. Pathol. 2002 June; 160(6):2009-18, and Victor-Vega et al., "Adenosine A2A receptor agonists promote more rapid wound healing than recombinant human platelet-derived growth factor (Becaplermin gel)," Inflammation 2002 February; 26(1):19-24.
Adenosine is believed to mediate gastrointestinal relaxation through two different inhibitory receptor subtypes; A1 receptors on the enteric neuron and A2B receptor on the smooth muscle in the guinea-pig distal colon. See Kadowaki et al., "Molecular identification and pharmacological characterization of adenosine receptors in the guinea-pig colon," Br. J. Pharmacol. 2000 March; 129(5):871-6.
Adenosine binds to the receptor subtypes and activates the receptors to produce G proteins. G proteins themselves can either stimulate (Gs) or inhibit (Gi) the enzyme adenylate cyclase so as to generate or prevent the manufacture of cyclic AMP. In addition, G coupled proteins can open potassium channels in cardiac tissue, resulting in depression of cardiac electrical activity. The following Table enumerates adenosine activity on different tissues.
TABLE 1Effect of Adenosine Receptor ActivationReceptorSubtypeHeartCNSKidneyOtherA1Heart Rhythm-Wakefulness-Anti-Anti-lipolyticdecrease indecrease indiuresisinsulin enhancerheart rate,electricalAntihypertensiveforce of atrialexcitabilityWound healingcontraction,and inhibitionHair growthandof excitatoryresponsivenessamino acidto adrenaline(EAA) releaseA2ARegulatesAnti-Wound healingblood vesselInflammatory-tone-dilationcerebral bloodof theflow increasecoronaryarteriessupplyingbloodto the heartmuscleA2BAllergicResponses GITract RelaxationAnti-InflammatoryA3Cardio-AllergicprotectiveResponses
Adenosine helps protect the heart muscle from damage when myocardial ischemia occurs. See Maddock H L et al., "Adenosine A3 receptor activation protects the myocardium from reperfusion/reoxygenation injury," Am. J. Physiol. Heart. Circ. Physiol. 2002 October; 283(4):H1307-13. When this happens, adenosine is released in the heart vessels and myocardium and acts to: enlarge vessels to increase blood and oxygen supply; improve energy supply for the myocardium and decrease energy needs; produces angina pectoris, the signature warning symptom of myocardial ischemia. Adenosine has a depressant effect on sinoatrial node activity and thus exerts an arrythmogenic effect. See Belhassen B., "Adenosine triphosphate in cardiac arrhythmias: from therapeutic to diagnostic use," Pacing Clin. Electrophysiol. 2002 January; 25(1):98-102; and Meester, B J et al., "Pharmacological classification of adenosine receptors in the sinoatrial and atrioventricular nodes of the guinea-pig," Br. J. Pharmacol. 1998 June; 124(4):685-92. This makes adenosine effective in treating tachyarrhythmias involving the sinoatrial node. Ongoing research suggests that adenosine will be important in protecting the heart during open-heart surgery. See Safran N et al., "Cardioprotective effects of adenosine A1 and A3 receptor activation during hypoxia in isolated rat cardiac myocytes," Mol. Cell. Biochem. 2001 January; 217(1-2): 143-52.
Adenosine signaling has also been implicated to play a role in various types of lung inflammation including those seen in asthma and chronic obstructive pulmonary disease (COPD). Asthma is an inflammatory disease of the lung characterized by acute nonspecific airway hyperreactivity in association with chronic pulmonary inflammation. The disease effects approximately 10% of children and 6% of adults in the United States alone, and its incidence is increasing at an alarming rate. COPD is a progressive disease process that most commonly results from smoking. COPD is characterized by difficulty breathing, wheezing and a chronic cough.
The major observations are that adenosine levels are elevated in the lungs of asthmatics, inhaled adenosine causes bronchoconstriction in asthmatics but not normal subjects, the pattern of adenosine receptor expression is altered in the lung of asthmatics, and theophylline, an adenosine receptor antagonist, has well recognized benefits in the treatment of asthma. In addition to this clinical evidence, there are many in vitro studies in both human and animal cells that implicate adenosine as a modulator of inflammatory processes that are central to asthma. Most notable are adenosine's ability to enhance mediator release from mast cells, and to influence eosinophil survival and chemotaxis. However, despite these lines of evidence, a clear implication for adenosine signaling in asthma, and the cell types and mechanisms involved, are unclear.
Adenosine is also a modulator of dopamine mediated motor responses. A new therapeutic approach to the treatment of Parkinson's disease is to synergistically modulate the effects of dopamine agonists in order to decrease the dosages of drugs used. Recent research suggests a potential positive role of A2A antagonists in Parkinson's disease. See "Adenosine Receptors and Parkinson's Disease," Hiroshi Kase (Editor), Peter J. Richardson (Editor), Peter Jenner (Editor), Academic Press; ISBN: 0124004059; 1st edition (Jan. 15, 2000). The current chronic treatment of Parkinson's disease with L-DOPA causes important complication as motor fluctuations and dyskinesias, thus new agents are needed that adequately treat Parkinson's Disease without concomitant dyskinetic side effects.
Adenosine has also been investigated as a potential mediator in regeneration of hematopoietic progenitor cells in mouse models of severe myelosuppression. In the study, drugs that elevate extracellular adenosine were shown to modulate regeneration from severe myelosuppression resulting from combined exposure of the animals to ionizing radiation and carboplatin. In the model, elevation of extracellular adenosine was induced by joint administration of dipyridamole (DP), a drug inhibiting the cellular uptake of adenosine, and adenosine monophosphate (AMP), serving as an adenosine prodrug. The test drugs were administered in a 4-day treatment regimen starting on day 3 after induction of myelosuppression. (The drug regimen was tested with and without co-administration of granulocyte colony stimulating factor.) The effects of the drug treatments on progenitor cells were reflected in the peripheral blood in later time intervals of days 15 and 20 after induction of myelosuppression, especially as significantly elevated numbers of granulocytes and less pronounced elevation of lymphocytes and erythrocytes. The results substantiate the potential of drugs elevating extracellular adenosine for clinical utilization in myelosuppressive states, e.g. those accompanying oncological radio- and chemotherapy.
New agents are needed that selectively act at specific adenosine receptors and may thus which be useful in the treatment of adenosine-mediated disorders. Such disorders include, for example, neurological disorders such as epilepsy, stroke and cerebral ischemia; heart failure; and regeneration of hematopoietic cells associated with myelosuppression caused by ionizing radiation therapy of cancer chemotherapy.

