A method and apparatus for compression molding plastic articles such as closures include a plurality of tools mounted in opposed pairs with the tools of each pair including opposed male and female mold sections. The tool pairs are mounted for motion in an endless path. The tool pairs and associated mold sections are closed during motion in the path for compression a molding charge in the mold cavity formed between the mold sections of each pair, and opening the mold cavity to release an article formed between the mold sections. A latch mechanism is associated with each pair of tools for holding the tools and mold sections in the closed position during motion in the path independent of the mechanism for closing the tools and mold halves. In this way, forces imparted to the mold halves and tools to hold the mold closed are isolated from the machine frame. The latch mechanism is selectively unlatched to permit opening of the mold halves and release of the article compression-molded between the mold halves.

U.S. Pat. No. 5,554,327, assigned to the assignee hereof, discloses a method and apparatus for compression molding plastic articles such as plastic closures. A plurality of tools are mounted in a circumferential array on a rotatable turret in a plurality of opposed coacting pairs. The tools of each pair carry opposed male and female mold sections that together, when closed, form a cavity mold for compression molding the desired articles. The turret is mounted on a machine frame that also carries cams for operative engagement with the tools for moving the tools of each pair toward each other during a portion of motion of the tools around the turret axis for compression molding articles between the tool pairs, and for moving the tool pairs away from each other during another portion of tooling travel for releasing articles molded between the tools. Fluid Cylinders are associated with each tool pair to provide a constant limiting molding force for each tool pair. U.S. Pat. No. 5,603,964, also assigned to the assignee hereof, discloses an apparatus for cutting and delivering extruded plastic gobs to the successive molds of the molding apparatus.
Although the methods and apparatuses disclosed in the noted patents address and overcome problems theretofore extant in the art, further improvements remain desirable. For example, it is desirable to hold the tools and mold halves in the closed and compressed position for as long as possible to improve cooling efficiency and part definition and quality during the molding process. However, it is also undesirable to employ the cams on the machine frame for holding the molds closed at normal molding force during most of the operating cycle because this would place undesirable forces on the machine frame and increase cam wear. For this reason, it is conventional practice to reduce mold forces during the curing portion of the cycle, with corresponding reduction in cooling efficiency and part quality. It is also desirable to improve machine efficiency by increasing the tooling density within a machine, and thereby increasing overall productivity per unit of plant floor space. However, employing conventional technology, this would only exacerbate the mold force problem, which in turn would require redesign of the machine frame, cams and bearings.
It is therefore a general object of the present invention to provide a method and apparatus for compression molding plastic articles that permit maintenance of full compression force on the mold elements during the forming and curing of the molded component while reducing wear on the cams that close the mold elements, and while reducing mold clamping reaction forces applied to the machine frame. Another object of the present invention is to provide a method and apparatus of the described character that achieve improved efficiency in terms of tooling density and utilization of plant floor space.

Apparatus for compression molding plastic articles


A method and apparatus is disclosed to analogically combine MR signals from RF coils to form multiple sets of analogically combined MR signals, and then digitally combine the analogically combined sets of MR signals to provide a digitized signal set for image reconstruction. The analogical combining followed by the digital combining of acquired MR signals improves intrinsic SNR of the RF coils used for data acquisition from a field-of-view (FOV) without compromising FOV for simultaneous MR data acquisition.

The present invention relates generally to magnetic resonance (MR) imaging and, more particularly, to a method and apparatus for multi-stage processing of channels of acquired MR signals to improve signal-to-noise ratio (SNR) without compromising field-of-view (FOV) for simultaneous data acquisition from an array of RF coils.
When a substance such as human tissue is subjected to a uniform magnetic field (polarizing field B0), the individual magnetic moments of the spins in the tissue attempt to align with this polarizing field, but precess about it in random order at their characteristic Larmor frequency. If the substance, or tissue, is subjected to a magnetic field (excitation field B1) which is in the x-y plane and which is near the Larmor frequency, the net aligned moment, or "longitudinal magnetization", Mz, may be rotated, or "tipped", into the x-y plane to produce a net transverse magnetic moment Mt. A signal is emitted by the excited spins after the excitation signal B1 is terminated and this signal may be received and processed to form an image.
When utilizing these signals to produce images, magnetic field gradients (Gx, Gy, and Gz) are employed. Typically, the region to be imaged is scanned by a sequence of measurement cycles in which these gradients vary according to the particular localization method being used. The resulting set of received NMR signals are digitized and processed to reconstruct the image using one of many well known reconstruction techniques.
For localized high-resolution MR imaging applications, an array of surface RF coils are typically used because a smaller or more localized RF coil has a higher B1 field and less loading-induced noise, which yields a higher intrinsic signal-to-noise ratio (SNR) for the receiver or coil. Generally, the following expression:
                    SNR        ≈                              V                                                                                ω              2                                    B1                                              4                            k                                                                                T                                                                                Δ                                                                                f                                                                                R                                                                    (                      Eqn            .                                                              1                    )                ;            where V is the sample volume, Δƒ is the receiver bandwidth, R is the total noise, may be used to define or quantify the SNR associated with a particular RF coil or receiver of an RF receiver coil array or system. As one skilled in the art will appreciate, as SNR decreases, the diagnostic value of the final reconstructed image also decreases. That is, as SNR decreases, resolution of the final reconstructed image decreases.
Current signal processing techniques support the combination of signals from individual coils or receivers into combo- or super-coils. This combination of coils effectively allows signals to be received from a desired FOV or area that is larger than that individually supported by a particular coil. The optimal area or volume supported by a particular coil depends, in large part, on the size of the coil. For instance, coil sensitivity decreases with increasing coil size. On the other hand, reducing coil size increases the total number of coils needed to receive signals from the desired FOV.
For any given application, there is an optimized coil size. To this end, using an oversized coil alone will result in intrinsic and undesirable SNR penalty. Quadrature analog combination is a signal processing technique that has been developed to address this SNR penalty associated with oversized coils, but with some limitations. Quadrature analog combination can provide √{square root over (2)} times higher SNR where the B1 field from each coil are orthogonal to each other. The B1 field between two quadrature coils, however, is not always orthogonal and, as such, the direction of B1 field between the coils may vary from place to place. Thus, the combined SNR can be worse than the respective SNR of the individual coils. This worsening of SNR may be attributed to phase cancellation. In this regard, the combined SNR does not yield consistent SNR improvement over the entire FOV. Furthermore, larger sized coils present more isolation problems between coil elements from the stronger inductive coupling therebetween which will inherently degrade the combined SNR. Therefore, the benefit of using a large quadrature pair of coils with quadrature analog combining to improve SNR over a large FOV is limited.
In contrast to analog combination, due to the fact that digital combination only combines the magnitude of each signal regardless of the phase between the received signals, the digital combination of signals received by independent receivers can be used to provide net gain of SNR instead of worsening of SNR over the desired and enlarged FOV. Accordingly, RF coils could be designed such that each coil element has an optimized size for B1 field penetration and utilize the MR system independent receivers to yield the desired FOV, provided that there are enough number of MR system independent receivers.
However, MR scanners are subject to a limited number of receivers and, as such, a tradeoff of designing coils having desirable FOV and designing coils having optimized SNR must be made.
It would, therefore, be desirable to have a method capable of combining MR signals received from an array of receiver coils so as to realize optimized SNR without compromising FOV for simultaneous MR data acquisition by the array.

Method and apparatus to improve signal-to-noise ratio without compromising field-of-view for simultaneous MR data acquisition by an array of RF coils of an MR scanner


Two-way displays include a transmissive display. A sensor detects an orientation of the transmissive display. A processor modifies a format of characters displayed on the transmissive display responsive to the orientation of the transmissive display. Mobile terminals including two-way displays and methods of operating the same are also provided.

The present invention relates to displays for electronic devices, such as radiotelephones and, more particularly, to two-way displays.
Manufacturers and designers of personal electronic devices, such as radiotelephones, frequently seek to reduce the overall dimensions of such devices while maintaining attractive style characteristics for the devices. One consequence of the reduced size for such devices is that less surface area may be available for a user display. Furthermore, many such devices include a flip to provide more surface area to the devices and/or for protection of the user interfaces of the devices. As a result, a dual display may be provided, one for when the flip is in an open position and a second for when the flip is closed. Alternatively, a single display may be positioned so that it is only partially blocked when the flip is closed.

Two-way displays and methods of operating the same


A technique and method for vehicle information delivery and management includes: receiving, by a management module of a service provider manager associated with a service provider, a notification from an application executing on a client device of an end user that vehicle data corresponding to a vehicle being viewed by the end user on a premises of the service provider has been displayed to the end user; storing, by the management module, the vehicle data corresponding to the viewed vehicle; and storing, by the management module, a time that the vehicle was viewed by the end user.

A vehicle information disclosure sheet, which can also commonly be referred to as a Monroney sticker, is typically affixed to a side window of a vehicle. Generally, a vehicle information disclosure sheet includes information such as the make, model and year of the vehicle, the vehicle identification number (VIN), the estimated fuel efficiency of the vehicle, a list of standard and optional features included in the vehicle, the manufacturer suggested retail price (MSRP) of the vehicle and other information pertaining to the vehicle. An addendum may also accompany and/or be affixed to the window of the vehicle near or adjacent the Monroney sticker that includes additional, locally-installed optional features available on the vehicle (e.g., dealer/seller add-ons, such as window tinting, wheel locks, upholstery protection, etc.) including their respective prices.
When a potential buyer views the vehicle information disclosure sheet and wishes to obtain additional information about a specific vehicle, the potential buyer usually will need to speak to a sales representative. However, this can be time consuming, especially if a sales representative is not readily available. Also, a potential buyer may be reluctant to speak to a sales representative for fear of receiving an aggressive sales pitch. In addition, when the dealer lot is closed, no sales representatives will be present to speak with the potential buyer.

