Action on the tested wafer 1 is rendered with X-ray beam 3 converging in a point located inside the wafer or under it. Determination of relative position of the interference maxima is performed for diffraction reflections from crystallographic planes having the form of {nKK}, where n is equal to H, K or L and differs for distinct crystallographic planes.

1. Field of the Invention
The inventions proposed are related to X-ray means for detecting of the elastic strains present in single-crystal wafers and are intended, in particular, for use in monitoring of the manufacturing process of printed-circuit substrates in microelectronics.
2. Description of Related Art
A method is known for detection of elastic strains present in a single crystal, is based on its interaction with monochromatic infrared radiation (see Y. Kawano et al., Infra Red System GaAs/AlGaAs., J. Appl. Phys. 2001, 89, p. 4037 [1]). At the sites of disturbances of periodicity and orientation of crystal lattice the interference maxima of infrared radiation are observed, and registered by semiconductor sensors.
In single-crystal materials with metallic interatomic bonds (germanium, silicon, arsenic, and others), transmission over them of thermal vibrations results in broadening of said maxima and rising of background level up to their merging. This makes the usage of said method in manufacturing wide assortment of single-crystal wafers impossible.
Also known is X-ray method for detection of elastic strains located in single-crystal wafers (see O. Brümmer. Zeitschrift für Naturforschungen, 15A, S.875, 1960 [2]).
This method is based on detection of crystallographic planes departures from relative orientation.
Surface of single-crystal wafer is illuminated with widely diverging X-ray beam. Diffracted radiation is registered with a flat X-ray film. The recorded diffraction of the interference pattern is compared with a reference pattern obtained for reference standard single-crystal wafer, and a conclusion about presence or absence of elastic strains in single-crystal wafer inspected is reached by the degree of their divergence. Angular divergence of illuminating beam is adjusted so as to ensure fulfillment of diffraction conditions for two or three sets of crystallographic planes. For the most of widely used materials of single-crystal wafers said angular divergence of illuminating beam can reached of 30–40°.
Using of a beam having such a large divergence implies large illuminated surface area of single-crystal wafer participating in diffraction and, as a consequence, results in generation of averaged interference pattern, induced by diffraction in different geometric points of a surface. Therefore, unambiguous interpretation of interference pattern of diffraction registered on the film is made difficult. Because of this, high probability of erroneous results of the control. Besides, photographic method of registration used requires large exposure times (several hours) as well as some satisfactions simultaneously the requirements to resolution and contrast. This constitutes the principal obstacle to establishing complete control in flow-line production, thus inducing forcedly random testing of a small number of wafers.
Method and device known from [2] are the most close ones to those proposed.

Method for determination of elastic strains present in single-crystal wafers and device for its realization

Abstract: Means 11 for beam shaping creates beam 3 simultaneously acting on multiple crystallographic planes. Detectors 13 receive diffracted radiation in the whole angular range containing the interference maxima corresponding to the reflections from the irradiated planes.


Multiple models for various stages of a non-linear process control are developed by clustering perturbation data obtained from the nonlinear process so as to permit multiple local data regions to be identified as a function of substantial similarity between the data, wherein the data of first data set represent the non-linear process. A discrete model corresponding to each of the local data regions is generated. The number of the discrete models may be reduced as a function of prediction error between actual outputs of the process and predicted outputs of the models and as a function of a gap metric based on closed loop similarity and frequency response similarity between the models.

Model based process control methods are typically deployed for flexible operation and improved productivity of a number of processes such as those related to chemicals, polymers, natural gas processing, pharmaceuticals, microelectronics, and pulp and paper industries. These processes often require product grade transitions to fulfill customer needs and to reap benefits of market dynamics.
Because such a flexible mode of operation is required, many processes need to be transitioned and regulated over a broad range of operating conditions. Because the dynamics of such processes change significantly during such transitions, the underlying dynamic models used in the controller need to be updated. It is desired that this updating result in the deployment of high fidelity models which will help to consistently improve productivity, flexible operability, safety, and profitability of the operating units.
Model Predictive Control (MPC) technology is quite popular in refineries where the process usually operates at steady state and the process dynamics can be adequately represented by linear models. However, there are important instances in other adjacent industries (such as those involving chemicals, polymers, natural gas processing, pharmaceuticals, microelectronics, and pulp and paper) where linear models do not adequately represent the process dynamics. These processes are either highly nonlinear at a particular steady state (e.g., pH control) or involve frequent process transitions from one operating point to another (e.g., grade transition in polymer industries, etc.).
It is highly desirable to regulate these processes at an operating point and to transition them from one operating point to another in an optimal and controlled manner. Such controlled and optimal transitions can deliver many economic incentives such as reduced transition times, reduced amounts of off-spec products, optimal utility consumptions, etc. To achieve controlled and optimal regulation and transition of these processes, nonlinear model predictive control is more suited to address the issue of process nonlinearity.
The nonlinear model predictive control that is recommended for regulation of such processes uses either nonlinear dynamic models or successively linearized dynamic models of the processes. However, the nonlinear dynamic models that are used are generally very complex, difficult, and expensive to build because they are based on the first principles (underlying mass, energy and momentum conservation equations) governing the process. Moreover, nonlinear model predictive control has to solve a suitably formulated optimization problem, which is well known to those skilled in the art, in real time at every control execution interval. The use of complex nonlinear models for nonlinear model predictive control can lead to numerical and computational issues. In some cases, the solution of the optimization problem can become infeasible or non-optimal.
An alternative approach that is attractive and that potentially solves such problems is to decompose the nonlinear dynamics into multiple linear models, and then switch smoothly among the models based on the current state of the process. In such a case, the nonlinear model predictive control optimization problem based on linearized models becomes better structured and can be solved quickly and in real time. However, this approach requires the building of a library of linear dynamic models spanning the expected range of operation.
As a practical matter, the identification of the models to be used in the control is a data driven procedure. In general, model identification requires the application of properly designed perturbation signals that perturb the nonlinear process in the expected range of operation. Measurements of the manipulated variables (MVs), disturbance variables (DVs), and controlled variables (CVs) of the process during perturbation are collected as the process output data and are subjected to data based modeling.
It is highly important to keep the process within safety limits during such perturbations. Data based model identification is important to the success of nonlinear model predictive control. For the identification of multiple models, model identification as proposed herein should address such issues as (i) the selection of the number of local models, (ii) the development of the local models, (iii) the switching strategy to be implemented in switching between the models when the models are deployed online, and/or (iv) the closed loop stability when the models are switched.
Various approaches of model de-composition of nonlinear dynamic processes have been attempted. One approach has been proposed by Wojsznis, et al. U.S. Patent Application Publication No. US 2005/0149209) "Adaptive Multivariable Process Controller Using Model Switching and Attribute Interpolation." The approach used by Wojsznis is to perform interpolation between local model parameters based on some heuristics and model validity measures. However, the heuristic based approach is inadequate for a wide variety of applications. This approach also assumes homogeneity of the local models and linear interpolation of the model parameters, an assumption that is not always valid.
An alternative approach is proposed by Narendra K., and Balakrishnan J. in "Adaptive control using multiple models", IEEE Trans. on Auto. Cont., 42(2), 171-187, (1997). However, this approach assumes availability of knowledge of various operating regions, their ranges, and their centers, an assumption that is again not always valid.
Gomez Skarmeta, A., F., Delgado M., and Vila M., A., have proposed a fuzzy classification based multi model decomposition approach in "About the use of fuzzy clustering techniques for fuzzy model identification", Fuzzy sets and Systems, 106, 179-188, (1999). However, this approach does not consider stability in selecting the optimal number of local models.
Galan et al., in "Gap Metric Concept and Implications for Multilinear Model-Based Controller Design," Ind. Eng. Chem. Res., Vol. 42, pp. 2189-2197, (2003), have applied the stability analysis in selecting the optimal number of local models in their paper. However, in this approach, the local models are not obtained via data based modeling but are developed using linearization of first principle based model.
Moreover, none of the above approaches has considered a smooth switching strategy for the selected local models.
The present invention overcomes one or more of these or other problems.

Decomposition of nonlinear dynamics using multiple model approach and gap metric analysis


A method and system are provided for detecting theft of a computer. A portable device is provided to wirelessly communicate with a theft deterrent function of the computer at a set frequency. In response to an increased distance between the portable device and the computer, a scan rate controller can automatically increase the scan rate for the wireless communication signal.

1. Technical Field
This invention relates to a theft deterrent system of a computing apparatus. More specifically, a method and apparatus are provided for changing the responsiveness of a theft deterrent function in relation to power consumption of the computing apparatus.
2. Description of the Prior Art
As technology advances, there is a strong desire for making electronic items smaller and more portable. Laptop computers are portable personal computers that can be easily carried from one location to another location. There is a need to secure laptop computers from theft as well as use by an unauthorized person, and to provide a theft deterrent system to mitigate access by an unauthorized person.
Japanese Patent Publication 2004-240744 to Tomoyuki discloses a monitoring device for movement of an item of interest. As disclosed, the '744 publication teaches a monitoring mode switched to an ON position in response to a relative location of the item of interest being moved. If the relative location of the item returns to a predetermined value, the monitoring mode is switched to a suspend mode. The '744 provides for one of two positions for monitoring an item, an ON position and a suspend position. Each of these positions is set in response to movement of a designated item of interest. However, there is no support for adjusting sensitivity of the monitoring mode after it has been switched to an ON position.
Japanese Patent Publication 2003-109127 to Yuukou et al. discloses a system for generating an alarm in response to theft of a portable article. There are two communication modules in the '127 alarm system. A first communication module is loaded on the portable article, and a second communication module is loaded on an article of a person. The first and second communication modules communicate through transmission of high frequency radio signals. While a high frequency signal is transmitted and received between the two communication modules and a burglar prevention mode is set to ON, a warning alarm remains silent. However, at such time as the portable article and the article of the person are separated beyond a tolerated distance and the high frequency signals between the two communication modules is not received, an alarm is generated. Accordingly, the '127 publication requires generation of high frequency signals at all times between the two communication modules when the alarm system is set and does not provide for adjustment of the frequency setting of the signals between the two communication modules.
Japanese Patent Publication 2002-092752 to Tokusho provides a device for a wireless theft detector of an object through a vibration sensor. A transmitting unit is provided to transmit a control signal to a receiving unit. An alarm is generated when it receives a signal from the vibration sensor or when it does not receive a communication from the transmitting unit. However, as in the '744 publication to Tomoyuki, there is no support in the '752 publication for adjusting the sensitivity of the control signal.
Each of the prior art publications discussed above utilize wireless communication between an item being monitored and a remote unit. In the each of these systems there is a constant transmission of radio signals between two units at a set frequency. Transmission of radio signals requires electricity. If the item being monitored has a battery supply, there is only a limited amount of electricity available for a limited amount of time. Most laptop computers come with batteries that deliver power to the computer when it is not otherwise receiving power from an alternative source. However, batteries have a limited amount of power, and when the power expires the battery requires recharging. There is no support or suggestion for enabling the communication of the radio signals between the two entities to be adjusted to compensate for a limited energy source. Accordingly, there is a need for a wireless system that monitors theft and/or vibration of a portable item while conserving energy and thereby extending the operable period of time.