Pharmaceutical composition of 1-(3,4-dimethoxyphenyl)-4-methyl-5-ethyl-7-methoxy-8-hydroxy-5H-2,3-benzodiazepine and uses thereof


A graphical user interface (GUI) tool for maintaining categorization schemes includes a categorization area that displays user-input fields which may be used to define a number of categories and a number of links that form a categorization scheme. The categorization scheme is organized to enable the computer-executed process to categorize the data. The categorization causes the selection of categories that correspond to the data. The selection is made by making a category determination beginning at the top level and proceeding to the children of categories that correspond to the data.

This document describes the use of graphical user interfaces (GUIs) to develop categorization schemes that computer-executed processes can use to categorize information, especially information contained in electronic messages. Exemplary processes that use categorization schemes may be designed to be executed on enterprise computing systems. One such enterprise computing system involves software for performing business processes that include responding to large volumes of inbound communications from customers. Such inbound communications are typically in the form of email messages, but they may also include other forms of inbound data, such as information entered by a customer over the Internet directly into a form located on an enterprise's website.
The productivity of an individual agent who is responsible for responding to large volumes of inbound communications affects the cost of performing that particular business process. However, in controlling the cost, the quality of the responses should be maintained so that the customer is well served. Thus, systems used to respond to inbound communications should provide high quality responses in an efficient manner.
Systems that respond to high volumes of inbound emails may be called Email Response Management Systems (ERMS). By using an enterprise computing system to automate some of the steps of an ERMS, the process of responding to a large volume of inbound e-mails can be made more efficient and cost-effective. As such, an enterprise can use ERMS software to enhance productivity.
To realize maximum productivity gains in the run-time environment, an enterprise usually must first customize the ERMS software in the design-time environment. Specifically, the ERMS software must be configured to perform the particular business process steps required by a particular enterprise. In addition, the enterprise must be able to reconfigure the ERMS software to reflect changes in the enterprise's business process steps over time. Thus, an enterprise should be able to customize and to maintain ERMS software so that productivity gains can be maximized.
When an enterprise uses ERMS software to handle a large volume of inbound email messages, for example, it is important for the enterprise to quickly and accurately determine how to respond to received messages. For one message, an appropriate response may be to ship a product to a customer. For other messages, an appropriate response may be to provide a map of driving directions, or to contact a subject matter expert who can answer detailed technical questions. Accordingly, some ERMS systems make classification decisions to determine how to respond to each received message.
That classification decision can be partially or wholly automated by using computer-executed processes to rapidly review the received messages and to determine how each should be classified so that the enterprise can take appropriate steps to respond to each message. The classification decision may be used, for example, to retrieve stored information from a database. The stored information may then be automatically suggested to an agent who is responsible for responding to the message. Because the content of the message has already been classified, only stored information that has predefined associations to the content of the message are suggested to the agent. As such, the agent does not need to manually search for the stored information, which would take more of the agent's time. In enterprises in which an agent is responsible for responding to many hundreds of messages each day, reducing the time required for an agent to respond to each message can significantly improve productivity and reduce the overall cost of responding to received messages.

User interface for maintaining categorization schemes


Electronic apparatus that stores user information received from a plurality of sensor that tracks user activities of a user over a specified time period. The electronic apparatus includes circuitry that detects a baseline emotion of the user based on the user information. The circuitry detects a dominant emotion of the user based on a change in an emotional characteristic of the user and the detected baseline emotion. The circuitry further recommends content and an emotional storyboard to the user based on specified emotion associated with the content, the baseline emotion, and the dominant emotion. The recommended content and the emotional storyboard is to induce a change in an emotional type of the dominant emotion from a negative emotional type to a positive emotional type.

Recent advancement in the field of human emotion detection have led to development of various technologies to monitor emotion of a user. Different users may respond differently to a given situation. Further, it is observed that an emotion is manifested on a user's face, behavior, or in presence of another individual in a given situation, is also specific for a specific user. Existing technology to detect emotions typically set blanket emotion detection rules that are almost the same for all users, and are thus not effective and accurate enough in emotion tracking for different users. Further, certain conventional solutions, which continuously monitor the emotion of a specific user, may lack an intelligent or enabling technology to improve an emotional state of the user. Thus, an advanced system may be desired to monitor emotion state of the user in detail, and provide technological solutions to improve the emotional state as well as health state specific to the user.
Further limitations and disadvantages of conventional and traditional approaches will become apparent to one of skill in the art, through comparison of described systems with some aspects of the present disclosure, as set forth in the remainder of the present application and with reference to the drawings.

Recommendation based on dominant emotion using user-specific baseline emotion and emotion analysis