Vehicle information delivery and management system and method


A saddle seat type fuel-cell electric vehicle includes a motor for driving rear wheels, a secondary battery for supplying electric power to the motor, a carrier for carrying luggage and a seat for supporting an operator, the carrier is located behind the seat and above the rear wheels. The secondary battery includes a plurality of cells each having an elongated boxlike shape, and it is stored in the internal space of the carrier, thereby increasing the flexibility of the layout of the vehicle body. Spacings functioning as air passages are defined between the inner wall of the carrier and the secondary battery. The carrier is formed with air inlet openings for introducing an air flow into the internal space and an air outlet opening for discharging the air flow out of the internal space. The plural cells are arranged adjacent to each other with given intervals on the same plane.

1. Field of the Invention
The present invention relates to a saddle seat type electric vehicle. More particularly, to a saddle seat type electric vehicle which can increase the flexibility of layout of a vehicle body, can support an increase in the size of a secondary battery, and can efficiently cool the secondary battery by improving an installation method for the secondary battery.
2. Description of Background Art
A saddle seat type electric vehicle is known that uses an electric motor as a driving source. In a saddle seat type vehicle with little empty space unlike a four-wheeled vehicle having a compartment, the presence of a secondary battery for storing electric power to be supplied to a motor has a large effect on the layout of a vehicle body. Accordingly, various improvements in installation methods for the secondary battery have been made in the prior art.
Japanese Patent Laid-open No. 2005-104243 discloses a scooter type hybrid vehicle using an internal combustion engine and an electric motor in combination, wherein a luggage storing space is provided below a seat for an operator and a platelike secondary battery is provided on each side of the luggage storing space in the lateral direction of the vehicle so as to cover this space.
According to the layout structure disclosed in Japanese Patent Laid-open No. 2005-104243, the luggage storing space can be made wide. On the other hand, the secondary battery mounted on an electric vehicle tends to be increased in size in order to meet the requirement for increasing mileage. Further, in the case of increasing the size of the secondary battery, it is necessary to efficiently dissipate the heat generated in recharging and discharging the secondary battery.


A composition comprising a soluble peptide of about 23 kD to about 29 kD, capable of causing neutrophil and macrophage chemotaxis, and which is substantially similar to chemotactic factor from peritoneal fluid of mammals with minimal or moderate endometriosis.

The underlying mechanisms indicating an association between minimal to moderate endometriosis and infertility are not clearly understood. Recent investigations have focused on the presence of an aseptic inflammation of the peritoneal cavity, resulting in a distortion of the normal function of the pelvic organs, as an important contributory mechanism. Other proposed causes for reproductive failure in the less severe cases of endometriosis include oligoanovulation, luteal phase defects, and luteinized unruptured follicle syndrome. However, these suggestions need to be clearly substantiated and each one cannot be considered the sole cause of infertility in patients with endometriosis. Other factors, which include alterations in the sperm-egg interaction with possible phagocytosis of the sperm or interference with early embryo development, may be taken into consideration when studying the associated infertility of these patients. The biochemical modifications that have been described in endometriosis include an increase in the concentration of prostaglandins, cytokines and complement components in the peritoneal fluid and activation of resident macrophages. Halme J., et al., Am J Obstet Gynecol 1983 145:333 and Hill J. A., et al., Am J Obstet Gynecol 1989 161:861. The activation of leukocytes within the peritoneal cavity is evidenced by cytoskeletal rearrangement of the cells and by changes in the lipid metabolism with activation of protein kinases or release of lysosomal enzymes.
The role of peritoneal fluid in the physiologic modifications of the peritoneal cavity of patients who otherwise would seem to have a normal pelvic environment has been studied. Endometriosis without severe anatomic distortion is associated with an increase in the peritoneal fluid volume, cell number, and concentration of lysosomic enzymes as compared with normal fertile controls. The peritoneal fluid arises primarily from two different sources: the plasma as a transudate and the ovary as an exudate; other sources are tubal fluid; retrograde menstruation, and secretions from the macrophages in the cavity. However, the exact source for the biochemical modifications observed in endometriosis is not clear.
Normally the peritoneal fluid contains several types of blood cells, with macrophages and lymphocytes being the most abundant; desquamated endometrial and mesothelial cells are also present. This cellular composition is modified in patients with endometriosis. Badaway S. Z., et al., Fertil Steril 1984 42:704. Several theories exist regarding the mechanisms responsible for these alterations, one of which is considered by the present invention--the presence of a chemotactic stimulus that would attract more cells into the peritoneal cavity, or alternatively, activate and induce proliferation of resident macrophages in response to these unknown factors.
Therefore to study the modifications seen within the pelvic cavity in endometriosis investigators have focused on the initial stages of the disease in which active endometrial glands and stroma are present and are clearly associated with changes in the peritoneal fluid. Some of the modifications include an increase in the concentrations of cytokines and the production of various growth factors by the infiltrating leukocytes. The contribution of these factors to the inflammatory changes of the peritoneal fluid is yet to be determined. Fakih H., et al., Fertil Steril 1987 47:213 and Halme J., et al., J Clin Endocrinol Metab 1988 66:1044.
The role of the peritoneal fluid of patients with minimal to moderate endometriosis was examined in the present invention as a contributor to the inflammatory changes observed in the pelvic cavity of these patients. Leiva, M., et al., Am J Obstet and Gynecol 1993 168:592. In this regard, the chemotactic potential of peritoneal fluid obtained from patients with minimal to moderate endometriosis was investigated. Responsive cells included neutrophils isolated from peripheral blood or HL60-C15-differentiated neutrophils and macrophages derived from U937 cells. These findings were compared with the activity observed in normal patients or patients undergoing medical treatment for this condition.
These results determine the potential of the invention to satisfy the great needs in the art of diagnosis and treatment of endometriosis. Accurate and early methods of detection of endometriosis are needed such that methods of treatment may begin promptly.

Antibody specific for an isolated chemotactic factor from patients with endometriosis

The Trustees of the University of Pennsylvania


A step drive for a movable step, the step drive being arranged below a swinging-sliding door. The step drive includes an opening-out mechanism located in a lower region of a secondary closing edge of the swinging-sliding door. The opening-out mechanism is connected to and actuated by a door drive and the opening-out mechanism interacts with the movable step.

The present disclosure relates to a step drive for a movable step, such as a folding step or sliding step. The step drive is arranged below a swinging-sliding door. In a lower region of a secondary closing edge, the swinging-sliding door has an opening-out mechanism which is connected to and can be actuated by the door drive.
Steps in rail vehicles are nowadays customarily driven by a dedicated motor or a pneumatic cylinder or rotary cylinder.
DE 42 18 006 discloses a drive device for foldable steps below a swinging-sliding door. The pivoting action of a pivoting roller lever comprising a journal engaging in a guide of the door leaf produces the swinging movement of the door leaf. The pivoting roller lever is coupled to the horizontal drive shaft of the step via a transmission shaft and a bevel gear mechanism. The pivoting roller lever is actuated via a dedicated drive element, for example, in the form of a pneumatic cylinder. The pivoting roller lever is not connected to the door drive arranged in the upper region of the door. The use of two independent drives requires not only an elaborate synchronization of the two drive elements but also incurs considerable costs owing to the respective double design of the drive, levers, cylinders, etc.
DE 20 57365 discloses a folding drive whose horizontal pivot shaft is connected to and controlled by the vertical rotary shaft of a pivoting door, swinging door or pivoting-folding door. An opening-out mechanism for the door in the lower region is not provided.
In a few isolated instances, solutions are also known in which the step is driven via a linkage which operates with a door drive arranged in the roof region of the vehicle.
DE 27 23 995 discloses a folding step for a swinging-sliding door which is connected to and can be pivoted by the door drive via a complicated lever mechanism in the region above the door leaf. A floor-side locking mechanism or opening-out mechanism for the door leaf is not provided. Such a complex lever mechanism connected to the folding step via a rod and a further lever is prone to failure and consequently requires frequent maintenance.
The prior art door drives are thus either directly connected to the door drive arranged in the upper region of the coach body via complicated, failure-prone and cost-incurring mechanisms, or require a dedicated drive synchronized with the door drive. The present disclosure relates to overcoming these disadvantages and providing a step drive which folds down and in, or extends and retracts, reliably with the opening and closing of the door.
According to the present disclosure, a step drive includes an opening-out mechanism that interacts with the step.
The step drive according to the present disclosure makes it possible for the opening-out or locking mechanism in the lower region of the door leaf to be used to drive the step. No additional drives, transmission mechanisms or the like are required. The step is thus brought into the folded-out state, or extended state in the case of sliding steps, at the same time as the door opens, and folds up, or retracts, as the door closes.
A folding step is actuated by a rod which is pivotally mounted on a lever of the opening-out mechanism and on the step.
In the case of sliding steps, the movement is transmitted either directly, for example, via an extension of a lever of the opening-out mechanism, or via connecting elements such as, for example, a lever system.
Other aspects of the present disclosure will become apparent from the following descriptions when considered in conjunction with the accompanying drawings.

Knorr-Bremse Gesellschaft mit beschrankter Haftung


A system for autonomous on-board determination of the position of an earth orbiting satellite consists of a biaxially measuring earth sensor which defines the z-axis (yaw axis) of the satellite and of several biaxially measuring sun sensor measuring heads which are arranged on the satellite structure such that, with the exception of earth shadow phases, they supply a direction vector measurement. Out-of-plane movement of the satellite is propagated by means of a precise model of the satellite dynamics including natural disturbance forces and thrusts during maneuvers on board. In order to compensate sensor uncertainties and the effects of thermal deformations, the satellite orbit is precisely measured at regular intervals (approximately 3 months), and by means of this information, a calibration function (time function for a day) for compensating measured values is determined. The in-plane movement of the satellite is not only propagated, but the propagation is supported by measured data (estimation), and the effects of out-of-plane movement and thermal deformations are taken into account, by means of the data of the calibration function (k(t) or of the propagation out-of-plane movement.