Provided is an image processing method of processing first red, green, and blue (RGB) data with a display device including a pixel configured with red, green, blue, and white sub-pixels and providing the processed data. The method includes receiving the first RGB data, rendering the first RGB data to generate second RGB data and white (W) data, converting the first RGB data into hue, saturation, and value (HSV) data, obtaining RGB compensation data by using the HSV data on the basis of a lookup table, compensating for the second RGB data by using the RGB compensation data, and outputting the compensated second RGB data and the W data.

The present disclosure herein relates to an image processing method and a display device using the same, and more particularly, to an image processing method using an HSV (hue-saturation-value) color space and a display device using the same.
New techniques are being developed for extending a color gamut of an image displayed on a display device.
Since a skin color among colors displayed on a display device corresponds to a memory color, humans feel more sensitive to a skin color distortion.
Various methods are being suggested to compensate for a distortion of a skin color, but existing methods typically require excessive matrix operations.
Accordingly, there is a need to accurately represent a skin color while reducing an operation amount compared to the existing methods.

Image processing method and display device using the same


A system and method for manufacturing an uncured concrete block using the dry-cast manufacturing process includes a mold box having a pair of side walls, a pair of side plates, an open top side and an open bottom side defining a mold cavity. One or more end liners are disposed within the mold cavity and are selectively shiftable within the mold cavity with hydraulic cylinders between a first position and a second position. The end liners can be provided with a three-dimensional textured face to impart a decorative face to a side surface of the concrete block formed in the mold or can also provide blocks with a tapered face when disposed in the second position while the mold is filled with concrete. Before the block is stripped from the mold, the end liners are returned to the first position, so that the side surfaces are not damaged as the block is released.

Concrete blocks are used to form free standing and retaining walls. In such applications, the visible face or faces of the blocks are often provided with a textured or decorative appearance. Concrete blocks for forming walls are used in a variety of applications from small gardening applications to large-scale construction projects. Blocks are stacked in horizontal rows called courses. Multiple successive courses may be used to create a vertically rising wall of a desired height.
The concrete blocks used in constructing such walls are often manufactured using the dry cast process, which uses dry-cast block machinery to form blocks at a relatively high rate of speed. In a typical dry-cast block machine, material is fed into an open top mold from the top side. The conventional mold consists of stationary sides, to define the sidewalls of the block, and an open bottom. A removable pallet is used to temporarily close the open bottom of the mold and serve as a base during the block forming operation.
During manufacture, the material introduced through the open top collects on top of the pallet and is bounded by the end and side panels. A compression head is then pressed downwards under high pressure onto the material through the open top of the mold to compact the material therein. The head forces material into the mold so as to conform to the shape of the mold. The mold may also be vibrated during compaction to promote uniform compaction. The head may also be provided with one or more shoes that have relief defined therein in order to impart detail into the material that is contacted by the head's movement.
After compaction and vibration, the bottom pallet drops down, the head follows the pallet and the newly made product downward while the sides of the mold remain in position, and when the product clears the bottom of the mold, the pallet moves away from the mold and another pallet moves in place to make the next product. The head returns to its original position and the feed drawer brings more material into the mold to make the next product. The molding machinery is able to cycle several times per minute.
U.S. Pat. No. 5,827,015 teaches the use of conventional dry cast molding methods to form a twinned concrete slug in the molding machinery. The slug is then split into two blocks after being cured. It should be appreciated that the top surface of the finished wall block made according to the conventional dry cast manufacturing method is formed by the surface of the steel pallet. The bottom of the block is accordingly formed by the stripper shoe.
The need to eject the formed blocks through the bottom of the mold used in dry cast manufacture places limitations on the ability to create a decorative front face on the block because the sidewalls of the mold shear across the side surfaces of the block when stripped from the mold. Therefore, efforts have been made to provide for a decorative front face on concrete wall blocks.
One common current method of producing a wall block with a decorative front surface is to split a cured block (or a twinned slug) so that the front surface of the block has a fractured concrete surface that looks somewhat like split rock. This is done by forming a slug in a mold and providing one or more grooves in the slug to function as one or more splitting planes. The slug is then split apart to form two or more blocks. The appearance of the face of such block is exhibited by U.S. Pat. No. D380,560. This gives the front face of structures built with these blocks some visual depth that makes the structure look more natural. The number of facets and their arrangement can be varied to provide for different looks such as shown in U.S. Pat. No. D429,006.
More recent references, such as U.S. Pat. No. 6,321,740, disclose modification of the splitter blade used in splitting the cured block to provide edges that appear more weathered. Splitting, however, adds additional production costs by requiring an additional step to the manufacturing process and results in waste material. Furthermore, split-faced concrete blocks do not sufficiently resemble natural stone to satisfy some consumer needs.
Another method to make blocks that have decorative front surfaces is described in U.S. Pat. Nos. 5,078,940; 5,217,630; and 6,224,815. These patents describe a method and an apparatus for manufacturing a concrete block having an irregular surface. The irregular surface can be made to look similar to split stone. This method includes pouring uncured block material into a mold cavity and causing a portion of the material to be retained in place relative to the cavity walls when the block is removed from the cavity. The result is a somewhat split appearance for the surface, without having to perform the splitting operation. However, the block produced from this method still does not satisfactorily resemble natural stone.
Other methods employed to provide for improved decorative appearance include spraying the front face of an uncured block to wash away some cement to leave exposed aggregate. Another method consists of "weathering" a cured block by tumbling it in a tumbler with tumbler chips that knock off random pieces of the block, which rounds the ends and creates a look closer to the appearance of weathered stone. These methods, however, are labor intensive and can damage the blocks, resulting in a higher overall cost of production.
Commonly owned, copending application Pub. No. US 2004/0218985, which is hereby incorporated by reference in its entirety, discloses an alternative method of providing a decorative simulated natural stone face to the front surface of a block while using the dry cast manufacturing method. The molding apparatus is configured such that the front surface of the block faces up in the mold and can therefore be provided with a pre-defined decorative face because the shoe stamps or contacts it directly. This process, however, limits the ability to provide for sidewalls that deviate from conformance to the smooth vertical sidewalls of the mold box because the downward movement of the block through the mold prevents a mold with stationary angled sidewalls or relief from being used.
U.S. Patent Pub. Nos. 2003/0126821 and 2003/0182011 disclose a block machine that stamps a face on the front surface of a block while also providing a tapered sidewall to the block by use of pivoting sidewalls. However, this system does not teach the ability to impart a complex decorative face on the side surfaces of the blocks. In addition, the mold must be taken apart to a degree that makes it difficult to perform maintenance or repairs of the biasing mechanisms. This difficulty can cause undesirable delays in production.
A block and a method of making a block having two or more adjacent decorative faces is disclosed in commonly owned, copending U.S. Patent Publication No. 2007/0193181. The method involves utilizing a core puller mechanism to move end liners to a first, or fill, position to impart one or more decorative side faces as the block is formed. Before the block is stripped from the mold, the core puller mechanism pulls the end liners back to a second, or strip, position so that the decorative side faces are not damaged as the block is released. A drawback, however, is that the core puller mechanism is a large and complex piece of machinery that requires a large amount of space on the production floor and can take a significant amount of time to setup and install. Additionally, the moving parts in the mold may sometimes lack sufficient stability during various stages of molding, thereby causing undesired cracking of the block.
What is still needed in the industry is a system and method of making a block having two or more adjacent decorative faces that may more closely resemble natural stone or other decorative masonry element.

System and method for manufacturing concrete blocks


A control device including a CPU is provided. The CPU divides a plurality of pulses into first and second groups, and creates a schedule in which on-timing and off-timing of the plurality of pulses are designated such that off-timing of a first pulse among the plurality of pulses and on-timing of a second pulse among the plurality of pulses are simultaneous with each other. The CPU sets in a timer for counting time, time from a time point where the timer finishes counting the time already set to on-timing or off-timing of a pulse to be first turned on or off after the time point in accordance with the schedule. Further, the CPU turns on or off the pulse in accordance with the schedule when the timer finishes counting the set time.

