The present invention provides a fail-safe combination of chemical and physical means for rendering a blood product which comprises a labile blood protein free of viruses without incurring protein denaturation. The blood product is contacted with an effective amount of a selected chemical disinfectant, preferably, sodium thiocyanate in combination with a physical process, preferably, ultrafiltration. The blood product may be plasma, serum, plasma concentrate, cryoprecipitate, cryosupernatant, plasma fractionation precipitate or plasma fractionation supernatant containing viruses such as hepatitis or human immunodeficiency virus.

1. Field of the Invention
This invention relates to methods for the inactivation of viruses in virus-contaminated pharmaceutical compositions containing proteinaceous components, such as coagulation factors, by the use of chemical inactivation and/or physical processes. In particular, this invention relates to blood plasma or other plasma protein-containing compositions which are to be rendered free of viral infectivity, such blood plasma or fractions thereof having valuable labile proteins, such as, for example Factor IX. .A specific method of the invention requires the use of sodium thiocyanate and ultrafiltration.
2. Description of Related Art
Blood is made up of solids (cells, i.e., erythrocytes, leukocytes, and thrombocytes) and liquid (plasma). The cells contain potentially valuable substances such as hemoglobin, and they can be induced to make other potentially valuable substances such as interferons, growth factors, and other biological response modifiers. The plasma is composed mainly of water, salts, lipids and proteins. Prior to the availability of a more detailed description of individual protein components, the proteins were divided into groups; initially as simply "albumins" and "globulins". Typical antibodies (immune serum globulins) found in human blood plasma include those directed against infectious hepatitis, influenza H, etc.
Whole blood must be carefully typed and cross matched prior to administration in blood transfusions. Plasma, however, does not generally require prior testing. For certain applications, only a proper fraction of the plasma is required, such as factor VIII complex for treatment of hemophilia or von Willebrand's disease. The rationale for use of specific fractions of blood is that blood contains a number of differently formed elements as well as various plasma proteins and constituents which have many functions. Thus, a single donation of a unit of whole blood can provide red blood cells, platelets, plasma, and cryoprecipitated factor VIII-fibrinogen concentrate. Pheresis procedures are able to supply large quantities of granulocytes, platelets, and plasma from single donors. The rationale for using blood components is that a patient usually requires replacement of only a specified component (See: Greenwalt et al: General Principles of Blood Transfusion, A.M.A. Editorial Board, 1978). Remaining components can be then used to treat patients who require other specific components, thereby allowing several patients to benefit from each blood unit donated, thereby maximizing the benefit realizable therefrom. The separation of blood into components and their subsequent fractionation allows the proteins to be concentrated. Of great importance, too, is the fact that the plasma fractions can be stored for much longer periods than whole blood and they can be distributed in liquid, frozen, or dried state. Finally, it allows, in some cases, salvaging from blood banks the plasma portions of outdated whole blood that are unsafe for administration as whole blood.
Proteins found in human plasma include prealbumin, retinol-binding protein, albumin, alpha-globulins, beta-globulins, the coagulation proteins (Factors II, VII, IX, X, V, VIII, XI, XII, XIII and inhibitors such as protein C, antithrombin III, etc.) fibronectin, immunoglobins (immunoglobulins G, A, M, D, and E), and the complement components. There are currently more than 100 plasma proteins that have been described. A comprehensive listing can be found in the "The Plasma Proteins", ed. Putnam, F. W., Academic Press, New York (1975)
Proteins found in the blood cell fraction include hemoglobin, fibronectin, fibrinogen, enzymes of carbohydrate and protein metabolism, etc. In addition the synthesis of other proteins can be induced, such as interferons and growth factors.
Plasma can be chemically fractionated to provide albumin or plasma protein fraction, Factor VIII concentrate, Factor IX complex and immune serum globulin.