This application claims the priority of German patent document 197 03 629.5, the disclosure of which is expressly incorporated by reference herein.
The present invention relates to a method for autonomous on-board determination of the position of an earth orbitting satellite.
In prior art systems of this type, the determination and holding of the position of a satellite normally does not take place automatically and autonomously. That is, an earth station determines the deviation of the actual orbit from the desired orbit, and corresponding correction maneuvers are then manually commanded from earth.
To save cost, it may be advantageous to carry out the tasks of "orbit determination" and "orbit correction" autonomously on board; that is, without the intervention of an earth station. The results of investigations of different methods for the board-side determination of orbit parameters and their correction largely independently of interventions of the earth station are described in P. Maute et al., "Autonomous Geostationary Station Keeping System Optimization and Validation", IAF-88-327,39. Congress of the International Astronautical Federation, 1988, Bangalore, India and J. Potti et al., "On-Board Autonomous Station Keeping (OBASK) Executive Summary, ESTEC Contract No. 9675/91/NL/JG GMVSA 2064/93, GMV S.A. 1993. However, in addition to measuring equipment which is already available on board such craft for the purpose of controlling the attitude (particularly earth and sun sensors), most systems of this type require additional measured-value generators which are used solely, or at least predominantly, for the purpose of determining orbit parameters. Particularly, the use of additional star sensors was found advantageous for this purpose.
One exception is indicated in K.D. Mease, et al., "An Approach to Autonomous On-Board Orbit Determination", The Journal of the Astronautical Sciences, Vol. 33, No. 2, pp 163-178, 1985, which indicates that the satellite orbit can be determined in a complete manner by means of a biaxially measuring earth sensor, a two-axis sun sensor and a Kalman filter. The sun sensor is mounted on the drive of the solar generator so that, in the case of the known position of the drive, the sensor measurements can be transformed into the system of body coordinates.
The known methods and systems for the autonomous orbit determination suffer from the following deficiencies:
The installation of additional measuring instruments, particularly star sensors, results in additional costs, weight and complexity of the measuring system. PA1 In the case of a polaris sensor, system-technical difficulties occur because, as the result of sun reflections, light scatter shields must be mounted on the solar generators which also result in additional weight. PA1 The use of a sun sensor mounted on the drive of the solar generator requires that the angular position of the driving motor with respect to the satellite be known precisely in order to transform the measuring information into the body-fixed satellite system. However, in the case of conventional driving motors (stepper motors), this generally cannot be ensured with sufficient precision. PA1 It can be demonstrated that the complete orbit information cannot be determined by means of a respective biaxial earth and sun sensor measurement. PA1 1. The system consists of a biaxially measuring earth sensor which defines the z-axis (yaw axis) of the satellite and of several biaxially measuring sun sensor measuring heads which are arranged on the satellite structure such that, with the exception of earth shadow phases, they supply a direction vector measurement. PA1 2. The out-of-plane movement of the satellite is propagated by means of a precise on-board model of the satellite dynamics including natural disturbance forces and thrusts during maneuvers. PA1 3. In order to compensate sensor uncertainties and influences of thermal deformations, the satellite orbit is precisely measured at regular intervals (approximately 3 months). By means of this information, a calibration function (time function for a day) is determined by means of which the measured values are compensated. PA1 4. The in-plane movement is not only propagated but the propagation is supported by measured data (estimation), and the effects of out-of-plane movement and thermal deformations are taken into account, by means of the data of the calibration function (k(t) or of the propagated out-of-plane movement. PA1 5. It is possible for the earth station to switch off the automatic and autonomous orbit determination and position holding as soon as larger deviations occur during the autonomous operating phase between the position computed autonomously on-board and the position (passively) monitored by the earth station.
It is therefore an object of the present invention to determine the orbit (position) of a satellite as far as possible autonomously on board the spacecraft, by using normally existing sensors (biaxially measuring earth and sun sensors), in order to facilitate optimal correction maneuvers by means of this orbit information.
In the following, it is assumed that the earth and sun sensors supply direction vectors of length I in the direction of the center of the earth and in the direction of the sun, respectively. Sensor errors, installation errors of the sensors, and relative position errors of the sensors because of thermal deformations of the satellite structure interfere with the directional measurements. The object of the invention therefore also includes the provision of methods for identifying and eliminating such error influences.
These and other objects and advantages are achieved by the process and apparatus according to the invention, which is characterized by the following features:
Other objects, advantages and novel features of the present invention will become apparent from the following detailed description of the invention when considered in conjunction with the accompanying drawings.

Method and system for the autonomous on-board determination of the position of a satellite


To provide an input/output circuit that includes a write path to which write data is supplied and a read path to which read data is supplied and first and second data lines that connect the input/output circuit to a memory cell array. The input/output circuit includes a write buffer that supplies the write data on the write path to the first data line, a read amplifier that supplies the read data supplied to the read path through the second data line, and a bypass circuit that supplies the write data on the write path to the read path in response to detection of matching between a write address and a read address. Thus, data collisions can be avoided.

1. Field of the Invention
The present invention relates to a semiconductor memory device, and more particularly relates to a semiconductor memory device to which successive accesses can be made.
2. Description of Related Art
Semiconductor memory devices represented by DRAM (Dynamic Random Access Memory) are generally configured such that a memory cell array is connected via an I/O line to an input/output circuit. During a write operation, write data is supplied from the input/output circuit via the I/O line to the memory cell array, and during a read operation, read data read from the memory cell array is supplied via the I/O line to the input/output circuit.
FIG. 41 is a circuit diagram showing a configuration of principal parts of a conventional DRAM.
The DRAM shown in FIG. 41 includes a memory cell array 1 that includes word lines WL0, WL1, . . . , bit line pairs BL0, BL1, . . . , and memory cells MC arranged at intersections of the word lines with the bit lines. A sense amplifier 2 is connected to each of the bit line pairs BL0, BL1, . . . . The sense amplifier 2 is connected via a corresponding column switch 5 to an I/O line LIO. Column select signals YS0, YS1, . . . that are output signals of column select drivers 4 are supplied to the respective column switches 5, so that any one of the switches is brought into on state.
The I/O line LIO is a wiring for transmitting complementary differential signals and connected to an input/output circuit 20. The input/output circuit 20 includes a write buffer 10 that supplies write data provided through a write bus WBUS to the I/O line LIO and a read amplifier 6 that supplies read data provided through the I/O line LIO to a read bus RBUS.
An operation of the DRAM with the configuration described above is described.
First, when a word driver 3 drives any one of the word lines WL0, WL1, . . . , the word line WL0 for example, signal charges stored in the memory cells MC are read to the respective bit line pairs BL0, BL1, . . . . Because the amounts of signals appearing in the bit line pairs BL0, BL1, . . . are small, however, the signals are amplified by the respective sense amplifiers 2. The bit line pairs BL0, BL1, . . . are driven in full amplitude, the selected memory cells MC are rewritten to be in a full level, and the amplified signals are held by the sense amplifiers 2.
Next, any one of the column select signals YS0, YS1, . . . is activated by the corresponding column select driver 4, thereby turning on the corresponding column switch 5. Any one of the bit line pairs is thus connected to the I/O line LIO.
However, the signal level read to the I/O line LIO is also small. Accordingly, to perform a read operation, the signal read to the I/O line LIO is further amplified by the read amplifier 6, latched at a hold circuit 7, and then outputted via a tri-state buffer 8 to the read bus RBUS. The read amplifier 6, the hold circuit 7, and the tri-state buffer 8 operate in synchronization with an activation signal RAE. The activation signal RAE is a timing signal during the read operation.
On the other hand, when a write operation is performed, write data supplied through the write bus WBUS is latched at a hold circuit 9 and then supplied to the I/O line LIO via the write buffer 10. The hold circuit 9 and the write buffer 10 operate in synchronization with an activation signal WBE. The activation signal WBE is a timing signal during the write operation. The write data provided to the I/O line LIO is supplied via a switched-on column switch 5 to any of the bit line pairs. The write data is thus forcibly overwritten in the sense amplifier 2 and this written data is to be written in the memory cells MC.
An operation timing when the write operation and the read operation are requested successively (write-to-read operation) is described next.
FIG. 42 is a timing diagram showing an operation timing when a write operation and a read operation are requested successively for the same address.
First, when a write request is issued at a time t1, write data D is supplied to the write bus WBUS after a predetermined period of time. At a time tWBE, the activation signal WBE is activated, so that the write data D is outputted to the I/O line LIO. The column select signal YS0 is then activated, so that the write data D is written in the corresponding bit line pair BL0. Next, when a read request is issued at a time t2, the data D written by the write request at the time t1 is read to the I/O line LIO. After a significant potential difference in the I/O line LIO, the activation signal RAE is activated at a time tRAE, so that read data D is read to the read bus RBUS.
When the write operation is completed within one clock cycle as described above, any data collision does not occur on the I/O line LIO and the bit line even if the write operation and the read operation are requested successively for the same address. Although not illustrated, when the read operation and the write operation are requested alternately and successively for the same address, when the write operation is requested more than twice consecutively for the same address, and when the read operation is requested more than twice consecutively for the same address, any data collision does not occur and accurate operations can be performed. That is, when the write operation or the read operation is completed within a clock cycle, the accurate operations can be performed no matter what accesses are requested. Accordingly, the I/O line LIO can be shared by the sense amplifiers 2 as shown in FIG. 41. The I/O line LIO literally serves as both an input and an output.
Recently, however, operations of memory devices have become complicated. Some cases that complicated calculations including coding are performed before write in a memory cell array will be probably increased. An example of such cases is a memory device having an ECC (Error Correcting Code) circuit incorporated therein. The write operation may not be completed within a clock cycle. In the case that the write operation cannot be completed within a clock cycle, when the write operation and the read operation are successively requested, the write operation cuts into the time that the subsequent read operation. Such a problem is described below in detail using a timing diagram.
FIG. 43 is a timing diagram showing an operation timing when the write operation and the read operation are successively requested (write-to-read operation) for different addresses in a memory that cannot complete the write operation in a clock cycle.
First, when a write request is issued first at the time t1, a calculation that takes a long time is performed. When the calculation is completed, write data D0 is supplied to the write bus WBUS. The activation signal WBE is then activated at the time tWBE, so that the write data D0 is outputted to the I/O line LIO. The column select signal YS0 is then activated and the write data D0 is written in the corresponding bit line pair BL0. When a read request is issued at the time t2, the corresponding column select signal YS1 is activated and read data D1 appears in the I/O line LIO. According to this example, the activation of the activation signal WBE at the time tWBE and the activation of the column select signal YS0 are naturally delayed from the write request at the time t1 by a calculation time. The column select signal YS1 rises when the write data D0 is being written in the bit line pair BL0 and the write data D0 is written even in the bit line pair BL1. The read data D1 from the bit line pair BL1 is thus affected by the write data D0 for BL0. Even if the read data D1 on the bit line pair BL1 is not inverted as shown in FIG. 43, the I/O line LIO is affected significantly by the write data D0. Accordingly, the value supplied to the read bus RBUS by the activation signal RAE that is activated at the time tRAE in response to the read request at the time t2 may be D0 not the expected D1. That is, incorrect data is read.
FIG. 44 shows an operation timing when the write operation and the read operation are successively requested (write-to-read operation) for the same address in the memory that cannot complete the write operation in a clock cycle.
The write operation is the same as the operation described with reference to FIG. 43. That is, in response to the write request at the time t1, the write data D is transmitted successively to the write bus WBUS, the I/O line LIO, and the bit line pair BL0. While the write data is being written in the bit line pair BL0, however, the column select signal YS0 rises in response to the read request at the time t2. When the activation of the activation signal RAE at the time tRAE is performed during an activating period of the write buffer 10 (WBE=H), the data D can be read correctly. When the activation of the activation signal RAE is performed after the activating period of the write buffer 10 (WBE=L) as shown in the example of FIG. 44, the bit line pair BL0 in amplitude is connected to the I/O line LIO and thus the potential of the I/O line LIO is drawn. Accordingly, when the signal amount on the I/O line LIO is small and the activation signal RAE is activated at the time tRAE, the correct value cannot be read to the read bus RBUS (X: undefined).
As shown in FIG. 43, when the write operation goes on into the subsequent read operation in the write-to-read operation for different addresses, it suffices that the I/O line LIO is divided into a data line for write and a data line for read. Data collisions between the write data and the read data are thus eliminated. Similarly, it suffices that the column select signal YS is divided into a column select signal YS1 for write and a column select signal for read. Such I/O division is also described in "Symposium on VLSI Circuits, Dig of Tech. Papers" (pp. 17-18, 1990, Y. NAKAGOME et al.) and "Super LSI Memory" (ITOH Kiyoo, published by Baihukan, November 1994, ISBN4563036099, pp. 165-167).
However, problems about the write-to-read operation for the same address shown in FIG. 44 cannot be solved only by the I/O division. Thus, the only way to perform correctly the write-to-read operation requested for the same address is to set a clock cycle to be longer, which hinders a high speed operation. Accordingly, a semiconductor memory device that can perform correctly the write-to-read operation for the same address and realize a high speed operation is desired.
When the write operation that takes time to start is required, a data collision occurs not only in the write-to-read operation but also in the write-to-write operation. Two kinds of write operations, that is, the write operation that takes time to start because of a calculation and the write operation that can start promptly depending on clocks as usual are provided. In this case, the write operation that takes time to start overlaps the next cycle, that is, the read operation in the next cycle or the write operation that can start promptly in response to clocks in the next cycle. Particularly when the write operation that takes time to start overlaps the write operation that can start promptly in response to clocks, this problem cannot be solved by dividing the I/O line into a data line for write and a data line for read. Such a problem occurs in the clearest manner when the write cycle is configured by two kinds of write operations, that is, the write operation that can start promptly in response to clocks and the write operation that takes time to start. Accordingly, a semiconductor memory device that can perform correctly the write-to-write operation for different addresses and for the same address and realize a high speed operation is also desired.