Conventionally, a pulse width modulation (PWM) control has been used to control a light source of an automobile as a plurality of loads described above (Patent Literatures 1, 2). By controlling the light source by the PWM control, brightness of the light source can be easily changed. Specifically, the brightness can be adjusted by changing a pulse width for one cycle. In addition, by gradually changing to a target duty, the light source can be gradually brightened or darkened.
The PWM control described above is performed using a PWM function of a general-purpose microcomputer. In the PWM function, a CPU of the microcomputer turns on (rises) a pulse and causes a timer to count time from on to off (fall) of the pulse based on the set duty. When the timer count ends, the CPU turns off the pulse, and then causes the timer to count the time from when the pulse is turned off to the end of one cycle of the pulse. When the timer count ends, the CPU then turns on the pulse again and repeats the above-described operation.
The CPU is provided with a plurality of ports so that a plurality of pulses can be output. In addition, the duties of the plurality of pulses can be set optionally. However, with the use of the timer described above, the timers are required for the number of ports, and it is necessary to use an expensive CPU, which is a problem in terms of cost.
In the PWM control described above, there is a problem that high frequency noise is generated when the pulse is turned on or off.

Control device, illumination device, and program for control device


A switching regulator. A pulse width modulation (PWM) unit comprises an output stage and generates a PWM driving signal to control the output stage, such that an inductor delivers an inductor current signal to the load, and a slope compensation unit outputs a slope compensation signal with a compensation slope proportional to a falling slope of the inductor current signal to the PWM unit according to the inductor current signal.

1. Field of the Invention
The invention relates to DC voltage conversion, in particularly to switching regulators with slope compensation and slope compensation method thereof.
2. Description of the Related Art
Battery life is a major consideration for portable electronic systems. This is particularly true for consumer electronics, such as cellular phones, digital cameras, portable computers and other handheld equipment. Designers of these products are faced with a continual need to reduce package size (and battery size) while increasing battery life to match or exceed competitive products.
To maximize battery life, it is necessary to optimize the performance of a wide range of different electronic components. Among the most important of these components are voltage regulators. In portable electronic systems, these devices perform a range of power handling tasks including increasing, decreasing and inverting voltage.
FIG. 1 shows a voltage-mode control switching regulator that converts high DC voltage to lower. The advantages of voltage-mode control are ease of analysis and a large ramp wave providing good noise immunity. However, in terms of transient-response, because any change in line or load must first be detected by the feedback resistor divider and then responded to via error amplifier and PWM generator, response speed is reduced. Further, because the output L-C network provides a complex-pole pair and the loop gain varies with the input voltage, loop compensation design is much more complicated.


A method of forming a side contact in a semiconductor device wherein a first insulating layer, first conductive and second insulating layer are formed over a substrate, and a contact hole through these layers exposes a portion of the substrate and a side edge of the first conductive layer. A refractory metal layer being formed in the contact hole, such that the natural oxide layer is changed into a conductive material by reaction with the refractory metal layer during a subsequent process step.

The present invention relates to a method for forming a side contact in a semiconductor device, and more particularly, to the method for forming a side contact in a semiconductor device having reduced contact resistance by exchange of the natural oxide film on the side contact with a conductive material.
In general, as supply voltages for semiconductor memory devices decrease with reductions in the devices' dimensions, memory cell stability during read/write operations has become an increasingly important issue in the development of high capacity, semiconductor memory devices, such as the static random access memory (SRAM). For 16 Mb SRAMs, a symmetrically split word line cell has been proposed which prevents degradation of cell stability. In the split word line cell structure, each cell has two word lines. Thus, a very tight bit line pitch is required. This creates problems in reducing the cell size and in obtaining higher speed operation. In order to overcome these problems, a center word line cell structure having the word lines located in the center of each cell has been proposed. See, for example, IEDM '93 at pages 817 through 820.
FIGS. 1-3 show the various layouts adapted for use with a conventional center word line cell. More specifically, FIG. 1 is the layout of a bulk transistor. FIGS. 2 and 3 are respectively layouts of a thin-film transistor (TFT), and a capacitor. Within these FIGS., reference numeral 1 denotes an active layer; 3, a first polysilicon layer for a word line and driving transistor; 5, a TFT gate electrode; 7, a TFT channel; 9, a self-aligned contact; 11, a capacitor electrode; 13, a ground plate; and 15, a side contact.
The above center word line cell has a symmetrical layout with word line (first polysilicon layer) 3 being located in the center of the cell. This cell structure saves space when compared to the additional word line used in the split word line cell. As such, cell size can be reduced while preserving sufficient space for the required bit-line pitch.
FIG. 4 is a cross-sectional view of the above center word line cell. Basically, the center word line cell is made of five layers of polysilicon placed over impurity regions 18 formed in a substrate 17. The five polysilicon layers consist of first polysilicon patterns 19a, 19b and 19c forming an access transistor, and a drive transistor; a second polysilicon layer 21 used as a load TFT gate electrode on the center of the cell; a third polysilicon layer 23 as a TFT channel; a fourth polysilicon layer 25 used as a capacitor electrode; and, a fifth polysilicon layer 27 used as a ground plate. Reference numeral 31 donates a bit line.
The center word line cell uses a side contact, shown in area "AA" of FIG. 4. First polysilicon plug 29a is commonly connected to first, second, third and fourth polysilicon layers 19a, 21, 23 and 25. In particular, first polysilicon plug 29a is connected at its side to second and third polysilicon layers 21 and 23. Second polysilicon plug 29b is also connected between ground plate 27 and impurity region 18 in substrate 17.
The noted side contact will now be explained in greater detail with reference to FIG. 5 which is a cross-sectional view of a conventional side contact. Here, an impurity region 42 has been selectively formed in substrate 41. First insulating layer 43, first conductive layer (polysilicon layer) 45, and second insulating layer 47 are each sequentially formed over substrate 41 with a contact hole through each layer to expose impurity region 42. Second conductive layer (polysilicon plug) 49 fills the contact hole to form the side contact structure.
In the foregoing structure of the conventional side contact, natural oxide layer 44 forms on the side edge of first conductive layer 45. The formation of natural oxide layer 44 increases the contact resistance between polysilicon plug 49 and first conductive layer 45. In extreme cases where contact resistance increases to unacceptable levels, electrical connection may ultimately prove impossible.

Method for forming side contact in a semiconductor device


The present disclosure is directed to a method for determining an aircraft minimum low pitch setting for a propeller assembly and minimum gas generator idle speed for a gas generator, in which the propeller assembly and the gas generator together comprise a gas turbine engine. The method comprises determining, via one or more controllers, an operating condition of the aircraft based at least on a weight on wheels (WoW) signal and a throttle lever position. The WoW signal produces a first mode or a second mode different from the first mode, and the throttle lever position defines at least a takeoff position and an idle power position.

Gas turbine engines, such as turboprop engines, generally include at least two operator manipulated input devices; a power lever for controlling a commanded power output of the engine, a condition lever for controlling fuel cut-off and manually setting a ground idle or flight idle setting of the gas turbine engine, and a propeller lever for controlling propeller pitch angle (i.e., feathering) and propeller speed. During ground conditions, it is generally desired to minimize thrust to mitigate aircraft brake usage and minimize fuel consumption. This is accomplished via manual controls and adjustments to the plurality of operator manipulated input devices.
In some engines, only a single idle setting is available, such as flight idle, which delivers more thrust at a ground condition than at a ground idle condition, thereby increasing brake usage and fuel consumption. An operator must therefore either manually adjust the propeller pitch angle to reduce delivered thrust, further apply the brakes, or both to control the aircraft. The operator may further be required to operate the engine higher than idle while modulating the brakes in order to mitigate operating the propeller at an avoid band at which excessive wear and deterioration may occur due to undesired vibratory modes. Therefore, under a plurality of conditions, an operator must modulate a plurality of input devices based on a plurality of conditions to achieve one or more desired outcomes.
As such, there is a need for a system and method of determining minimum pitch and minimum gas generator idle condition for a gas turbine engine that may improve ground operation of the aircraft, mitigate operation of the propeller in an avoid band, improve fuel consumption, and generally improve operation of the aircraft and gas turbine engine.

System and method for determining minimum pitch and minimum gas generator idle condition


If only a specific color and its nearby colors of image data are adjusted, density discontinuation occurs in the image as a whole. If masking is performed to avoid this problem, the adjustment range cannot be bounded, so the processing time increases. On an adjustment parameter designating unit, a user designates, as parameters, a reference color, the adjusted value of the reference color, and an adjustment region in a color space. A coordinate transformer transforms the coordinates of image data as an element of a color correction table, on the basis of a transformation matrix for transformation to an object color space. This transformation matrix is formed on the basis of the parameters by a transformation matrix calculator. If a region determinator determines that the image data is in the adjustment region, an adjusted value calculator calculates an adjusted value on the basis of the parameters.

When an image displayed on a monitor of a computer system or the like is to be printed out from a printer, a so-called color matching process is generally required which performs adjustment so that the appearance of printed colors substantially equals the appearance of monitor display colors, since the color reproduction region of a monitor largely differs from that of a printer. A known example of this color matching process is a method of looking up a color correction table which is formed by taking account of the color characteristics of a monitor and a printer.
After this color matching process is executed, the user sometimes determines, on the basis of the image printed by a printer, that a specific color and its nearby colors further require fine adjustment. This fine adjustment is performed by changing the values of the above-mentioned color correction table for color matching, or by changing the values of individual pixels of the image data.
If, however, only a specific color is changed in a pinpoint manner in order to perform fine adjustment as in the above conventional method, density discontinuation occurs particularly in gradation images.
To prevent this problem, there is an adjustment method where a masking coefficient is calculated in such a way that a specific color becomes a desired color, and colors distant from the specific color change only slightly. Using the calculated coefficient, a masking process is performed for all values in the color correction table (or for all pixel values in image data). This method does not cause any density discontinuation as described above. With this method, however, it is difficult to limit the range over which the adjustment has its effect. The method also requires a long processing time.