Blood plasma fractionation generally involves the use of organic solvents such as ethanol, ether and polyethylene glycol at low temperatures and at controlled pH values to effect precipitation of a particular fraction containing one or more plasma proteins. The resultant supernatant can itself then be precipitated and so on until the desired degree of fractionation is attained. More recently, separations are based on chromatographic processes. A survey of blood fractionation appears in Kirk-Othmer's Encyclopedia of Chemical Technology, Third Edition, Interscience Publishers, Volume 4, pages 25 to 62.
The major components of a cold ethanolfractionation are as follows:
______________________________________ Fraction Proteins ______________________________________ I fibrinogen; cold insoluble globulin; Factor VIII; properdin II and III IgG; IgM; IgA; fibrinogen; beta-lipoprotein; prothrombin; plasminogen; plasmin inhibitor; Factor V; Factor VII; Factor IX; Factor X; thrombin; antithrombin; isoagglutinins; ceruloplasmin; complement C'1, C'3 IV-1 alpha-1-lipoprotein, ceruloplasmin, plasmin-inhibitor; Factor IX; peptidase; alpha-and-beta-globulins IV-4 transferrin; thyroxine binding globulin; serum esterase; alpha-1-lipoprotein; albumin; alkaline phosphatase V albumin; alpha-globulin VI alpha-1-acid glycoprotein; albumin ______________________________________
The above fractionation scheme can serve as a basis for further fractionations. Fraction II and III, for example, can be further fractionated to obtain immune serum globulin (ISG), a mixture primarly of Igb antibodies.
Another fractionation scheme involves use of frozen plasma which is thawed into a cryoprecipitate containing AHF (antihemophilic factor) and fibronectin and a cryosupernatant. The cryoprecipitate is then fractionated into fibronectin and AHF.
Polyethylene glycol is among the agents which have been used to prepare high purity AHF and non-aggregated ISG.
In the development of new products from human plasma, at least three major problems are always present. These are contamination with pyrogens (endotoxins), transmission of viral hepatitis or other viral diseases, and activation of the coagulation enzymes.
Solutions of pharmaceutical compositions which are intended to be parenterally administered in man (or in veterinary applications) are required to be sterilized from infective microorganism such as bacteria and fungi. A common method is to subject the composition to steam sterilization (autoclaving) at temperatures in excess of 100.degree. C. at hyperbaric pressures for a time sufficient to be efficacious. This treatment kills viruses but can be deleterious or destructive to certain heat-sensitive compositions such as those which contain proteinaceous components such as coagulation Factors VIII, IX, II, VII, X, and the like.
Pyrogens are lipopolysaccharides (LPS) derived from the outer cell wall of gram-negative bacteria. They are toxic materials which are also known as endotoxins to distinguish them from toxic substances synthesized and excreted by the intact bacterium. Pyrogens have numerous biologic activities which include the production of fever, activation of clotting mechanisms and induction of shock. Consequently, in addition to the need for sterility from infectious agents, it is essential that pyrogenic substances be removed and that the causative bacteria be rendered innocuous by sterilization or other such treatment of the final plasma product.
Blood coagulation factors play a vital role in the normal coagulation mechanism. For instance, patients with a deficiency of Factor IX exhibit severe bleeding problems ("Hemophilia B"). It would be desirable to be able to isolate substantial quantities of Factor IX and other vitamin K-dependent proteins for therapeutic administration, as well as for scientific study.
Factor IX complex is a lyophilized pooled plasma derivative rich in Factors IV, VII, IX and X. It is an alternative to plasma therapy. It supplies vitamin K-dependent clotting factors in a much smaller volume than plasma but with a significantly higher hepatitis risk.
Factor IX containing concentrates are a unique and highly valuable blood product which are life-saving when used to control bleeding in patients suffering with Factor IX deficiency (Hemophilia B). These products have also been used to treat those patients afflicted with Hemophilia A having inhibitors, although clinical verification of this application is still in progress. Factor IX containing concentrates are also used to arrest serious hemorrhages or to avert operative and post operative bleeding in patients with other congenital clotting factor deficiencies and for multiple factor deficiency induced by an overdose of warfarin-type drugs, i.e., oral anticoagulants.