Semiconductor memory device that can perform successive accesses


This invention concerns novel safe compositions containing as an active antioxidant or antiinflammatory agent and thiol-repleting agent, the amino acid methionine, and/or one or more related compounds including certain metabolic precursor compounds, and novel methods employing the compositions for treating or amelio-rating symptoms of human immunodeficiency virus infection and AIDS, such as weight loss, increased red cell sedimentation, and leukoplakia; novel methods employing the compositions for treating or inhibiting symptoms resulting from nutritional deficiencies of methionine; and novel methods employing the compositions for inhibiting or preventing triglyceride elevation due to low dose methionine consumption. The compounds include the methionine hydroxy analogs, as well as compounds having the structural formula ##STR1## 1-, dl- or d- form and pharmaceutically acceptable N- (mono- and di-carboxylic acid) acyl derivatives and alkyl esters thereof.

1. Field of the invention
This invention concerns improved antiinflammatory compositions containing the amino acid methionine (also known as "Met"), and/or one or more related compounds including certain metabolic precursor compounds with the amino acids glycine and serine to reduce side effects of methionine at low doses and novel methods employing the compositions for ireating inflammatory AIDS symptoms and HIV infection in man. Compositions are suitable for the treatment of disease conditions of man that may be attributable to or result from nutritional deficiency or illness resulting from uncontrolled inflammatory responses.
2. Description of the Related Art
A variety of efforts have been made over many years to elucidate the mechanisms and origins of inflammation and the various forms of disease it may cause and to identify disease conditions which involve inflammatory damage. Limited success has been achieved in identifying such conditions in alleviating the symptoms of diseases having inflammatory components. Oxidative stress has been implicated in many of these diseases, and antioxidant therapy has been recommended as one method to alleviate the damage it causes (Cross, et. al., Annals of Internal Medicine, 107:526-45, 1987). Successful prevention of oxidative stress damage requires that normal physiological parameters and functions be maintained so that undesired side effects do not occur.
It is now generally accepted that an essential component for the occurrence of the disease known as AIDS (Acquired Immunodeficiency Syndrome) is an infection by a virus now designated Human Immunodeficiency Virus (HIV). This virus can be transmitted by the exchange of body fluids, including unprotected sexual intercourse, blood transfusions, and through sharing of non-sterile hypodermic needles. Blood borne occupational exposure is also known.
What has puzzled doctors and researchers in trying to understand the disease of AIDS is the aspect of latency. Latency is the term used to describe the long time period between a cause and its effect. With regard to the progression of the AIDS disease from an early symptomless stage of infection which can be demonstrated by the production of antibodies to the virus to the eventual occurrence of symptoms typical of the disease state, such as recurrent infections, weight loss, Karposi's sarcoma, etc., the period of latency can be longer than 7 years. In one study (Arendrup, et al., Scand. J. Infect. Dis. 21:19-26, 1989) 5 of 10 persons with HIV antibodies remained healthy over a 5 year period. In most disease conditions the symptoms of the infection occur immediately or soon after the infection. The progression from the state of being healthy but showing evidence of infection with HIV to becoming sick with AIDS symptoms is associated with decrease in the number of T-helper cells designated CD4, a decrease in the body's production of antibody to the viral antigen p24, and increase in HIV antigen in the blood (Bottiger, et al., Scand J. Infect. Dis. 21:507-14,1989).
Because of the long latency that particular individuals show after HIV infection it seems clear that other factors in addition the virus itself contribute to the occurrence of the disease symptoms. By understanding the important elements operating that may allow infected individuals to delay the deleterious effects of the virus infection, considerable health benefits can be achieved for the antibody-positive, HIV infected person.
A benefit of compounds which modulate the activity of the immune system of HIV-infected people is based on the hypothesis that the initial stages of the disease result in generalized immune system activation. Over time, this generalized stimulation results in activated immune cells which do not respond to further stimulation. The hypothesis includes the concept of immune system failure after an extended period of hyper-activity (Ascher and Sheppard, J. Acquired Immune Deficiency Syndromes, 3:177-91, 1990). The authors postulate that one possible mode of therapy is ". . . to target specific mediators that produce fever, cachexia, and diarrhea, and inhibit their action."
Recent identification of homology between the HIV viral protein designated "Nef" and a region of the histocompatibility antigens of HLA II, lends support to the hypothesis of an important involvement of autoimmunity in leading to eventual HIV immunosuppression (Vega, M. A., Guigo, R., and Smith, T. R., Nature 345: 26 (1990). The underlying theory is that the "Nef" protein region serves as a false signal to the immune system mimicking that signal responsible for the stimulation which results when the histocompatibility antigen sites of immunoglobulins stimulate these cells as antigen-antibody complexes.
Severe liver damage occurs after consumption of large doses of acetaminophen. Acetaminophen is converted by a cytochrome P-450 oxidase to a reactive metabolism that is then inactivated by conjugation with glutathione. When large doses of acetaminophen are consumed, hepatic glutathione stores are depleted, and excess reactive metabolites cause cell damage (Vale, et.al., Arch. Internal Med., 141:394-6, 1981). Thus, acetaminophen poisoning is a good model to study the effects of thiol depletion. N-acetylcysteine (NAC) and 1-methionine are the currently used antidotes for acetaminophen overdoses. Intravenous administration of NAC can cause anaphylactoid reactions, and large oral doses of methionine can cause nausea and vomiting (Neuvonen, et al., Internat. Jour. Clinical Pharmacology, Therapy and Toxicology, 23:497-500, 1985). The addition of selenium and serine to the methionine and vitamin B6 dosage allows the hepatic cells to maximize the production of intracellular glutathione and extracellular glutathione peroxidase (Luo, et. al., Am.J. Clin. Nutrition, 42:4-48, 1985, and Sunde and Evenson, J. Biol. Chemistry, 262:933-7, 1987). The ability to maximize elutathione and elutathione peroxidase production, while having an immediate antioxidant benefit and glutathione-sparing effect may be of value in other disease states where reduction of glutathione levels may be a toxic mechanism. Reduced glutathione effects include:
1) ataxia-telangiectasis (Meredith and Dodson, Cancer Research, 47:4576-81, 1987); PA1 2) human immunodeficiency virus infection (HIV) where blood levels of glutathione are reduced in HIV positive persons (Buhl, et. al., The Lancet, Vol. 1 No. 8675, p. 1294-8, 1989); PA1 3) rheumatoid arthritis (Braven et al., Br. J. Rheumatology, 28;212-15, 1989; and Banford, et al., Rheumatology Internat 2:107-11, 1982); PA1 4) Parkinson's Disease (Riederer, et. al., Jour. of Neurochemistry, 52:515-20, 1989). PA1 1. Providing methyl groups for many methylation reactions. PA1 2. Providing homocysteine for the transulfuration pathway through cystathionine for the production of the amino acid cysteine, which is present in high concentrations in hair. PA1 3. Through cysteine production it provides glutathione, a three amino acid compound which acts as an antioxidant in cells and in the blood. PA1 4. Through cysteine production and the conversion of cysteine by the body to hypotaurine, another antioxidant which is normally present in the seminal fluid. PA1 5. Through hypotaurine production and conversion in the body it provides taurine, another antioxidant amino acid, which is the highest in concentration of all the free amino acids in cells. It is especially high in concentration in nerve cells and some white cells.
dl-Methionine is a chemically manufactured source of the essential amino acid 1-methionine which contains an equal amount of the mirror image d-methionine analog. The d-analog is not converted to the natural 1-methionine by humans (although it can be utilized by animals such as dogs, chickens, etc.) and thus does not have nutritional value for protein production. 1-Methionine is converted in the body tissues to the amino acid cysteine, the other sulfur amino acid present in most proteins, by enzymatic reaction with another amino acid serine. Multiple benefits of dl-methionine when taken with the amino acid serine, or the amino acid glycine, which is converted to serine in the body, are thought to arise from both the metabolic and anti-oxidant properties of dl-methionine. The metabolic properties of 1-methionine include:
Additional serum antioxidant properties are provided by the use of d-methionine which is due to the ability of d-methionine to provide sustained elevated blood levels of methionine. This occurs because d-methionine is poorly metabolized. However d-methionine is equally as effective as 1-methionine as an anti oxidant. (Stegink, et al., Jour. Nutrition, 116:1185-92, 1986) and (Tsan and Chen, J. Clinical Investigation 65:1041-50, 1980).
The amino acid glycine may be included when seeking optimal benefits of the antioxidant methionine metabolites such as cysteine, glutathione, hypotaurine and taurine because when normal subjects are given 9 grams of 1-methionine per day on an adequate diet, urinary glycine excretion levels are reduced. No other urinary amino acid was altered (Block, et al., J. Nutrition, 86:256-64, 1965).
Consumption of oral methionine at 8 grams daily caused a 30% reduction in serum folate levels in five healthy subjects (Connor, et al., Postgraduate Medical Jour., 54:318-20, 1978).