Image processing apparatus and method, and image processing system


An absorbent article having a main body having a liquid-permeable topsheet, a liquid-impermeable backsheet and an absorbent core sandwiched between the topsheet and the backsheet is disclosed. The main body has longitudinal and transversal axes. The article has two wings extending asymmetrically outward from a crotch portion of the main body with respect to the longitudinal axis. The wings each have a means for fastening them to a garment when folded over the main body towards the longitudinal axis. The fastening means for each wing are offset from each other in the longitudinal direction. A method for manufacturing the absorbent article is also disclosed.

Absorbent articles, for example in the form of sanitary napkins and panty liners, are well known. The general purpose of such absorbent articles is to absorb, distribute and store various types of body exudates while providing a high level of comfort and sense of dryness to the wearer during use of the absorbent article. Also, such absorbent articles are arranged to prevent the wearer from getting the clothes soiled by body exudates.
A conventional sanitary napkin is normally designed with a main body which comprises a liquid-permeable topsheet, a liquid-impermeable backsheet and an absorbent core which is sandwiched between the topsheet and the backsheet. The main body is arranged along a longitudinal axis and a transversal axis which extends in a perpendicular direction in relation to the longitudinal axis.
Furthermore, absorbent articles in the form of sanitary napkins are often provided with two wings, i.e. two wing-shaped fastening elements, extending outwardly from the main body in opposite directions and generally along the transversal axis. The purpose of the wings is to allow fastening of the sanitary napkin to an undergarment of a user. To this end, the wings are arranged to be folded over the main body and towards said longitudinal axis. In order to allow fastening of the sanitary napkin to the undergarment, each wing is provided with fastening means such as an adhesive material. In this manner, the sanitary napkin can be attached and held in place in the undergarment during use.
According to prior art, the wings of a sanitary napkin can be formed in a symmetrical manner, i.e. so that the entire sanitary napkin can be said to define a contour which is symmetrical with reference to its longitudinal axis. Alternatively, it is also known that the wings can be formed in an asymmetrical manner with reference to the longitudinal axis.
A previously known absorbent article having asymmetrical wings of the above-mentioned type is known from the patent document U.S. Pat. No. 5,401,268. This document shows a sanitary napkin having two wings which are arranged asymmetrically along opposite sides of a longitudinal edge of the napkin.
The wings disclosed in U.S. Pat. No. 5,401,268 are formed of two triangular pieces which comprise semi-circular indentations on the base of said pieces, and also a rounded cutout at the top of each triangular piece. The purpose of the wings shown in U.S. Pat. No. 5,401,268 is to provide a relatively large surface for fixing the sanitary napkin to an undergarment.
Even though the article disclosed in U.S. Pat. No. 5,401,268 fulfills the basic requirements regarding absorbent articles provided with wing-shaped fastening elements, there is a need for further improvements within this field of technology.
In particular, there is an increasing requirement to provide a more optimized use of a fastening means, comprising an adhesive, on each wing. In this regard, manufacturers of absorbent articles are often limited to using strips of adhesive material applied on each wing.
In such a process, there is a need to use a sufficient amount of adhesive, while at the same time minimizing the use of release paper, which is regarded as causing a relatively high cost.
Furthermore, it can be noted that the wings of the article shown in U.S. Pat. No. 5,401,268 are relatively long. This factor is of importance during manufacturing of said article, which is based on a process in which a rectangle of material—having dimensions exceeding the outer dimensions of the backsheet and topsheet of the article—is cut so as to correspond to the outer shape of the article. This means that a relatively high amount of material is needed since the entire article must fit within said rectangle. This also means that the longer the wings, the larger rectangle is needed. Consequently, a higher amount of material must be cut away and discarded during the manufacturing process, which is a disadvantage.
In summary, there is a need for improved articles having asymmetric wings with sufficient area and sufficient amount of adhesive but without resulting in too much waste material for forming the topsheet and backsheet.
Furthermore, the adhesive material must be used on the wings in a manner so that it does not give rise to any unwanted forces in the garment of the user, which otherwise may cause discomfort.
Consequently, there is a need for further improvements within the above-mentioned field of technology.

Absorbent article and method for manufacturing an absorbent article


A handheld dishwashing device for cleaning dishes and utensils includes a handle, a clean water tube for receiving and transferring a pressurized flow of heated water, a soap tube for receiving and transferring a flow of soap, a first and second clean water discharge port in fluid flow communication with the clean water tube, a trigger for selectively operating the flow of water to the first and second clean water discharge ports, at least one cleaning head component, a soap discharge port in communication with the soap tube for emitting the soap onto the cleaning head component, a cleaning head extension bar, and a rinse extension bar being structured and disposed for pivotal movement relative to the handle for holding the cleaning head component, thereby allowing for selective use of one of either the top or bottom sides of the cleaning head component.

Field of the Invention
The present invention relates to a handheld dishwashing device and, more particularly, to a handheld dishwashing device that allows for easy, one-handed operation of the handheld dishwashing device, and requires a minimal amount of water, which can be accessed from direct hook up to plumbing or from a contained water supply.
Discussion of the Related Art
Over the years, automatic dishwashers have become commonplace in households in the United States, and provide a convenient method of cleaning and sterilizing dishes and eating utensils. Typically, dirty dishes are loaded into the dishwasher, which, in operation, sprays heated water at 130-150 degrees Fahrenheit onto the dishes. A detergent and water mixture is then used to clean the dishes, followed by clean water to remove the detergent residue. While such represents the typical dishwashing cycle process in both residential and commercial dishwashers alike, a number of advances have been made in recent years in an effort to further enhance the cleansing capabilities of dishwashers, such as the use of multiple wash and rinse cycle periods as well as the inclusion of rinsing aids.
A considerable drawback of traditional automatic dishwashers is the large amount of water required during each wash and rinse cycle. Such a negative characteristic becomes readily apparent when an automatic dishwasher is used when it is not filled to full capacity, which is likely to occur in households of one to three persons. Furthermore, a number of situations may present themselves to an individual who may have dirty dishes but is in a location lacking an automatic dishwasher. For example, a college dorm room rarely comes equipped with an automatic dishwasher, however, college students often utilize micro-refrigerators that include an attached microwave, which is used to heat entire meals. Consequently, college students must either purchase disposable paper plates and plastic eating utensils or engage in the cumbersome task of hand washing the dirty dishes.
Only a few dishwashing devices have been developed that can be used in a portable fashion. A number of these portable dishwashing devices are non-electric, and are powered by water pressure alone. For example, U.S. Pat. No. 4,542,756 discloses a portable non-electric dishwasher system that is especially suited for insertion within a sink and includes an enclosed dish-holding container, and is entirely reliant on the water pressure supplied by an outside source. Suspended throughout the interior of the enclosure is a series of expansible water bladders having multiple apertures for spraying water on the dirty dishes. With the application of the pressurized water, the bladders expand, which effectively scrubs the dirty dishes. The continued expansion of the bladders eventually triggers an outflush of water from the apertures, thus rinsing the dirty dishes. This scrub and rinse cycle continues over a period of time as determined by the user.
U.S. Pat. No. 5,518,014 discloses a portable countertop dishwasher that is electrically powered and structured for placement alongside a sink. The portable countertop dishwasher includes a housing cavity with a fluid handling assembly contained therein and having an upper pump and a lower pump, each within its own housing. In operation, the pumps distribute fluid amongst the dishes within the housing cavity, with an outlet conduit serving to release the fluid from the housing.
While the portable dishwashing devices described above are useful for their intended purpose, there remains a need for a more practical and efficient portable dishwashing device that is easily transportable and allows for quick and easy cleansing of dirty dishes. The present invention seeks to address the limitations and shortcomings of presently known portable dishwashing devices, as well as to effectively minimize the amount of water that is wasted during the cleansing process.

This patent is subject to a terminal disclaimer.


A new and distinct cultivar of Spathiphyllum plant having darker and more rounded leaves and a greater compactness than other varieties and by having a greater suckering propensity than its parents and more resistance to the burn problems than the pollen parent.

This invention relates to a new and distinct plant variety of the Araceae family and, specifically, to a new and distinct plant variety of Spathiphyllum which is named Araceae Spathiphyllum `31581`.
Certain plant varieties of the Araceae family are well known in the foliage plant market and among these is the `Viscount` variety of the Spathiphyllum. This variety is characterized by, among other things, foliage with leaf blades that have a solid green field and an inflorescence with a spathe of white tending to a pure snow white.
The variety forming the subject matter of this application is hybrid of interspecific genetic background from a cross between `Viscount` (unpatented) and `Petite` (unpatented). A general objective of the invention has been to provide a variety of the Spathiphyllum genus which would be distinguishable from the other known varieties of this species and suitable for sale in the foliage plant marketplace.
This new variety of Spathiphyllum was asexually reproduced by tissue culture near Apopka, Fla. and such reproduction has shown this new variety to come true in successive generations. This propagation of the new variety by tissue culture in the usual controlled environment clearly shows the continued maintenance of the characteristics described herein which distinguish this new variety from the parent varieties and all other known and related varieties mainly by the darker and more rounded, less elongated and thicker leaves and its greater resistance to the burn problems associated with `Petite`. The length of the leaves is about 20% greater than their width. Furthermore, this novel variety has about a 30% greater propensity to sucker than do its parents. The length of the peduncles is about 30% less than that of the parents, thus contributing to a compact size, thereby adding to its overall attractiveness and facilitating the packaging of the same for shipment.


A method for error detection and correction comprising performing a first modulation error scan of said modulation symbol, marking data that fails to comply with a predetermined criteria, demodulating said modulation symbols, computing a first error syndrome using said demodulated symbols, and correcting errors using said error syndrome computation.