Commercial concentrates of Factor IX have been previously prepared using ion exchange resins to bind vitamin K-dependent clotting factors and separate these proteins from the bulk of other plasma proteins. These clotting factor concentrates are then eluted from the resin and vialed for therapeutic use without further purification. Such concentrates tend to have thrombogenic potential probably because they contain extraneous vitamin K-dependent clotting factors and/or phospholipid. Further, such concentrates have been a suspected vehicle in the transmission of viral diseases including hepatitis and acquired immune deficiency syndrome ("AIDS"). Further, crude concentrates of Factor IX are not stable for long periods in solution and therefore cannot be used for constant infusion therapy which limits their value in chronic replacement therapy.
Recent efforts to create Factor IX using a recombinant DNA approach have been frustrated by the difficulty encountered in separating Factor IX from culture supernatants with currently accepted techniques. (See: Anson DS, Austen DEG, and Brownless GG. "Expression of active human clotting Factor IX from recombinant DNA clones in mammalian cells." Nature 1985; 315:683-685; de la Salle H. Altenburger W. Elkaim R., Dott K., et al. "Active gamma-carboxylated human Factor IX expressed using recombinant DNA techniques." Nature 1985; 316:268-270; and Busby S., Kumar A., Joseph M., Halfpap L. Insley M. et al. "Expression of active human Factor IX in transfected cells." Nature 1985; 316:271-273). Thus, there remains a medical need for a safe preparation of Factor IX obtained from human plasma.
Numerous attempts have been made to inactivate viruses such as lipid-containing viruses of hepatitis B virus (HBV) and human immunodeficiency virus (HIV) in mammalian, especially, human, blood plasma. It is the practice in some countries to effect inactivation of the hepatitis B virus in the blood plasma by contacting the plasma with a viral inactivating agent of the type which crosslinks with the proteinaceous protein of hepatitis B virus or which interacts with the nucleic acid of the virus. For instance, it is known to attempt to inactivate hepatitis B virus by contact with an aldehyde (such as formaldehyde) whereby crosslinking to the protein is effected and the hepatitis B virus is inactivated. It is also known to effect inactivation of the virus by contact with beta-propiolactone (BPL), an agent which acts on the nucleic acid as well as protein components of the virus. It is further known to use ultraviolet (UV) light, especially after a beta-propiolactone treatment. It is believed that these methods are not suitable for the inactivation of the virus in plasma due to the observation that most of these inactivating agents (formaldehyde, beta-propiolactone and sodium hypochlorite) denatured or altered the valuable proteinaceous components of the plasma, especially so-called "labile" blood coagulation factors of the plasma.
The removal of bacteria and fungi from such heat-sensitive proteinaceous compositions is generally accomplished by the use of a bacterially retentive filter. Typical examples are the membrane filters in the porosity range 0.1-0.2 microns (100-200 nanometers) produced by Pall Corporation and Millipore Corporation. Generally, the proteinaceous components in the pharmaceutical composition remain undamaged. However, it is known that membrane filters can fail to retain highly infectious and dangerous microorganisms such as virus particles. Filter devices can be designed to retain some virus particles if the effective filter porosity is of a small enough size. Such devices have sometimes been used to harvest viral particles, e.g., during the manufacture of viral vaccines. Most viral particles, however, are smaller in size than the effective porosity of the membrane filter and are not retained. For example, the hepatitis B virus, which may be present in coagulation factor solutions made from human plasma, has a diameter of 42 nanometers (nm) and will readily pass through a 100 nm (0.1 micron) membrane filter.