Excess methionine causes the urine to become acid and in so doing stimulates the excretion of calcium (Tschope, Mineral Electrolyte Metab. 11:137-9, 1985). Calcium supplementation of about 20 milligrams per gram of methionine consumed would compensate this additional loss.
HIV-positive persons have benefitted from antioxidants. Studies with compounds that act as water-soluble antioxidants often have serious side-effects.
A recent study of 13 asymptomatic HIV infected patients treated with oral D-penicillamine demonstrated complete inhibition of virus expression in 60% of those treated (Schulof, et al., Arzneim.-Forsch. Drug Res. 86 (II), No. 10, 1986). The basis for the human experiment was a previous cell culture test which showed the D-penicillamine totally inhibited viral growth at 40 microgram/ml, less that 10% of the cellular toxic dose. Of 10 patients completing at least 2 weeks of treatment, 3 tested negative for HIV six weeks after cessation of treatment by measurement of reverse transcriptase, antigen p15 and antigen p24. Side effects of the treatment protocol were significant with 4 of the 13 patients developing skin rashes and 2 developing mild elevations of hepatocellular enzymes (SGOT, SGPT) indicative of liver damage.
The rationale for testing D-penicillamine in HIV infection was based on its ability to interact with proteins and peptides by the formation of mixed disulfides and thus inactivate cysteine-rich essential viral proteins, a high concentration of which are found in HIV.
D-penicillamine is used to treat rheumatoid arthritis where its benefit is thought to arise by reducing the damage done by the oxidative products released during inflammation (Munthe. et al., In: Modulation of Autoimmunity and Disease, Maini and Berry, Eds., Praeger, London, 1981, p. 134-42) and (Cross, et al., Annals of Internal Medicine, 107:526-45, 1987). Of particular concern are the polymorphonuclear neutrophils (PMNs). These cells release relatively large amounts of oxidizers and proteolytic enzymes when activated (Weiss, New Eng. J. Medicine, 320:365-76, 1989). They can cause wide-spread tissue damage, with oxygen metabolites being identified as the most destructive toxins. Thus, in active disease states due to infection, highly reactive free radicals can be expected to be released by immune cells, including the PMN and the macrophage.
The benefit of reducing compounds in the treatment of AIDS was shown in a double-blind clinical trial using diethyl-dithiocarbamate (DTC) as a reducing agent. The treatment of HIV-positive persons once a week for a 4 month period showed in the treatment group (1) fewer persons progressing to AIDS, (2) a high percentage showing disappearance of diarrhea, weight loss or persistent fever, and (3) disappearance of splenomegaly. No change was detected in virus blood levels as measured by reverse transcriptase activity (Lang, et. al., Lancet, Sep. 24, 1988, p. 702-6). In another study this same compound slowed the progression of the disease during the 6-month trial period (Reisinger, et. al., Lancet, 335:679-82, 1990). DTC is known to interfere with glutathione metabolism, while substituting for it as an anti-oxidant. When the AIDS patients were removed from DTC, clinical benefits were progressively lost.
In a separate study using DTC, which was administered by injection rather than orally, there was significant improvement in symptoms and in reduction of lymphatic disease (Brewton, et al., Life Sciences 45: 2509-2520, 1989). Benefits of DTC may be due to reduction of fungal infections (Allerberger, F., et al., Mycoses 32: 527-530, 1989).
Free radical reducing compounds may benefit HIV patients as a result of the maintenance of blood and tissue glutathione levels. Glutathione serves as an intracellular reducing agent and antioxidant (Deneke, et al.,. Am. J. Physiology, 257:163-73, 1989). Buhl, et al. (Lancet, Vol. 2 No. 8675, Dec. 2, 1989) showed that symptom-free HIV positive individuals have only about half the level of plasma glutathione as compared to healthy controls. A majority of HIV-positive patients tested, had abnormally low glutathione levels in lung epithelial lining fluid. Dworkin, et. al. (Biological Trace Element Research 15:167-77, 1988) showed that glutathione peroxidase, which is an extracellular antioxidant, was 47% less in 13 AIDS patients, compared to 14 healthy controls. Plasma selenium was also similarly reduced in AIDS patients.
In animal cell studies methionine is equally as effective as cysteine as a precursor for glutathione biosynthesis (Reed and Orrenius, Biochem, Hiophys, Res, Comm. 77: 1257-64, 1977). Rat feeding studies show that methionine can raise liver and muscle glutathione levels (Seligson and Rotruck, J. Nutrition 113:98-104, 1983). In humans, the plasma half-life of a 100 mg i.v. dose of glutathione is 1.6 minutes (Wendel and Cikryt, FEBS Letters, 120: 209-11, 1980).
Kalebic, et al., (Proc Natl. Acad. Sci. USA, 88:986-90, 1991) show that glutathione, glutathione ester, and N-acetylcysteine, at a dose of 15 mM, were able to suppress HIV protein synthesis in vitro. The authors speculate that ". . . these or similar agents may have therapeutic value in HIV-infected patients."
One mediator produced by the activated macrophage is a hormone called "cachectin" or "tumor necrosis factor". This hormone produces anorexia and profound wasting then injected chronically into mice (Beutler, B., Nutrition Reviews, 46: 369-73, 1988). It also causes the PMN (polymorphonuclear neutrophil white cell) to degranulate, release its granule contents, and activate the respiratory burst which releases oxidative radicals (Balkwill, F. R., British Medical Bulletin, Vol. 45 No. 2, p. 389-400, 1989 and Larrick, et al., Blood, 69:640-4, 1987). AIDS patients have been shown to have increased serum values of cachectin/Tumor necrosis factor (Lahdevirta, et al.. Am. J. of Medicine, 85:298-91, 1988). AIDS patients also show elevated levels of circulating triglycerides (Grunfeld, et al., Am. J. of Medicine 86:27--, 1989) which may be an effect of cachectin which has been shown to inhibit lipoprotein lipase (Fried and Zechner, J. of Lipid Research, 30:1917-23, 1989).
Tumor necrosis factor stimulates the production of HIV virus in MOLT-4 cells while another neutrophil (PMN) activator, phorbol 12-myristate 13-acetate, stimulates HIV virus replication in human peripheral blood mononuclear cells. N-acetyl cysteine, (NAC) an antioxidant utilized to counteract oxidative stress such as that which occurs with acetaminophen overdose, and which also increases intracellular glutathione, has been tested for its effect on virus replication in MOLT-4 cells and mononuclear cells (Roederer, M., et al., Proc. Natl. Acad. Sci. USA 87: 4884-4888, 1990). NAC at 3 mM reduces virus production in MOLT-4 cells by more than half, but more than 10 mM is required to reduce virus production by this amount when the virus production is stimulated by tumor necrosis factor. In human mononuclear cells, NAC reduces phorbol-induced virus production by more than half at 1 mM. More than 3 mM NAO is required to reduce virus production in infected, unstimulated mononuclear cells. Doses of NAC required to achieve blood or tissues level above 3 mM are much higher than those achieved by previously approved uses of NAC.
PMNs have also been demonstrated to predominate in the cerebrospinal fluid (OSF) of AIDS patients who have cytomegalovirus infection in the nervous system (de Gans, J., et al., J. of AIDS, 3:1155-8, 1990).
Anemia is another complication of AIDS. Anemia of chronic disease is commonly seen, and may be due to inflammatory mediators released by macrophages. Controlling inflammation in AIDS may allow blood values to normalize (Baer, et al., Seminars in Arthritis and Rheumatism, 19 (4): 209-23, 1990).
A recent study in mice showed that infection with influenza virus led to a forty-fold increase in an enzyme called xanthine oxidase. This enzyme causes a generalized oxidative reaction in tissue. Administration of superoxide dismutase, a free radical scavenger, could prevent death in mice which would otherwise occur. Virus titers dropped by day four, while xanthine oxidase conversion peaked on day eight, when death occurred, unless SOD was intravenously administered. The implication of these studies is that the oxidative attack generated by xanthine oxidase was the direct cause of death, not the virus (Oda, et. al., Science, 244:974-6, 1989). Xanthine oxidase is produced in tissues by the oxidation of exposed sulfhydryls in xanthine dehydrogenase. This oxidation can be accomplished by oxygen introduced during reperfusion, or presumably by oxidative products of PMN (Parks and Granger, Acta Physiol. Scand. Suppl. 548:87-99, 1986). Another study, using the hamster cheek pouch method, shows that methionine was able to completely inhibit the vascular changes which xanthine oxidase would otherwise induce (Del Maestro, et al., In: Biological and Clinical Aspects of Superoxide and Superoxide Dismutase, No. 62, Bannister and Bannister, Eds., New York, 1978, p. 127-40). This inhibition was believed to be due to the known hydroxyl radical scavenging effect of methionine. Methionine has been shown to inhibit both PMN oxidative products as well as xanthine oxidase free radical production. It has been hypothesized that the damage seen in AIDS is oxidative in nature, and that the use of appropriate antioxidants is warranted (Papadopulos-Eleopulos, E., Medical Hypotheses 25:151-62, 1988).
In addition to its potential antioxidant benefits, dl-methionine provides 1-methionine for supplemental nutrition. Methionine and cystine blood levels are reduced 25% in AIDS patients (Droge, et al., Biol. Chem. Hoppe-Seyler 369:143-8, 1988), which further reduces the body's ability to produce glutathione (see above). This reduction is significant in light of the fact that plasma methionine levels were not reduced in eight healthy subjects after seven days of starvation (Martensson, J., Metabolism 85:118-21, 1986).
Another problem found in pediatric AIDS is a large reduction of folic acid (80% of normal) in cerebral spinal fluid (OSF), which may cause the demyelination of nerve fibers seen in AIDS. Accompanying the folate reduction was a 50% reduction of CSF S-adenosyl-methionine, the principal methyl donor in the brain (Surtees, et al., The Lancet, 335:619-21, 1990).