Numerous applications utilize digital data storage and transmission for data communication, such as sending information via internet web sites or storing information on compact discs. Digital transmission systems or digital data storage systems typically use a sequence of binary information, either delivered to a receiver across a transmission channel or stored to a medium (e.g., CDROM). However, the binary information may become corrupted during storage or transmission, which could impair the accuracy of the information.
As a result, error control coding is often applied to the transmitted or stored data. Techniques known as forward error correction schemes have been developed to improve the reliability of the data communicated in digital applications. Forward error correction schemes are error control techniques that can detect and correct corrupt data without requiring the transmitter to re-send the information. An example of such a scheme is the Reed-Solomon code.
Many forward error correction schemes, such as the Reed-Solomon code, typically encode a group of data symbols into blocks of a predetermined size. For each block, an additional number of "parity" symbols are computed and added. The resulting augmented block is typically referred to as a "codeword." Following transmission, or following reading of the stored data, a decoding technique is applied to the codeword to correct for errors that occurred during storage or transmission to thus restore the original data.
While such techniques have improved the reliability of transmitted digital data, further improvement is desireable. Despite the use of current error correction techniques, undetected errors may still occur, or errors may be detected but not properly corrected. This results in data that is less reliable than desired.

Error detection and correction employing modulation symbols satisfying predetermined criteria

Hewlett-Packard Development Company, L.P.


In the case when there are two objective biological activities, and the aim is to isolate a compound having at least one biological activity, the present inventors developed an assay method wherein a common detection marker is utilized for separately detecting the presence or absence of each of the biological activities. The present inventors discovered that a compound having at least one of two or more distinct biological activities can be efficiently and conveniently detected by simultaneously assaying at least one test sample or more by the above-mentioned method. Furthermore, for a test sample that proved to be positive by the detection method, they found that it is possible to efficiently and conveniently screen for a test sample having an objective specific biological activity by combining with a method wherein an individual activity of a test sample can be detected to specify the biological activity.

Hematopoietic factors represented by erythropoietin (EPO) and granulocyte-colony stimulating factor (G-CSF) have already been developed as pharmaceutical agents, and have been utilized for the treatment of various diseases. Cytokines, such as interferon, and hormones, including insulin and growth hormone, are also commercially available as pharmaceutical agents. Most of the biologically active proteins used as pharmaceutical agents have been produced by genetic engineering techniques. Low molecular weight compounds are being screened as the next-generation drugs replacing biologically active proteins. For instance, if it was possible to find low molecular weight compounds having the same activities as biologically active proteins, such compounds will be useful as pharmaceutical agents, since they may be orally administered. Therefore, there is a need to develop efficient methods for screening low molecular weight compounds that have biological activities similar to naturally existing ligands.
Several screening methods are already known. For example, when screening for a ligand of a receptor whose amino acid sequence and function are known, there is a method in which a chimeric receptor comprising the intracellular domain of a receptor with a known function and the extracellular domain of a receptor of interest is prepared, and the chimeric protein is used to screen for a ligand of the receptor of interest (Ishizaka-Ikeda, E., Pro. Natl. Acad. Sci. USA (1993) 90, p123-127; U.S. Pat. No. 4,859,609 and U.S. Pat. No. 5,030,576). Using the insulin receptor as the extracellular domain and the EGF receptor as the intracellular domain, these US patents describe a method that assays in a cell-free system chimeric receptor phosphorylation induced by the binding of a ligand. A method using a chimeric receptor that consists of the extracellular domain of the EGF receptor and the intracellular domain of the EPO receptor, has also been reported (WO94-29458). These approaches may also be applicable to the screening of ligands for an orphan receptor, whose natural ligand is not yet known.
However, in each of these screening methods, only one kind of receptor is used as the receptor of interest, and one screening can only detect the effect a test sample has on that single receptor. Therefore, in order to assay the effect on several receptors, the same number of screenings as that of receptors of interest is required. Also, these approaches are inefficient for a preliminary screening of a vast number of test samples that have different structures and whose activities are unconfirmed, since activities of most ligands cannot be detected. It is, therefore, necessary to develop a method that can efficiently and rapidly screen a vast number of test samples.

Screening methods for biologically active ligands


The present invention provides improved methods and compositions for treating and preventing autoimmune and allergic diseases. More specifically, the invention relates to new immunomodulating complexes that are fusion proteins comprising a mutant subunit of the A1-subunit of the cholera toxin (CTA1), a peptide capable of binding to a specific cellular receptor, and one or more epitopes associated with an autoimmune or allergic disease. In the mutant CTA1 subunit, the amino acids corresponding to the amino acid 7, arginine, and amino acid 187, cysteine, in the native CTA1 have been replaced.