It is well-known that plasma and products made from plasma may transmit hepatitis. Initially, interest in viral transmission focused primarily on hepatitis B antigen (HB.sub.s A.sub.g) as an indicator of the presence of the offending agent (hepatitis B virus) and attempts at eliminating this agent have led to widespread screening of all plasma used in transfusion by commercially available and approved laboratory procedures. While such laboratory screening has apparently decreased the incidence of hepatitis B in patients receiving whole blood transfusions, there has not been significant improvement in the incidence of the disease transmitted from plasma products Chronic users of blood products are at risk from the disease unless maintained in an immune state by innoculation with a vaccine. While effective, this may have other clinical risks associated with it. Attempts to remove the virus by various adsorption procedures or precipitation techniques, e.g. with polyethylene glycol, have not proven to fully eliminate infectivity. There is some evidence that the combination of ultraviolet light and B-propionolactone may be helpful in inactivating the virus in certain plasma products. However, there is some apprehension the B-propionolactone has carcinogenic properties.
In order to increase the safety of pharmaceutical compositions which contain heat-sensitive proteinaceous components and which may contain dangerous virus particles, additional processing is required. This processing includes heating solutions of the proteinaceous components with special stabilizers to protect biologic potency, heating lyophilized preparations of the proteinaceous components, and treating solutions of proteinaceous components with organic solvents and other virucidal agents. Most of these methods are burdensome, time consuming, or destructive of the protein due to the rigorousness of the treatment. There are still questions about the efficacy of any one of these procedures applied singly to plasma products.
While the development of screening tests for hepatitis B has been of limited value in reducing transmission of the disease, the identification of this virus (as well as the hepatitis A virus) has led to the recognition of a third virus which is apparently responsible for the majority of cases of hepatitis transmitted by blood plasma derivatives. This virus is referred to as "non-A, non-B hepatitis".
Methods for the inactivation of hepatitis B virus in the plasma are known but are usually impractical. One method involves the addition of antibodies to the plasma whereby an immune complex is formed. The expense of antibody formation and purification add significantly to the cost of the plasma production; furthermore, there is no assurance that a sufficient quantity of non-A, non-B virus is inactivated since the method is specific for the hepatitis B virus. There is currently no approved and available test for non-A, non-B antibodies or virus, though there are reports of progress in achieving this; hence, it is not as yet possible to select plasma containing high titers of anti non-A, non-B antibody, nor indicate that this approach would be practicable.
As progress has been made in the development of human plasma derived therapeutics, the necessity of viral sterilization has become manifest. Stable plasma protein solutions can withstand pasteurization but labile blood coagulation factors are most often inactivated or significantly reduced in potency during such heating. This restricts practical applications. As a result, recipients of Factor VIII, gamma-globulin, Factor IX, fibrinogen, etc., must often accept the risk that the valuable protein components being administered may be contaminated with hepatitis viruses as well as other infectious viruses. As a result, these recipients face the danger of becoming infected by these viruses and having to endure the damage which the virus causes to organ systems and consequent incapacitation and illness which may lead to death. Therefore, there is a need for a more effective yet practicable method for purification of the heat-sensitive plasma, specifically a method for viral sterilization without the use of heat.
Thus a very special need exists for the development of means and methods for the manufacture and isolation of highly purified Factor IX which can thereafter be formulated into a potent, quick-acting, therapeutic blood product which is stable in vitro and which provides effective relief for patients encountering a critical bleeding incident.
The present invention is directed to achieving three goals, namely, (1) a safe, 2) viral inactivated protein-containing composition, (3) without incurring substantial protein denaturation. These three goals are not necessarily compatible since, for example sterilization inactivates viral infectivity, but substantially denatures the valuable plasma proteins, for example, beta-propiolactone inactivates viral infectivity but is unsafe, and substances such as formaldehyde inactivate viruses, but also substantially denaturate the valuable plasma proteins, for example, Factor IX.
It is therefore desirable to provide a process for obtaining protein-containing compositions which does not substantially denature the valuable protein components therein and which does not entail the use of proven carcinogenic agents (such as B-proprionolactone). More especially, it is desirable to provide blood protein, containing compositions in which substantially all of the hepatitis viruses and other viruses present are inactivated. It is a further object to provide products from cancer or normal cells or from fermentation processes of cells following given insertion of recombinant DNA which are substantially free of virus, including lipid-containing viruses, which comprise a category containing known infective agents of plasma.