Folate deficiency has also been reported in HIV infected adults at various degrees of progression of the disease. Simple folate supplementation corrected this deficiency (Boudes, P., Zittoun, J., and Sobel, A., Lancet 335: 1401-1402, 1990).
The pharmacopeia advises that methionine should not be taken by persons with active kidney or liver disease. Persons on chemotherapy taking folate inhibitors such as methotrexate or trimetrexate should not take methionine or folate.
Methionine is not recommended for persons being treated with monoamine oxidase inhibitors such as deprenyl. Schizophrenic patients given 300 mg per kg of 1-methionine per day exhibited symptoms of intoxication (The Martindale Pharmacopoeia, 26th Ed., The Pharmaceutical Press, London, p 76, 1972)
Methionine deficiency is not recognized as a disease state in modern countries where adequate total protein is generally available. While it is recognized that humans, in contrast to most other mammals, cannot utilize d-methionine as a source of methionine, it is generally assumed that humans can utilized methionine sulfoxide as a source of methionine. The only suggestion that methionine sulfoxide might not be nutritionally equivalent to methionine is the lack of increase of blood 1-methionine after administration of 1-methionine sulfoxide. Human enzymes have been found that can reduce methionine sulfoxide to methionine.
Methionine is known to be affected by a variety of food processing activities. 1-Methionine is converted to d-Methionine when proteins are heated and a significant amount of the nutritional value of methionine can be lost by this mechanism. However, most of the potential loss of available methionine occurs through the mechanism of oxidation of methionine to methionine sulfoxide. The bleaching of flour may be the major cause, when during the process of bleaching the chlorine is able to react with methionine. When proteins are heated with reducing sugars methionine is readily oxidized so that items such as fruit "canned" in natural sugars are potential sources of food source with a deficiency of available methionine. More recently, as unsaturated fats replace saturated fats in prepared food sources, additional cases of methionine oxidation occur. For example, the unsaturated fats in cake-mixes held in a hot warehouse would result in oxidation of methionine to its sulfoxide. Published evidence for an extensive loss of methionine in food processing as regards human nutrition occurred in the manufacture of instant oatmeal where the product used in nitrogen balance studies apparently had no nutritionally available methionine (see Kies, et. al., J. Nutrition, 105:809-4, 1975). In the cooking of several types of beans 40% to 50% of the methionine is not available to rats (Sawar and Peace, J. Nutrition. 116:1172-84, 1986). The dietary requirement for methionine plus cysteine is based on nitrogen balance studies where a total of 800 mg per day is required to bring 50% of adults into positive nitrogen balance. No attempt has been made to determine the level of methionine that might be optimal for the prevention of oxidative damage.
Methionine has been shown to be a target for the products of stimulated polymorphonuclear neutrophils (Tsan and Ohen, J. Olin. Invest., 65:1041-50, 1980). The granular fraction of the PMNs oxidizes methionine to its sulfoxide in the presence of peroxide. Peroxide does not oxidize methionine to its sulfoxide at normal physiological concentrations.
Some of the differences measured in the relative effectiveness of methionine compounds and other chemicals, especially sulfhydryl reducing substances, may be attributed to the control mechanisms that operate in animals and man to regulate the amounts of these substances, where giving more of a substance does not significantly increase blood and tissue levels of that substance. Stegink, (Jour. Nutrition,116:1185-92, 1986), showed that 0.5 gm of methionine elevated total blood methionine 2-fold for 2 hours with 1-methionine but 3-fold for 4 hours with d-methionine. In the same study it was shown that methionine sulfoxide administration did not result in elevation of blood methionine. This observation suggests that methionine sulfoxide is not readily reduced to methionine but it is possible that this reduction occurs in tissues where the methionine remains sequestered. 1-Methionine is an essential amino acid for human nutrition. The normal serum level of methionine in man is 15 ppm. dl-Methionine is available as a one-a-day food supplement in 500 mg. oral tablet form.
Regarding human nutrition, 1-methionine is an essential amino acid whereas d-methionine is non-nutritive. For purposes of metabolism, 1-methionine via S-adenosylmethionine has an important methylating function. In this function it loses a methyl group from its sulfur atom to become homocysteine. Homocysteine in excess can lead to homocysteinuria, and may be heart disease associated (Malinow, et al., Circulation 79:1180-88, 1989 and Olszewski and Szostak, Atherosclerosis 69:109-13, 1988). Folic acid has been shown to be an innocuous method to reduce plasma homocysteine levels (Brattstrom et al., Scand. J. Clin. Lab. Invest. 48:215-221, 1988). Administration of 8 grams of 1-methionine to adult subjects for four days caused a greater than 30% reduction in serum folate levels (Conner, et al., PostGrad. Med. J. 54:318-20, 1978).
Administration of large amounts (5 to 10 grams per day) of 1-methionine can cause gastrointestinal upset. Many people report a burning sensation in the stomach after taking methionine, along with an upset stomach and flatulence (Delrieu, et al, Revue du Rhumatisme, 55:995-7, 1988) Enteric coating and timed-release formulations should avoid the stomach problems and allow even elevations of blood methionine for maximum anti-oxidant effect. Typical enteric coating agents include cellulose acetate phthalate, and other cellulose ethers and derivatives (Johnson, J. C., in Sustained Release Medications, Noyes Data Corp, N. J., 1980, p.14).
The Food and Nutrition Board of the U.S. National Academy of Sciences has established the Recommended Daily Allowance (RDA) for nutrients for most healthy individuals. For a discussion, see The Nurses Guide to Drug Therapy, Eisenhauer and Gerald, Prentice-Hall, New Jersey, 1984-5, pages 84-602). RDA's include: Vitamin A: 5000 I.U.; Vitamin B12:3 mcg.; Vitamin B6: 2 mg; Vitamin B3: 18 mg ; Folic Acid: 400 mcg.; Vitamin C: 100 mg ; Vitamin D: 400 I.U ; Vitamin E: 15 I.U : Calcium: 800-1200 mg.; Iron: 18 mg.: Selenium: No RDA has been established, but the maximum non-toxic suggested dose is 200 mcg. per day; zinc: 15 mg. For a review of lifestyle risk factors and of protective factors in the diet, see the article by Bruce N. Ames entitled "Dietary Carcinogens and Anticarcinogens", Science, 221:256-68, 1983.
Epidemiological evidence in man correlates elevated blood level of triglycerides with increased occurrence of gallstones. Also, low serum cholesterol levels are associated with a high prevalence of gallstone disease. Thus, dietary methods to lower serum cholesterol may increase the risk of gallstones if serum triglyceride levels are not lowered at the same time. (Angelico, et al., In: Epidemiology and Prevention of Gallstone Disease, Capocaccia, L., et al, eds. MTP Press Ltd., Boston, 1984, p. 77-84). Yanagita et al., (Agricultural and Biological Chemistry, 48:815-6, 1984) show that administration of methionine to rats causes a doubling of hepatic triglycerides. However, Sugiyama, et al , (Agric. Biol. Chem., 49:3455-61, 1985) showed that the addition of glycine to a methionine supplemented diet had no effect on the elevation of triglycerides caused by the methionine.
The patent to Scheinberg U.S. Pat. No. 4,315,028 describes a method of treatment of arthritis employing substituted cysteines.
The S-methyl derivative of methionine, S-methyl methionine, also known as vitamin U has been shown to have benefit as an anti-ulcer compound and to have benefit for allergies. The same benefit is shown for carboxyl esters and N-acyl derivatives (Kowa, DT 282-704). However, in this teaching no distinction is made for the d- and 1- isomers of S-methyl methionine or its derivatives and no claim is made that these compounds act through anti-inflammatory mechanisms.
The patent to Damico, U.S. Pat. No. 3,952,115 describes foodstuffs containing N-acyl 1-methionine esters and N-acyl 1-cysteine esters. d-Isomers are specifically excluded because they are "not nutritionally available".
The patent to Fahim, U.S. Pat. No. 4,711,780, shows the benefit of the combination of cysteine with vitamin C and zinc salts in a topical mixture for stimulating cell proliferation. The benefit of methionine is claimed but not shown. No demonstration of benefit or claim for systemic administration is made.
The patent to Bayless, U.S. Pat. No. 4,902,718, describes the use of methionine compounds for respiratory. The patent to Bayless, U.S. Pat. No. 4,927,850, describes the use of methionine compounds for calcium normalization, hypertension and osteoporosis. The patent the Hirsch, U.S. Pat. No. 5,053,429 describes the use of methionine compounds for inflammatory pain. The patent to Hirsch, U.S. Pat. No. 5,084,482, describes the benefits of methionine compounds for ischemic thrombotic and cholesterolemic diseases. These patents also teach the use of glycine and serine alone or in addition with vitamins and minerals to reduce the side effects which are associated with elevated homocysteine resulting from methionine consumption.
From the extensive infection of humans with HIV and the impending epidemic of AIDS there is an immediate need for improved and safe means of treating disease conditions and delaying the onset of symptoms of AIDS.
It is an object of the invention to provide methods for the treatment of disease conditions and delay the onset of symptoms which occur in AIDS.
It is also an object of the invention to provide means prevent or alleviate elevation of serum triglycerides that may result from excess methionine intake.
It is also an object of the invention to provide a safe means of thiol repletion.
These and other objects, features and advantages will be seen from the following detailed description of the invention.