Autoimmune Disease and Modulation of the Immune Response
Autoimmune disease is any disease caused by immune cells that become misdirected at healthy cells and/or tissues of the body. Autoimmune disease affects 3% of the U.S. population, and likely a similar percentage of the industrialized world population (Jacobson et al., Clin Immunol Immunopathol 84: 223-43, 1997). Autoimmune diseases are characterized by T and B lymphocytes that aberrantly target self-proteins, -polypeptides, -peptides, and/or other self-molecules, causing injury and or malfunction of an organ, tissue, or cell-type within the body (for example, pancreas, brain, thyroid or gastrointestinal tract) to cause the clinical manifestations of the disease (Marrack et al., Nat Med 7: 899-905, 2001). Autoimmune diseases include diseases that affect specific tissues, as well as diseases that can affect multiple tissues. For some diseases, this may, in part, depend on whether the autoimmune responses are directed to an antigen confined to a particular tissue, or to an antigen that is widely distributed in the body. The characteristic feature of tissue-specific autoimmunity is the selective targeting of a single tissue or individual cell type. Nevertheless, certain autoimmune diseases that target ubiquitous self-proteins can also affect specific tissues. For example, in polymyositis, the autoimmune response targets the ubiquitous protein histidyl-tRNA synthetase, yet the clinical manifestations primarily involve autoimmune destruction of muscle.
The immune system employs a highly complex mechanism designed to generate responses to protect mammals against a variety of foreign pathogens, while at the same time preventing responses against self-antigens. In addition to deciding whether to respond (antigen specificity), the immune system must also choose appropriate effector functions to deal with each pathogen (effector specificity). A cell critical in mediating and regulating these effector functions is the CD4+ T cell. Furthermore, it is the elaboration of specific cytokines from CD4+ T cells that appears to be the major mechanism by which T cells mediate their functions. Thus, characterizing the types of cytokines made by CD4+ T cells as well as how their secretion is controlled is extremely important in understanding how the immune response is regulated.
The characterization of cytokine production from long-term mouse CD4+− T cell clones was first published more than 20 years ago (Mosmann et al., J Immunol 136: 2348-2357, 1986). In these studies, it was shown that CD4+ T cells produced two distinct patterns of cytokine production, which were designated T helper 1 (Th1) and T helper 2 (Th2). Th1 cells were found to produce interleukin-2 (IL-2), interferon-γ (IFN-γ) and lymphotoxin (LT), while Th2 clones predominantly produced IL-4, IL-5, IL-6, and IL-13 (Cherwinski et al., J Exp Med 169:1229-1244, 1987). Somewhat later, additional cytokines, IL-9 and IL-10, were isolated from Th2 clones (Van Snick et al., J Exp Med 169:363-368, 1989) (Fiorentino et al., J Exp Med 170:2081-2095, 1989). Finally, additional cytokines, such as IL-3, granulocyte macrophage colony-stimulating factor (GM-CSF), and tumor necrosis factor-α (TNF-α) were found to be secreted by both Th1 and Th2 cells. Recently, it was reported that CD4+ T cells isolated from the inflamed joints of patients with Lyme disease contain a subset of IL-17-producing CD4+ T cells that are distinct from Th1 and Th2 (Infante-Duarte et al., J. Immunol 165:6107-6115, 2000). These IL-17-producing CD4+ T cells are designated Th17. IL-17, a proinflammatory cytokine predominantly produced by activated T cells, enhances T cell priming and stimulates fibroblasts, endothelial cells, macrophages, and epithelial cells to produce multiple proinflammatory mediators, including IL-1, IL-6, TNF-α, NOS-2, metalloproteases, and chemokines, resulting in the induction of inflammation. IL-17 expression is increased in patients with a variety of allergic and autoimmune diseases, such as RA, MS, inflammatory bowel disease (IBD), and asthma, suggesting the contribution of IL-17 to the induction and/or development of such diseases.
There is ample evidence showing that suppressor T cells, now called regulatory T cells (Treg cells), suppress autoreactive T cells as an active mechanism for peripheral immune tolerance. Thus far, it is firmly established that Treg cells can be divided into two different subtypes, namely natural (or constitutive) and inducible (or adaptive) populations according to their origins (Mills, Nat Rev Immunol 4:841-855, 2004). In addition, a variety of Treg cell subsets have been identified according to their surface markers or cytokine products, such as CD4+ Treg cells (including natural CD4+CD25+ Treg cells, IL-10-producting Tr1 cells, and TGF-β-producing Th3 cells), CD8+ Treg cells, Veto CD8+ cells, γδ T cells, NKT (NK1.1+CD4−CD8−) cells, NK1.1−CD4−CD8− cells, etc. Accumulating evidence has shown that naturally occurring CD4+CD25+ Treg cells play an active role in down-regulating pathogenic autoimmune responses and in maintaining immune homeostasis (Akbari et al., Curr Opin Immunol 15:627-633, 2003).
Autoimmune disease encompasses a wide spectrum of diseases that can affect many different organs and tissues within the body (see, e.g., Paul, W. E. (1999), Fundamental Immunology, Fourth Edition, Lippincott-Raven, New York.)
Current therapies for human autoimmune disease include glucocorticoids, cytotoxic agents, and recently developed biological therapeutics. In general, the management of human systemic autoimmune disease is empirical and unsatisfactory. For the most part, broadly immunosuppressive drugs, such as corticosteroids, are used in a wide variety of severe autoimmune and inflammatory disorders. In addition to corticosteroids, other immunosuppressive agents are used in management of the systemic autoimmune diseases. Cyclophosphamide is an alkylating agent that causes profound depletion of both T- and B-lymphocytes and impairment of cell-mediated immunity. Cyclosporine, tacrolimus, and mycophenolate mofetil are natural products with specific properties of T-lymphocyte suppression, and they have been used to treat systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and, to a limited extent, vasculitis and myositis. These drugs are associated with significant renal toxicity. Methotrexate is also used as a "second line" agent in RA, with the goal of reducing disease progression. It is also used in polymyositis and other connective-tissue diseases. Other approaches that have been tried include monoclonal antibodies intended to block the action of cytokines or to deplete lymphocytes (Fox, Am J Med 99:82-88, 1995). Treatments for multiple sclerosis (MS) include interferon and copolymer 1, which reduce relapse rate by 20-30% and only have a modest impact on disease progression. MS is also treated with immunosuppressive agents including methylprednisolone, other steroids, methotrexate, cladribine and cyclophosphamide. These immunosuppressive agents have minimal efficacy in treating MS. The introduction of the antibody Tysabri (natalizumab), an alpha 4-integrin antagonist, as treatment for MS has been overshadowed by incidences of progressive multifocal leucoencaphalopathy (PML) in patients receiving the therapy. Current therapy for RA utilizes agents that non-specifically suppress or modulate immune function such as methotrexate, sulfasalazine, hydroxychloroquine, leuflonamide, prednisone, as well as the recently developed TNFα antagonists etanercept and infliximab (Moreland et al., J Rheumatol 28: 1431-52, 2001). Etanercept and infliximab globally block TNFα, making patients more susceptible to death from sepsis, aggravation of chronic mycobacterial infections, and development of demyelinating events.
In the case of organ-specific autoimmunity, a number of different therapeutic approaches have been tried. Soluble protein antigens have been administered systemically to inhibit the subsequent immune response to that antigen. Such therapies include delivery of myelin basic protein, its dominant peptide, or a mixture of myelin proteins to animals with experimental autoimmune encephalomyelitis and humans with multiple sclerosis (Brocke et al., Nature 379: 343-6, 1996; Critchfield et al., Science 263: 1139-43, 1994; Weiner et al., Annu Rev Immunol 12: 809-37, 1994), administration of type II collagen or a mixture of collagen proteins to animals with collagen-induced arthritis and humans with rheumatoid arthritis (Gumanovskaya et al., Immunology 91: 466-73, 1999; McKown et al., Arthritis Rheum 42: 1204-8, 1999; Trentham et al., Science 261: 1727-30, 1993), delivery of insulin to animals and humans with autoimmune diabetes (Pozzilli and Gisella Cavallo, Diabetes Metab Res Rev 16: 306-7, 2000), and delivery of S-antigen to animals and humans with autoimmune uveitis (Nussenblatt et al., Am J Ophthalmol 123: 583-92, 1997). Another approach is the attempt to design rational therapeutic strategies for the systemic administration of a peptide antigen based on the specific interaction between the T-cell receptors and peptides bound to MHC molecules. One study using the peptide approach in an animal model of diabetes resulted in the development of antibody production to the peptide (Hurtenbach et al., J Exp Med 177:1499, 1993). Another approach is the administration of T cell receptor (TCR) peptide immunization (see e.g. Vandenbark et al., Nature 341:541, 1989). Still another approach is the induction of oral tolerance by ingestion of peptide or protein antigens (see e.g. Weiner, Immmunol Today 18:335, 1997).
Mucosal tolerance refers to the phenomenon of systemic tolerance to challenge with an antigen that has previously been administered via a mucosal route, usually oral, nasal or naso-respiratory, but also vaginal and rectal (Weiner et al., Annu Rev Immunol 12:809-837, 1994). Mucosal tolerance was discovered early in the 20th century in models of delayed-type and contact hypersensitivity reactions in guinea pigs, but the mechanisms of tolerance remained ill-defined until the era of modern immunology. The use of cell separation techniques, tests for production of cytokines and transgenic models in which antigen-specific T cells can be tracked in vivo have gradually elucidated mechanisms of mucosal tolerance (Garside and Mowat., Crit Rev Immunol 17:119-137, 1997). It has become evident that antigen administration via mucosal routes can result in distinct types of tolerance, depending on the route of administration and dose of antigen. For example, a high dose of oral antigen induces T-cell activation followed by deletion or anergy of responding T cells (Chen et al., Nature 376:177-180, 1995), analogous to parenteral administration of high-dose soluble antigen. This results in extinction of T cells specific to that antigen and unresponsiveness to subsequent antigen challenge, i.e. passive tolerance. In contrast, a low dose of oral antigen does not induce deletion or anergy but, when given repeatedly, induces a distinct type of immune response characterized by the appearance of regulatory-protective T cells, Treg cells, that secrete anti-inflammatory cytokines, i.e. active tolerance (von Herrath, Res Immunol. 148:541-554, 1997). These Treg cells usually belong to the class of CD4 (helper) T cells. Instillation of intact protein antigen onto the nasopharyngeal mucosa also induces Treg cells that are protective. In this case, both CD4 and CD8 T cells may be induced. Regulatory Treg cells induced after oral or intranasal antigen administration produce anti-inflammatory cytokines such as IL-4, IL-10 and TGF-β. To induce mucosal tolerance, antigen can also be given in the form of aerosol. Administration via these three routes, oral, intranasal and aerosol-inhalation, results in antigen uptake and presentation in different lymphoid compartments in each case. Accordingly, oral antigen is presented to T cells mostly in mesenteric lymph nodes and to some extent in Peyer's patches, intranasal antigen in deep cervical lymph nodes and inhaled antigen in mediastinal lymph nodes. Repeated exposure to antigen in each case is able to induce regulatory T cells, but the nature of these cells differs, depending on the route and form of antigen. While regulatory cells induced by oral antigen are CD4 T cells and express T cell receptors (TCR) consisting of αβ heterodimers, in the case of naso-respiratory antigen, the regulatory cells can also be CD8 T cells expressing a γδ heterodimer TCR (i.e. γδ T cells). Some of these cells may also have a CD8 receptor that is an αα homodimer instead of the conventional αβ-heterodimer TCR. A majority of cells that carry the CD8αα and γδ TCR reside in skin or mucosal tissues.
Over the past decades, there has been a significant increase in both the incidence and prevalence of allergic disease in western countries. Allergic rhinitis is the most common of these diseases, affecting 15-20% of the population. The allergic reaction is triggered by allergen-mediated cross-linking of specific IgE on the surface of mast cells and basophils, leading to release of histamine and other mediators, thus causing an acute allergic reaction, followed by a late-phase reaction characterized by an influx of eosinophils, neutrophils and Th2 cells producing IL-4, IL-5 and IL-13.
Specific immunotherapy (SIT) is recognized as an effective treatment of allergic rhinitis. Traditionally, SIT has been conducted by repeated subcutaneous administration of small amounts of specific allergen. Although this form of treatment can be an effective therapeutic option, concerns exist with the safety of this form of immunotherapy as well as with the difficulty of standardizing the allergen extract used as vaccine. Consequently, there is strong interest in the development of alternative and novel treatments against allergic diseases. One of the approaches is the use of mucosal vaccines (Widermann, Curr Drug Targets Inflamm Allergy 4, 577-583, 2005). Other alternatives are based on the use of allergen derivatives with reduced or no allergenicity as vaccines (Vrtala et al., Methods 32, 313-320, 2004). These include allergens obtained by protein engineering and synthetic peptides representing immunodominant T-cells epitopes of allergens. For example, Ole e1 has been identified as the most relevant allergen of olive pollen (Wheeler et al., Mol Immunol 27, 631-636, 1990).
Immune responses are currently altered by delivering polypeptides, alone or in combination with adjuvants (immunomodulating agents). For example, the hepatitis B virus vaccine contains recombinant hepatitis B virus surface antigen, a non-self antigen, formulated in aluminum hydroxide, which serves as an adjuvant. This vaccine induces an immune response against hepatitis B virus surface antigen to protect against infection. An alternative approach involves delivery of an attenuated, replication deficient, and/or non-pathogenic form of a virus or bacterium, each a non-self antigen, to elicit a host protective immune response against the pathogen. For example, the oral polio vaccine is composed of a live attenuated virus, a non-self antigen, which infects cells and replicates in the vaccinated individual to induce effective immunity against polio virus, a foreign or non-self antigen, without causing clinical disease. Alternatively, the inactivated polio vaccine contains an inactivated or 'killed' virus that is incapable of infecting or replicating and is administered subcutaneously to induce protective immunity against polio virus.
DNA therapies have been described for treatment of autoimmune diseases. Such DNA therapies include DNA molecules encoding the antigen-binding regions of the T cell receptor to alter levels of autoreactive T cells driving the autoimmune response (Waisman et al., Nat Med 2:899-905, 1996; U.S. Pat. No. 5,939,400). DNA molecules encoding autoantigens were attached to particles and delivered by gene gun to the skin to prevent MS and collagen induced arthritis. (WO 97/46253; Ramshaw et al., Immunol Cell Biol 75:409-413, 1997). DNA molecules encoding adhesion molecules, cytokines (e.g., TNFα), chemokines (e.g., C—C chemokines), and other immune molecules (e.g., Fas-ligand) have been used for treatment of autoimmune diseases in animal models (Youssef et al., J Clin Invest 106:361-371, 2000; Wildbaum et al., J Clin Invest 106:671-679, 2000; Wildbaum et al., J Immunol 165:5860-5866, 2000).
Methods for treating autoimmune disease by administering a nucleic acid encoding one or more autoantigens are described in WO 00/53019, WO 2003/045316, and WO 2004/047734. While these methods have been successful, further improvements are still needed.
Bacterial enterotoxins are used as immunostimulating adjuvants in vaccines for the prevention of infectious diseases. Cholera toxin (CT) and the closely related E. coli heat-labile toxin (LT) are perhaps the most powerful and best studied mucosal adjuvants in experimental use today (Rappuoli et al., Immunol Today 20:493-500), but when exploited in the clinic, their potential toxicity and association with cases of Bell's palsy (paralysis of the facial nerve) have led to their withdrawal from the market (Gluck et al., J Infect Dis 181: 1129-1132, 2000; Gluck et al., Vaccine 20 (Suppl. 1): S42-44, 2001; Mutsch et al., N Engl J Med. 350: 896-903, 2004). The bacterial enterotoxins CT and LT have proven to be effective immunoenhancers in experimental animals as well as in humans (Freytag et al., Curr Top Microbiol Immunol 236: 215-236, 1999). Structurally, these enterotoxins are AB5 complexes, and consist of one ADP-ribosyltransferase active A1 subunit and an A2 subunit that links the A1 to a pentamer of B subunits. The holotoxins bind to most mammalian cells via the B subunit (CTB), which specifically interacts with the GM1-ganglioside receptor in the cell membrane. Whereas the holotoxins have been found to enhance mucosal immune responses, conjugates between CTB and antigen have been used to specifically tolerize the immune system (Holmgren et al., Am J Trop Med Hyg 50: 42-54, 1994). Studies in mice have shown that CT and LT can accumulate in the olfactory nerve and bulb when given intranasally, a mechanism that is dependent on the ability of the B subunits of CT or LT to bind GM1-ganglioside receptors, present on all nucleated mammalian cells (Fujihashi et al., Vaccine 20: 2431-2438, 2002). Although less toxic mutants of CT and LT have been engineered with substantial adjuvant function, such molecules still carry a significant risk of causing adverse reactions (Giuliani et al., J Exp Med 187: 1123-1132, 1998; Yamamoto et al., J Exp Med 185: 1203-1210, 1997), especially when considering that the adjuvanticity of CT and LT appears to be a combination of the ADP-ribosyltransferase activity of the A subunit and the ability to bind ganglioside receptors on the target cells (Soriani et al., Microbiology 148: 667-676, 2002). These observations and others preclude the use of CT or LT holotoxins in vaccines for humans. On the other hand, recent observations have demonstrated that it is possible to retain adjuvant functions of these molecules with no toxicity or greatly reduced toxicity by introducing site-directed mutations in the gene coding for the A1 subunit. Examples of mutant molecules that have proven to be effective adjuvants are LTK63 and LTR72 (Giuliani et al., J Exp Med 187: 1123-1132, 1998), the former with no enzymatic activity and the latter with significantly reduced ADP-ribosylating ability. Notwithstanding this, the GM1-ganglioside receptor-dependent binding remains a problem in these mutants, and may therefore still cause nerve cell accumulation and neurotoxicity.
A better solution to this dilemma of efficacy versus toxicity is the CTA1-DD molecule that has proven to be a highly effective mucosal and systemic adjuvant (Ågren et al., J Immunol 158: 3936-3946, 1997; U.S. Pat. No. 5,917,026). This unique adjuvant is based on the enzymatically active A1-subunit of CT, combined with a dimer of an immunoglobulin-binding element from Staphylococcus aureus protein A. The molecule thereby avoids binding to all nucleated cells, which could result in unwanted reactions, and exploits fully the CTA1-enzyme in the holotoxin. Accordingly, all studies to date have found that CTA1-DD is nontoxic and has retained excellent immunoenhancing functions. When given systemically, CTA1-DD provides comparable adjuvant effect to that of intact CT, greatly augmenting both cellular and humoral immunity against specific immunogens coadministered with the adjuvant. It also functions as a mucosal adjuvant and should be safe, as it is devoid of the B subunit that is a prerequisite of CT holotoxin toxicity. CTA1-DD cannot bind to ganglioside receptors; rather, it targets B cells, limiting the CTA1-DD adjuvant to a restricted repertoire of cells that it can interact with. However, the adjuvant effect is not completely dependent on B cells, as been shown in strong induction of specific CD4 T cell immunity following intranasal immunizations using the CTA1-DD adjuvant in B-cell deficient mice (Eliasson et al., Vaccine 25: 1243-52, 2008, Akhiani et al., Scand J. Immunol 63: 97-105, 2006).
The adjuvant effect of CTA1-DD was absent in mutants CTA1-E112K-DD and CTA1-R7K-DD, which lack the ADP-ribosylating enzymatic activity (Lycke, Immunol Lett 97: 193-198, 2005).
WO 2009/078796 further describes immunomodulating complexes comprising the mutant CTA1-R7K-DD, and more specifically the immunomodulating complexes comprising CTA1-R7K-DD linked to the shared immunodominant collagen II peptide comprising amino acids 260-273 (CII260-273).
A conjugate of CTB and a peptide derived from bovine collagen II has been shown to be able to protect mice from developing collagen induced autoimmune ear disease as well as collagen-induced arthritis (Kim et al., Ann Otol Rhinol Laryngol 110: 646-654, 2001; Tarkowski et al., Arthritis Rheum 42: 1628-34, 1999). However, CTB may not be suited for human use due to its GM1-ganglioside-binding properties and potential neurotoxic effects, as discussed above.
The immunomodulating complexes of the present invention differ from the immounomodulating complexes comprising the mutant CTA1-R7K-DD according to WO 2009/078796 at least in that amino acid 187 has been changed from cysteine to alanine and, optionally, in that a lysine residue has further been inserted in the N-terminal of the mutant CTA1 subunit.
The inventors of the present invention have surprisingly found that further replacement of amino acid 187 cysteine by an alanine of the immunomodulating complexes comprising the mutant CTA1-R7K-DD according to WO 2009/078796, and in particular the immunomodulating complexes comprising CTA1-R7K-DD linked to the shared immunodominant collagen II peptide, provides a significantly improved therapeutic effect on arthritis, with significantly lower incidence and severity of arthritis in mice.
Without being bound by theory, the mechanism behind the surprising improvement in therapeutic effect of the CTA1-R7K/C187A-DD according to the present invention as compared to CTA1-R/K-DD according to WO 2009/078796 would seem explainable by the fact that the replacement of amino acid 187 cysteine by alanine abolishes the formation of dimers through disulfide bonds.
It was a priori unknown whether obtaining a therapeutic effect would be dependent on at least some or even a substantial degree of dimerisation of the resulting fusion-protein. Therefore, before the surprising findings of the present inventors, it was not predictable whether trying to avoid dimerisation would in fact be detrimental to therapeutic activity of the immunomodulating complexes, and whether making this amino acid replacement would result in a fusion-protein having at least as good therapeutic effects as the CTA1-R7K-DD construct.
Furthermore, the present inventors have surprisingly found that the insertion of a lysine residue in the N-terminal of the fusion protein drastically increases the expression and production of the fusion protein, K-CTA1-R7K/C187A-DD, without any loss with regard to the therapeutic efficacy of the protein due to misfolding, translocation or proteolytic degradation. Thus, it was hitherto unknown whether the insertion of a lysine residue in the N-terminal would be detrimental to the biological availability and therapeutic activity of the fusion protein (e.g. due to effects on folding, etc.), and whether the insertion of lysine in the N-terminal would result in a fusion protein with at least as good therapeutic effects as the CTA1-R7K-DD construct.