Methods for the inactivation of viruses in viral-contaminated pharmaceutical compositions

Rhone-Poulenc Rorer Pharmaceuticals Inc.


A water-circulating type ice maker of the present invention comprises a refrigerating capacity detecting means for detecting the refrigerating capacity of the ice maker at a set temperature, which is slightly above the temperature where the ice-making water starts to freeze in the state of partial ice, and an ice-making plate temperature lowering means for lowering the temperature of the ice-making plate as a counter measure against partial ice generation so that the ice-making plate temperature lowering means starts operating when the refrigerating capacity detected by the refrigerating capacity detecting means is lower than a predetermined capacity. The comparison of the refrigerating capacity detected by the refrigerating capacity detecting means and the predetermined capacity can be made by detecting the high side pressure, the low side pressure, the condensing temperature or the evaporating temperature when the ice-making water reaches the set temperature. Furthermore, the ice-making plate temperature lowering means can be one that ,for example, stops the ice-making water circulation pump.

1. Field of the Invention
The present invention relates to a water-circulating type ice maker having a refrigerating circuit comprising an ice-making water circuit where ice-making water is circulated and supplied to an ice-making plate by a circulating pump, an evaporator provided at the ice-making plate for freezing the circulating water on the ice-making plate, and a condenser which is cooled by the air surrounding the ice maker or a cooling medium such as cooling water; in particular, the present invention relates to a device capable of preventing the phenomenon of generating cotton-like or slushy partial ice, which are characteristic of this type of an ice maker, (hereinafter referred to as partial ice) immediately before freezing.
2. Description of the Related Art
A water-circulating type ice maker is an ice-maker for producing pure ice where the impurities are eliminated at the surface of the ice-making plate by repeating the process of flowing ice-making water on the surface of the ice-making plate during the freezing cycle. Various kinds of ice makers having different types of ice-making plates such as a vertical flat-plate type, a vertical pipe type, and a spray type are known. When freezing ice-making water, however, all of these water-circulating type ice makers have a common problem: cotton-like or a slushy ice is generated before freezing begins because the freezing temperature of the ice-making water becomes 0.degree. Celsius or less.
The type of ice generated depends upon the flow rate, plate surface temperature, etc. Among the above-mentioned examples, in the case of the spray type ice maker, which has the highest flow rate and a low plate surface temperature, cotton-like ice develops momentarily in the water-gathering pan or the water tank into which unfrozen water falls. Further, in the case of the vertical flat-plate type ice maker which has the lowest flow rate and a high plate surface temperature, slushy ice may develop partially on the ice-making plate to disturb the circulation of the water.
Various methods are conventionally known to prevent the generation of the partial ice, such as slushy or cotton-like ice. For example, Japanese Patent Application Laid-open No. 58-15706 discloses a technique for preventing generation of partial ice by predicting the generation of partial ice when the ice-making water reaches a predetermined temperature and temporarily stopping the supply of ice-making water from the ice-making water tank to the ice-making plate so as to either supercool the ice-making plate or form an initial ice film, and then resuming the operation of the ice-making water circulating pump.
Furthermore, Japanese Patent Application Laid-open No. 6-21753 discloses a technique for preventing generation of partial ice (cotton-like ice) by predicting the generation of partial ice when the ice-making water reaches a predetermined temperature and temporarily closing a solenoid valve or the expansion valve in the refrigerating circuit of the ice maker so as to rapidly lower the temperature of the ice-making plate to form the ice core necessary for ordinary ice growth on the ice-making plate.
Although both of the above-mentioned methods can prevent the generation of partial ice, they have the following problems.
For example, in the case of the former method of stopping the ice-making water circulating pump, since the refrigerating load becomes essentially zero with a long stop time, the liquid refrigerant returns from the evaporator to the compressor without evaporating and there is a risk of liquid compression in the compressor. However, the length of the stop time required to generate liquid compression in the compressor varies depending upon the temperature of the ice-making water at the time of the stoppage, the size of the refrigerating capacity with respect to the freezing load, etc.