Treating aids and HIV infection with methionine


A zoom lens camera including a zoom taking lens having a zooming function, a motor for driving the zoom taking lens, a telephoto switch which is actuated to effect the motor to drive the zoom taking lens in a manner that increases the focal length thereof, a wide angle switch which is actuated to effect the motor to drive the zoom taking lens in a manner that decreases the focal length thereof, and a zooming speed controller for varying the zooming speed of the zoom taking lens when a predetermined condition is satisfied during the zooming operation when one of the telephoto switch or wide angle switch is actuated.

1. Field of the Invention
The present invention relates to a motor driven zoom lens camera. More precisely, it relates to a zooming speed control apparatus thereof.
2. Description of Related Art
A known motor driven zoom lens camera has zoom switches including a telephoto switch for increasing the focal length and a wide angle switch for decreasing the focal length. When one of the zoom switches is actuated (turned ON), a drive motor is rotated in the forward or reverse directions to effect a zooming operation in the telephoto direction or the wide angle direction, respectively. In a conventional zoom lens camera, the zooming speed in the telephoto or wide angle directions is constant.
In a recent zoom lens camera, when a main switch is turned ON or OFF, a zoom taking lens is moved between a photographing position in which a picture can be taken and a retracted position in which the zoom taking lens is retracted, respectively. It is known to provide a zoom lens which is operable, in accordance with the operation of the main switch, at a speed higher than the speed at which the lens is driven in a normal zooming operation. However, even in a known zoom lens camera in which a higher speed of the zoom taking lens is effected when the main switch is turned ON or OFF, accelerated movement is not available during the normal zooming operation.


A fastening system fastens a radiator, an electric fan support and a fan shroud as a single unit. The radiator has lower and upper posts to which slotted plates protruding from the fan support and fan shroud fit over. A structural sandwich is formed with the fan support lying between the radiator and the fan shroud. A flexible lever arm with a locking tab lies adjacent to the upper post of the radiator and connects to the radiator. When the fan support is fitted over the posts, the top plate of the electric fan support locks under the first lever arm tab. The fan shroud also has two slotted plates that also fit over the posts of the radiator. The fan shroud locks into place when a lever arm with a tab on the fan shroud locks under a tab that protrudes from the top plate of the fan support.

The statements in this section merely provide background information related to the present disclosure and may not constitute prior art. Traditionally, engine cooling modules have been assembled using traditional fasteners, such as screws or a bolt and nut arrangement. While these fasteners have proven satisfactory for their purpose, such traditional fastener methods have not been without their share of limitations.
There are multiple limitations of traditional fastener systems. One such limitation is that traditional fasteners, whether clips, screws, or a bolt and nut combination, may vibrate loose due to vibrations caused by an engine or road surface as a vehicle travels on a road. Loose fasteners may eventually fall out of their originally secure location. Another limitation is that traditional fasteners are physically separate components from the parts that need to be fastened, and as such, the fasteners must be brought to the parts for which fastening is desired. This represents an added fastener cost and assembly time to install such fasteners. Another limitation is that in a location where installation and removal space of the attached parts is limited, traditional fasteners may be difficult or even prevent certain designs because traditional fasteners require space for installation and removal tools as well as space for the person or machine who installs such parts. Still yet another limitation is that traditional fastening devices do not permit stacking, or a series assembly, of multiple parts of a module, that can be accomplished in a fast, convenient, and reliable manner.
What is needed then is an attachment device that permits a fast and secure connection of parts, such as parts assembled in series, without the space and tools necessary to install separate, traditional fasteners.

Fastenerless attachment system applied to vehicle engine cooling module components


Enhanced product tracking, in which a data collection interface is established between a first supply management device and a transaction database, the data collection interface providing the transaction database with access to identification data and event data, the identification data uniquely identifying a pharmaceutical, and the event data relating to a supply chain process step for the pharmaceutical. Tracking also includes receiving a tracking request for formatted identification data and/or event data from a second supply management device; and establishing a data conversion interface between the second supply management device and the identification data and/or the event data, the data conversion interface providing the second supply management device with access to the identification data and/or the event data, according to the tracking request.