Mutant CTAI fusion protein for treatment of allergy and autoimmune disease


A most recent value of data fetched from a plant facility is temporarily stored and extracted and then stored in a plant history data table. On another front, a monitoring point for monitoring a plant error is registered in response to an operator request. A monitoring point is used as a key to select and register a main variable point having a strong correlation from the plant history data table. A statistical upper/lower limit function is defined on the basis of time-series plant data of monitoring points and main variable points. By referring to information in a table in which a limit value function is stored, the limit value is periodically matched with the content of a plant-data most-recent-value table. If the most recent value is outside the limit range, deviation information is stored in a determination result table. If a new plant error occurs, an error signal and the content of the determination result table is outputted and displayed.

1. Field of the Invention
The present invention relates to a plant operation data monitoring apparatus for detecting an error by monitoring plant data.
2. Related Art
In order to detect a plant error in a power plant, a point (sensor value) to be monitored is specified in advance and the presence or absence of a plant error is determined by comparing a specified fixed upper/lower limit and most recent plant data to see whether the limit is exceeded (see Japanese Patent Laid-Open No. 05-120582). Further, a technique has been introduced, which the limit is calculated by using an average value, a standard deviation and the like of historical plant data in a monitoring point to improve the accuracy of detecting a plant error (see Japanese Patent Application No. 2004-346716).
Unfortunately, according to the aforementioned prior art, when a plant operating state (activating, loading up, terminating, or the like) is changed, a value at a monitoring point may exceed the upper/lower limit to be used to detect a plant error in spite of a normal operation state, and an operator may be informed of a false alarm.
Therefore, there is a problem in that it takes knowledge of a skilled plant operator to determine an optimum upper/lower limit, or it takes time and efforts such as repeating a plant test operation and changing limit values many times.

Plant operation data monitoring apparatus


A hair roller is provided around which hair can be wound easily with tension toward the outside acting on the hair, without a fear that the distal ends of the hair are folded, with ease in handling, and with good operativity, and with which the wound state can be maintained, regardless of the level of skill, i.e., even by a beautician who lacks experience or an amateur. A hair roller comprises a rod having a hair winding portion where at least a portion around which hair is wound is resiliently restitutively compressed and deformed and also having a hair distal end retaining member for retaining distal ends of hair and a wind maintaining member for maintaining the state of hair wound around the rod with tension.