When the former technique is applied in an ice maker having a harvesting water tank, the cooled and circulated ice-making water returns to the ice-making water tank during the stoppage of the ice-making water circulating pump without making ice so that the amount of water in the ice-making water tank increases. Then, since any cooled ice-making overflow water flows down into the harvesting water tank, energy is wasted. Furthermore, since the temperature of the harvesting water in the harvesting water tank is lowered due to the overflow water, the harvesting time is prolonged, and the problem of decreased ice-making capacity occurs.
In the case of the latter technique of opening the solenoid valve or the expansion valve, since the ice-making water circulating pump is not temporarily stopped, the above-mentioned problem of the former technique can be solved. However, since the refrigerant is not supplied from the compressor to the evaporator and the refrigerant left in the evaporator is sucked by the compressor, a long stop time involves the risk of stopping the operation of the ice maker due to the low pressure of the refrigerating circuit so that the low pressure switch functions to stop the compressor. The length of stopping time required to cause the operation of the ice maker to halt varies depending upon the temperature of the ice-making water at the time of the stoppage, the size of the refrigerating capacity with respect to the freezing load, etc.
The mechanism of partial ice generation has not been completely clarified. However, according to the knowledge and experience of the inventors, it is understood that when the refrigerating capacity is smaller than the refrigerating capacity necessary to cool and freeze the ice-making water, that is, the refrigerating load for making ice when the temperature is slightly above the temperature where the ice-making water starts freezing, partial ice is generated. On the other hand, when the refrigerating capacity is sufficiently large with respect to the refrigerating load for making ice, partial ice is not generated.
The size relationship between the refrigerating capacity of the ice maker and the refrigerating load for making ice varies depending upon the number of times the freezing cycle has been repeated since starting operation of the ice maker. For example, when operation of the ice maker is resumed after a long stoppage, the temperature of the components comprising the ice maker are high in the initial freezing cycle. Further, the refrigerating load for making ice can be roughly divided into the refrigerating heat quantity needed for cooling the ice-making water and the refrigerating heat quantity needed for cooling elements excluding the ice-making water, such as the components comprising the ice-making water circulation path. Therefore, in the initial freezing cycle, the refrigerating heat quantity needed for cooling the elements excluding the ice-making water is large. Accordingly, the refrigerating capacity is small with respect to the refrigerating load for making ice and it can be said that partial ice can be generated easily.
The relationship between the refrigerating capacity of the ice maker and the refrigerating load for making ice also varies depending upon the surrounding air temperature. For example, the higher the surrounding air temperature, the smaller the refrigerating capacity of the ice maker becomes. Accordingly, the refrigerating capacity easily becomes small with respect to the refrigerating load for making ice, and partial ice can be generated easily.
The relationship between the refrigerating capacity of the ice maker and the refrigerating load for making ice also varies depending upon the frequency level of the power source of the ice maker. For example, when an ice maker compatible with both a 60 Hz power source and a 50 Hz power source is used with the 50 Hz power source, the refrigerating capacity of the ice maker becomes smaller than when it is used with the 60 Hz power source. Therefore, the refrigerating capacity easily becomes small with respect to the refrigerating load for making ice, and thus the partial ice can be generated easily.
Furthermore, as mentioned above, generation of partial ice depends upon the size of the refrigerating load for making ice with respect to the refrigerating capacity of the ice maker. This relationship is particularly important when the ice-making water changes state to ice.
More specifically, since 80 kcal of latent heat is necessary per 1 kg of water for a state change of the ice-making water to ice, a maximum refrigerating capacity is required at the time of this state change. The state change is denoted as the maximum load point. If the refrigerating capacity for cooling the ice-making water is insufficient at the maximum load point, the cooling rate of the ice-making water becomes slow so that the time to pass through the maximum load point increases, and the generation of partial ice becomes likely.
According to the above-mentioned partial ice generation mechanism, partial ice is not always generated when ice-making water reaches a certain temperature, but is generated when the refrigerating capacity is small with respect to the freezing load when the ice-making water reaches the certain temperature.