1. Field of Invention
The present invention relates to a system, computer program product and method for tracking processing events for a meat animal from its conception to its consumption, by using data entry devices that minimize keyboard entry and multiple interconnected databases such that a particular animal history can provide both quality assurance source verification and performance tracking.
2. Description of Related Art
Overview
There is a need, for both economic and quality assurance reasons, for an efficient and cost-effective method for identifying and tracking livestock, and for the monitoring of the processing of those livestock. Throughout the livestock production and processing cycle, there is a need for more detailed information so that ranchers, stockmen, feedlots, packers, distributors retailers, consumers, and others can make informed decisions about factors and variables such as genetics, herd management, purchasing, feed strategies, and ship dates. Producers who improve their animal performance can realize greater returns with performance based compensation when accurate information about the history and the value of each animal is easily available.
There is also a growing concern about quality assurance in the livestock processing cycle; and there is an opportunity for producers and processors who can establish that quality assurance to improve their compensation. Effective quality assurance programs such as HACCP, or Hazards Analysis and Critical Control Points, programs require accurate and timely information about the history of each animal. The certification of organic food products, hormone-free food products, and non-genetically modified food products requires an accurate history of those food products.
The Beef Industry
The beef industry is a good example of the livestock industry. Traditionally, there are four segments to the U.S. beef industry: the cow/calf producer, the stockman, the feedlot, and the packer.
The commercial cow/calf producer has a herd of mother cows that are used to produce calves. The cows are bred to bulls so that, ideally, each cow has a new calf each year. The calf crop that is produced each year is used primarily for meat production, with some calves retained as replacements for the herd. The calves are usually weaned from their mothers at between six and eight months of age. The traditional producer will sell his animals once they are weaned. Typically, the main objectives of the producer are to have a calf from each cow each year; to have healthy, vigorous calves with the highest weaning weights at the lowest cost; and to produce the best meat, by factors such as tenderness and taste, at the lowest cost.
In order to support these objectives, the producer is interested in efficient systems for identifying and tracking individual animals as they rotate through the producer's pastures; identifying which animals have a good calving history; monitoring the performance of various pastures; recording calf birth date and birth weight statistics and tracking the genetic history of each animal; evaluating the performance of calves from particular cows or bulls; recording the weaning date and weaning weight of each animal; and recording treatments, vaccinations, and other significant events that have occurred in the animal's life.
The stockman receives the weaned calves when they weigh approximately 500 pounds, and feeds them for four to six months until they weigh 700 to 800 pounds. The stockman's typical objective is to add weight as fast as possible, while keeping the animals healthy. In order to support these objectives, the stockman is interested in collecting and using information such as identifying and tracking individual animals as they rotate through the stockman's pastures; recording beginning, ending, and periodic weight measurements and treatments; and recording vaccinations, movement and ownership changes, and other significant events that have occurred in the animal's life in order to track of the success of treatments as well as to eliminate duplicate treatments.
After the stockman phase, the animals are typically sent to a feedlot where they are fed a high-energy diet for about 150 days. At the feedlot, the cattle are in a finishing stage, where the main objective is to add pounds quickly while keeping the animals healthy. The cattle will be finished when they reach a weight of approximately 1,100 to 1,200 pounds. The feedlot is interested in animal weight gain, animal health, the effectiveness of various feed ration formulations, the characteristics of the feed consumed by an animal, required waiting periods on shipping animals after drug treatments, and animal origin and history.
The slaughter facility or packer typically slaughters the animal and then chills, ages and cuts the carcass into the various cuts of meat and packs those cuts for shipment to distributors and retailers. The packer also provides grade and yield ratings for the carcass. Important quality factors include the live animal weight, the carcass weight, a chilled weight; and the yield, grade, and quality of the carcass and carcass defects. The information collected by the packer is important to all of the upstream participants, because it allows them to adjust their management practices based on the actual quality and economic result for each animal. The upstream data is important to the packer because it permits the packer to select animals that produce the results desired by its customers.
Typically, each of these four segments, the cow/calf producer, the stockman, the feedlot, and the packer, have attempted to optimize their own operations, and there has been relatively little emphasis on cooperative optimization efforts. There is a growing recognition across these industry segments, however, that for both quality assurance reasons and for the improvement of the industry in general, it is desirable to improve data collection and data management. An object of the present invention is to provide improved data collection and data management and reporting.
Variability and Quality Control
There is variability in individual animal production efficiency and in individual carcass quality characteristics such as weight, frame size, muscling, fat content, marbling, and feed efficiency. This variation is due to a combination of genetic factors and environmental factors such as health and drug treatments, nutrition, growth history, and environmental and management factors such as geography, weather, and animal husbandry. Many of the genetic and environmental factors can be controlled or managed to improve both quality and economic return on investment if accurate historical information were available throughout the production cycle.
The livestock industry has recognized that certain livestock species and breeds outperform other species during production and processing. The prior art has used data collection systems and statistical analysis of data related to livestock breeds in order to identify higher performance breeds. There is a need to extend this data collection so that individual producers can make informed decisions about individual animals in order to further improve their herds.
Electronic Identification
Although it is possible to use manual identification methods for livestock and to employ manual data entry methods, it is desirable to automate the identification and data entry in order to reduce expense and to improve accuracy of the data. These devices typically produce either a unique alphanumeric code or a unique decimal code.
Electronic identification devices and systems have provided a good method for providing identification of livestock. Typically, electronic identification systems utilize a passive electronic identification device that is induced to transmit its identification signal by an externally radiating source. These passive electronic identification devices may be a transponder carried with the individual animal on a collar as illustrated and described in Carroll U.S. Pat. No. 4,475,481, issued Oct. 9, 1984, entitled "Identification System" and in Kuzara U.S. Pat. No. 4,463,353, issued Jul. 31, 1984, entitled "Animal Feeding and Monitoring System"; in an ear tag such as those commercially available from Destron/Fearing, Inc., Allflex USA, Inc. and Avid Marketing, Inc.; in a transponder implanted in the animal as illustrated and described in Pollack U.S. Pat. No. 4,854,328, issued Aug. 8, 1989, entitled "Animal Monitoring Telltale and Information System" and in Hanton U.S. Pat. No. 4,262,632, issued Apr. 21, 1981, entitled "Electronic Livestock Identification System"; or in a bolus such as illustrated and described in U.S. Pat. No. 4,262,632, issued Apr. 21, 1981, entitled "Electronic Livestock Identification System" by John P. Hanton and Harley A. Leach.
Although electronic identification through radio frequency identification (RFID) tags or barcodes are used in some phases of the livestock production cycle, there is a need to provide a means for individual animal identification throughout the production cycle and to minimize the difficulty of data entry throughout the industry, by interfacing with identification technologies such as RFID, barcode, retina scan, iris scan, DNA, and visual identification.
RFID Readers
Several RFID readers are commercially available, typically from the transponder suppliers, including models from Destron/Fearing, Inc., Allflex USA, Inc., Avid Marketing, Inc., and Tag Tracker™ from InfoClip LLC.
The prior art includes RFID readers that can distinguish multiple types of RFID transponders as illustrated and described in U.S. Pat. No. 5,235,326, issued Aug. 10, 1993, "Multi-Mode Identification System" to Michael L. Beigel, Nathaniel Polish, and Robert E. Malm.
Databases and Management Systems
At different stages of the production cycle, there are different databases, which exist for different business purposes. The rancher will typically maintain his own database, a stockman will have an inventory system, a feedlot will have a management database, and a packer will have its own inventory and management system. There is also a trend toward larger marketing alliance or national databases that include some data from each of these industry segments.
U.S. Pat. No. 5,322,034, which issued Jun. 21, 1994 to Richard L. Willham, for a "Livestock Record System" describes a method for storing the individual animal's identification and performance data on a programmable electronic identification and data storage module carried with the animal. An object of the present invention is to provide a low-cost per animal system for obtaining and maintaining source verification and performance databases that are independent of the animal.
U.S. Pat. No. 5,315,505 issued to William C. Pratt on May 24, 1994 for a "Method and System for Providing Animal Health Histories and Tracking Inventory of Drugs" describes a method and system for providing improved drug treatment to selected animals in a retained group. A computer system is used to provide an operator with the health and drug treatment history of an animal. With this information and a diagnosis of the animal's health condition, a drug treatment is chosen. The diagnosis and treatment are entered into the computer system to update the animal's health and treatment history. An object of the present invention is to provide complete source verification and performance databases for all key livestock events.
U.S. Pat. No. 5,673,647 for a "Cattle Management Method and System", issued on Oct. 7, 1997 to William C. Pratt, describes an automated method and system for providing individual animal electronic identification, measurement and value based management of cattle in a large cattle feedlot. That method includes individual animal identification, a computer system, and multiple measurements coupled with a cattle handling and sorting system. An object of the Pratt patent was to build a feedlot database to more accurately identify and measure characteristics such as weight, so that subsequent animals could be produced and fed for more effective value-based selection and management of the animals. In particular, that database related to calculations for economic management of feeding and shipping to permit optimum weight gains and feedlot ship dates. Whereas the feedlot patent disclosed identifying a particular animal on arrival at the feedlot, an object of the present invention is to track individual animals throughout the production cycle and to maintain performance and source verification data in the least disruptive manner to existing databases and management systems.

This patent is subject to a terminal disclaimer.


The present invention provides a method for preparing a cell culture medium comprising a mixture of blood products from two or more donors, comprising the steps of: a) providing at least a first blood product from a first donor; b) measuring the concentration of at least one quality factor in the first blood product; c) comparing the measured concentration of a quality factor to a concentration range predefined for the quality factor; d) selecting the first blood product for the cell culture medium if the concentration measured for the quality factor is in the predefined range and optionally converting the first selected blood product into a first processed blood product or else unselecting the first blood product.

One of the most promising advances for the treatment of cancer is a new therapeutic class called active cellular immunotherapy. Active immunotherapies, stimulate the patient's immune system with the intent of promoting an antigen specific anti-tumor effect using the body's own immune cells. For this the immune cells are cultured in-vitro to increase the number of cells and influence the differentiation.
For culturing cells in-vitro several basic environmental requirements have to be met such as controlled temperature, substrate for cell attachment, and appropriate growth medium and incubator that maintains correct pH and osmolality.
Cell culture media formulations have been well documented in the literature and a number of media are commercially available. Cell culture media generally comprise an appropriate source of energy and compounds which regulate the cell cycle. A typical culture medium is composed of a complement of amino acids, vitamins, inorganic salts, glucose, and serum as a source of growth factors, hormones, and attachment factors. In addition to nutrients, the medium also helps maintain pH and osmolality.
Cell culture media formulations have been well documented in the literature and a number of media are commercially available. For cultivation and expansion of immune cells, in particular lymphocytes, typically the cell culture medium is derived from serum or plasma as these provide an environment for the immune cells that is similar to the natural environment of the body.
However, the proliferation rate and activity of lymphocytes expanded in a culture medium of the state of the art is not yet sufficient. Moreover, predictable results regarding the quantity, quality and viability of the lymphocyte expansion results are so far rare and the necessity of testing several batches of serum in order to identify the required quality is common practice.
Accordingly, it an object of the present invention to overcome at least one of the disadvantages of the prior art.

Culture medium for cellular immunotherapy


The present disclosure provides a light emitting diode package including a substrate, a first electrode and a second electrode located on a first surface of the substrate, a plurality of light emitting diodes (LEDs) located between the first electrode and the second electrode, a plurality of retaining ring located on the first surface of the substrate. The LEDs are surrounded by the retaining ring therein. An encapsulation layer is mounted in the retaining ring and covers the LEDs therein. The encapsulation layer includes a first surface and an side surface extending from edges of the first surface. The side of the encapsulation layer contacts an inner surface of the retaining ring. The present disclosre also provides a method for manufacturing the above light emitting diode package.

A light emitting diode (LED) package generally includes a substrate, an LED chip mounted on the substrate, and an encapsulation layer formed on the substrate and covering the LED chip therein for preventing the LED chip from the water vapor and the dust. The encapsulation layer includes glue and phosphors mixed in the glue.

Light emitting diode package and method thereof

ADVANCED OPTOELECTRONIC TECHNOLOGY, INC.


A pre-startup control method for a boiler or water heater includes: providing a controller operatively coupled to a boiler or water heater unit; performing a unit shutdown operation; enabling a pre-start up mode; at about a same time or in any order, moving an air fuel valve by a controller to a non-off position with a gas supply to the water heater or boiler turned off, wherein the controller turns on a blower at an operational level, and causes an ignitor to spark; and displaying parameters which allow an affirmation of a safe and reliable ignition prior to a gas turn on of the boiler or water heater unit. A flow balancing method and a programmed auto run method are also described.

Newly installed or new construction commercial gas fired water heaters or boilers often require a gas company representative be present when the water heater or boiler is first fired. Some commercial installations operate a series of water heaters or boilers at the same time for increased heating capacity. Once operational, there can be certain sequences or profiles of operation which repeat only occasionally or seemingly at random times.