1. Field of the Invention
The present invention relates to a hair roller, and more particularly, to a hair roller onto which hair is wound with tension toward the outside acting on the hair utilizing shape restitutive force.
2. Description of the Related Art
Regardless of age or sex, people attempt to show their originality or to create an atmosphere by adopting various kinds of hairstyles. Although a hairstyle can of course be expressed by a haircut, there are many cases in which a hairstyle is expressed by curling hair the curled state of which is retained by a hair roller.
As the hair roller, a hollow cylindrical member such as a rod is often used. FIG. 31 shows, as such an example, a hair roller used when hair is permed. A hair roller 110 shown in the figure comprises a rod 111 around the surface of which hair is wound, a rubber band 112 for fastening the rod 111 along the longitudinal direction of the rod 111 with hair wound around it, and a pin 113 for forming a space between the rubber band 112 fastening the rod 111 and hair wound around the rod 111 for the purpose of preventing a mark of the rubber band 112 from remaining on the hair wound around the rod 111.
The process of winding hair onto the conventional rod 111 is shown in FIG. 32. First, an appropriate amount of hair 120 is scooped up with a comb or the like, and the hair 120 is sandwiched by a sheet body 114 or the like formed of paper with good water absorption or the like folded in two (FIG. 32A). Here, the hair 120 is easy to handle if the hair 120 is moistened in advance. Next, the hair 120 is wound onto the rod 111 together with the sheet body 114 from the side of distal ends 121 of hair (FIG. 32B). Then, the rod 111 with the hair 120 wound around the rod 111 is fastened by the rubber band 112 along the longitudinal direction of the rod 111 (FIG. 32C). After that, the pin 113 is put between the rubber band 112 and the hair 120 for the purpose of preventing a mark of the rubber band 112 from remaining on the hair (FIG. 32D).
In case a curl wound in the longitudinal direction is desired, a nearly conical long rod 115 as shown in FIG. 33 is used, and hair is spirally wound around the rod 115.
The rods 111 and 115 are used, other than in perming, when hair wound onto the rod is curled by heated by a hair drier and the like or by maintaining the wound state for a predetermined time period, for example.
However, there are problems in case hair is wound onto a conventional hair roller. More specifically, in order to beautifully curl hair, it is desirable to curl hair onto a rod with tension. However, since the surface of the rods 111 and 115 is slippery, the work at the beginning of winding hair is especially difficult. Further, since the rods 111 and 115 are generally made of a nonresilient material such as plastic, it requires practice to wind hair with tension toward the outside acting on the hair.
Still further, if a beautician who lacks experience or an amateur winds the hair 120 onto the rod 111 or 115, the hair is often wound with the distal ends 121 of hair or the like being folded. If the hair is permed with this state, the folded state of the distal ends 121 of hair is fixed, and it is difficult to improve the state even with heat by a hair drier. Still further, even if the rubber band 112 or the like fastens the rod 111 with the hair wound around the rod 111 for the purpose of preventing the rod 111 from rotatably moving, if the position of the fastening is inappropriate, the rod 111 easily rotatably moves and it is difficult to retain the wound state.
As described in the above, since it requires skill to some extent to wind the hair 120 around the conventional rod 111 or 115, and especially, since it requires practice to wind the hair 120 with tension toward the outside acting on the hair 120, there are problems that, if a beautician who lacks experience or an amateur carries out the above described work, it takes a lot of time to wind the hair 120 or the finished hairstyle is unsatisfactory.
The present invention is made in view of the above, and an object of the invention is to provide a hair roller around which hair can be wound easily with tension toward the outside acting on the hair, without a fear that the distal ends of the hair are folded, with ease in handling, and with good operativity, so that the wound state can be maintained regardless of the level of skill, i.e., even by a beautician who lacks experience or an amateur.


A diagnostic test and method is provided comprising mixing blood or another biological fluid sample with a test compound and spotting the blood on filter paper for subsequent analysis of the effect of the test compound on the blood. The biological fluid can be a cerebrospinal fluid, a peritoneal fluid, a cyst fluid, an amniotic fluid, a lavage fluid, a saliva, a cell extract or a tissue extract. The compound is chosen among an amino acid, a peptide, a protein, a carbohydrate, an oligosaccharide, a polysaccharide, a glycoprotein, a lipid, a lipoprotein, a glycosaminoglycan, a hormone, a steroid, a vitamin, a low molecular weight synthetic or natural compound which influences the blood to cause an alteration of its composition, e.g., a toxin, allergen, autoantigen, bacterial protein or polysaccharide, viral protein, fungal protein or polysaccharide, parasitic protein or polysaccharide, bacterial lipopolysaccharide or any other compound relevant to diseases.

Blood is a complex mixture composed of plasma and cells [(Beck W S (Ed.). Hematology. MIT Press 1985; Bloom A L, Thomas, D P (Eds.). Haemostasis and thrombosis. Longman 1987; Janeway C A, et al., Immunobiology. Elsevier 1999)]. The plasma can be separated from the cells by centrifugation and other techniques. If the plasma is allowed to stand it will clot by coagulation and serum may be separated from the blood clot. The coagulation may be inhibited by addition of various anticoagulants, including EDTA, EGTA, heparin, citrate and others. The cells of the blood include dendritic cells, macrophages, monocytes, neutrophils, T lymphocytes, B lymphocytes, natural killer cells, red blood cells and various stem cells including hemopoietic stem cells. In addition megakaryocyte-derived platelets are present in large numbers. The plasma contains thousands of proteins, in principle any protein of the human proteome [Thadikkaran L, et al, Recent advances in blood-related proteomics. Proteomics. 2005; 5:3019-34; Anderson N L and Anderson N G. The human plasma proteome: history, character, and diagnostic prospects. Mol Cell Proteomics. 2002; 1:845-67)]. Some of the proteins are involved in transport, blood clotting or immune defence, while others function as signalling molecules between cells of the blood and cells of the tissues. In particular, the activity of the cells of the immune system (dendritic cells, macrophages, T cells, B cells, natural killer cells) is regulated by a complex network of signalling molecules (e.g. interleukins, chemokines, growth factors), tissue antigens and receptors (Janeway, cited above; Steinke J W, et al, Cytokines and chemokines. J Allergy Clin Immunol. 2006; 117:S441-5; Blach-Olszewska Z. Innate immunity: cells, receptors, and signaling pathways. Arch Immunol Ther Exp. 2005; 53:245-53. Lapidot T, Petit I.
Current understanding of stem cell mobilization: the roles of chemokines, proteolytic enzymes, adhesion molecules, cytokines, and stromal cells. Exp Hematol. 2002; 30:973-81. Cravens P D, Lipsky P E. Dendritic cells, chemokine receptors and autoimmune inflammatory diseases. Immunol Cell Biol. 2002; 80:497-505.] The activity and specificity of immune system cells can be investigated and quantitated by several methods and assays. T cells, B cells and other cells can be quantitated by fluorescence-activated cell sorting using antibodies to cell surface marker molecules (Villas B H. Flow cytometry: an overview. Cell Vis. 1998; 5:56-61. Stelzer G T, Robinson J P. Flow cytometric evaluation of leukocyte function. Diagn Clin Immunol. 1988; 5:223-31.] Specific T cells can be measured by cytotoxicity assays, chromium release assays and cytokine release assays (e.g. ELISPOT) (Jerome K R, et al., Measurement of CTL-induced cytotoxicity: the caspase 3 assay. Apoptosis. 2003; 8:563-7; Andersen M H, et al, Cytotoxic T cells. J Invest Dermatol. 2006; 126:32-41. Troutt A B, et al, Quantitative analysis of lymphokine expression in vivo and in vitro. Immunol Cell Biol. 1992; 70:51-7; Schmittel A, et al., Quantification of tumor-specific T lymphocytes with the ELISPOT assay. J Immunother. 2000; 23:289-95; House R V. Theory and practice of cytokine assessment in immunotoxicology. Methods. 1999; 19:17-27.) and by using various peptide-major histocompatibility complex (MHC) protein constructs (Meidenbauer N, et al, Direct visualization of antigen-specific T cells using peptide-MHC-class I tetrameric complexes. Methods. 2003; 31:160-71; Bousso P. Generation of MHC-peptide tetramers: a new opportunity for dissecting T-cell immune responses. Microbes Infect. 2000; 2:425-9). The activity of B cells can be measured by determining the levels of specific antibodies released from the B cells (Hogrefe W R. Biomarkers and assessment of vaccine responses. Biomarkers. 2005; 10:S50-7; Manz R A, et al, Maintenance of serum antibody levels. Annu Rev Immunol. 2005; 23:367-86).
A major problem in measuring signalling molecules released from blood cells is that of storage and transport in relation to quantitation. Many blood constituents (e.g. cytokines) are labile and short lived, resulting in degradation during incubation, storage and transport. For this reason, comparative analyses and diagnostic tests have to be carried out immediately upon blood collection and incubation in central laboratories. Ideally, all samples to be compared should be analyzed consecutively using a calibrated instrument.
This is not always practical, e.g. when taking blood samples in remote areas, when doing in vitro and in vivo time-studies or when comparing samples from many different individuals. One solution to this problem is to freeze samples for transport and storage. This, however, does not guarantee preservation of constituents, requires large freezing, transport and storage capacity, requires thawing each time an analysis is performed, and is vulnerable with regard to shortage of electric power supply. For this reason, there is a need for reliable methods of blood and biological sample preservation and a need for diagnostic tests employing reliable sample preservation in combination with sample manipulation.
The use of filter paper for spotting blood for subsequent analysis is well known, e.g. for analysis of blood samples of newborn babies for inherited metabolic diseases (Mei J V, et al., Use of filter paper for the collection and analysis of human whole blood specimens. J Nutr. 2001; 131:1631S-6S. The advantages of this are good preservation of blood constituents, easy transport and facile long term storage. However, the use of filter paper and similar methods for drying and storing blood samples after incubation with test compounds has not been used or described before, possibly because this has been anticipated to be impossible or impractical.
What are needed are improved methods for transporting and storing biological samples.

Diagnostic blood test using adsorption on filter paper