However, conventional techniques always dealt with measures for preventing the generation of partial ice only when the ice-making water reaches a predetermined set temperature. Therefore, the conventional techniques facilitated the above-mentioned accompanying problems when the counter measures for partial ice generation were not necessary.
As mentioned above, in general, both the refrigerating capacity of the ice maker and the refrigerating load for making ice vary according to the operating conditions. Furthermore, the refrigerating capacity of the ice maker can be theoretically calculated from the cooling heat source such as the external air, and from the temperature of the ice-making water. On the other hand, the refrigerating load for making ice includes the refrigerating heat quantity for freezing the ice-making water and the refrigerating heat quantity for cooling the elements excluding the ice-making water. Among the heat quantities, the former can be calculated theoretically. However, it is difficult to calculate the latter theoretically, and it can only be estimated based on the value obtained from experience or experiment. Thus, it may drastically vary according to the operating conditions. Therefore, it is considered difficult to predict the refrigerating load for making ice, and to determine whether or not the refrigerating capacity of the ice maker is insufficient with respect to the predicted refrigerating load.


A configurable SRAM for a field programmable gate array. Two memory arrays each have a data input, a data output, a write enable input and port A and B address inputs. First and second address buses are selectively coupled to the port A and port B address inputs through multiplexers such that different configurations can be achieved. The multiplexers are controlled by a dual port/single port steering signal and a x1/x2 steering signal such that the following configurations can be achieved: 32 x1 dual port; 32 x1 single port and 16 x2 single port. In dual port configurations, simultaneous read and write operations to different cells can occur. In x2 configuration, each array is operated as an independent memory with its own address input, its own data output and its own data input. In x1 single port configuration, one data input line and one data output line and one address bus are shared between the two arrays, and an extra address bit is used to steer the write enable signals and the output multiplexer circuitry such the write enable signal reaches the proper array and the data output from the array being read reaches the shared output line.

In FPGAs, it is useful to have static RAM in the logic blocks. Sometimes this RAM is used for general purposes and only needs to have a single port. In other instances, to give the designer greater flexibility to implement FIFOs, the SRAM needs to have dual port capability so that simultaneous read and write operations using two different ports can be accomplished. In other instances, a logic block has more memory cells than are needed, but the designer can use all the cells if the memory could be split into two separate RAM memories, each with its own I/O address and data inputs and data output, and each configured to be single port.
Thus a need has arisen for a SRAM architecture which can be switched between dual port and single port configurations, and which can be either a x1 configuration where all cells are unified in a single memory or a x2 configuration where the memory cells available are split into two separate RAMs, each single port and each with its own I/O.

Configurable SRAM for field programmable gate array


A workflow manager system provides computer-assisted, graphical tools for defining and managing complex processes in terms of a workflow. A workflow includes a number of steps having step encapsulations and dependency relationships. Step encapsulations define the work to be performed by a step in a work flow such as launching a design tool. The dependency relationships represent the conditions that must be satisfied before a step can be performed and can be expressed in terms of boolean relationships using step and data states or data values as arguments. The workflow system manages the state of a workflow including the state of steps and data, and makes the workflow and its related data accessible to multiple users.

As the speed, and capacity of computers has increased, engineers and developers have relied more frequently on computer based tools to assist them in solving a wide range of problems. In the design automation field, computers are effective tools for organizing complex data, performing complex computations, and representing design data in easily understood formats.
The electronic design automation (EDA) field has produced a number of computer-based design tools to assist in the development of complex electronics. To list a few examples, there are computer-based tools to synthesize, simulate, and test an electronic circuit design. These tools have enabled design teams to decrease significantly the design cycle for complex electrical components.
Even with the array of design tools available to assist the design team, the design problem is still very difficult to manage. Many of today's computerbased design tools only assist in a single step in the design process such as helping design the physical layout of components on a circuit board or simulating the behavior of a circuit design. In most electronic design problems however, there are a number of steps, each potentially involving a number of designers and a large amount of data. In this complex design environment, it is very difficult to track the design steps and to organize the design data generated from those steps. Thus, while today's design tools help developers and engineers perform their design tasks, they do not adequately address the issue of managing the design process as a whole.
Groupware presents an alternative solution for helping designers manage shared data relating to a design problem. Groupware products facilitate the sharing of information in the form of documents among members of an organization. They enable users of computers in a network to edit and view information stored in shared documents.
Though effective at maintaining shared information, current groupware tools do not guide designers through related process steps. Groupware does not allow a designer to define a model for an arbitrary process. More specifically, groupware does not allow a user to describe steps in the process and the dependencies among these steps. In a typical design process, there are a number of steps which must be performed in a particular order. As designers perform these steps, they create or transform design data. Groupware cannot effectively model a design process because it cannot model the dependency among steps, and it cannot manage the creation and transformation of data from process steps.
Apart from groupware, a number of computerbased tools in the EDA marketplace purportedly address the concept of a design process. These design tools fall into one of the following categories: (1) Tool Launchers; (2) Tool Sequencers; and (3) Flow Sequencers.
Tool launchers are understood to provide nothing more than a centralized location for invoking other computer-based design programs.
Slightly more effective than tool launchers, tool sequencers control the order in which a user can invoke a design tool. Tool sequencers, however, are typically only single user tools, designed mainly to guide novice users through a tool set.
Flow sequencers provide a very basic capability to define a dependency between steps in a process. This capability is rather limited, however. Typically, a parent step must complete before a child step can start.
Existing computer-based tools that fall in the above categories suffer from a number of additional drawbacks making them unsuitable for managing complex design processes. Many of these tools are single user tools, which limits their utility in the typical design team environment. These tools fail to allow users to define and modify arbitrary and sufficiently robust models or "templates" of design processes. As such, they provide no means for managing the dependency relationship among steps, or the underlying design data created or transformed during a design step. Finally, existing tools or design tool frameworks known to the inventor are not based on an open architecture, but rather, rely on certain proprietary features of their environment. Therefore, they are incompatible with a number of other computer based tools.
In light of the various deficiencies of existing design tools, there is substantial need for an improved computer-based tool for defining and managing complex processes.


The present invention relates to compositions for fortifying food and/or beverages with iron. More specifically, the present invention relates to compositions comprising Fe(III), phytic acid, a hydrolysed protein and an acidity regulator, which provide stable and soluble sources of iron for fortifying food and/or beverages.

Nutritional mineral deficiencies (also referred to as micronutrient malnutrition) affect a large proportion of the human population and are particularly widespread in developing countries. Deficiency in iron is especially common, affecting more than two billion people world-wide, and is the only nutrient deficiency that is significantly prevalent in industrialised countries. Iron deficiency is associated with a range of health problems, including impairment of work performance, increased maternal and child mortality, and poor cognitive development in children.
Iron deficiencies originate when physiological requirements are not met by mineral absorption from the diet, for example due to low iron bioavailability. Dietary iron bioavailability may be low, for example, in populations having monotonous plant-based diets with little meat. Indeed, a major cause of low iron bioavailability is related to the presence of anti-nutritional factors that are naturally present in cereals and legumes. These factors form insoluble complexes with iron and interfere with its absorption.
Fortifying food with iron is a well-known approach to increase dietary iron intake, but can pose a number of difficulties. A significant problem is caused by the general incompatibility between bioavailability and stability of iron compounds. Typically, the most bioavailable iron compounds (e.g., ferrous sulphate) are the most reactive within the food matrix. As such, fortifying foods with iron can lead to a number of undesirable changes in properties of the food, in particular organoleptic properties of the food. For example, iron can accelerate oxidation reactions, adversely altering a food's flavour, and iron can also form complexes with phenolic chromophore compounds, leading to unwanted colour changes in the food.
For example, ferrous (i.e. Fe(II)) sulphate, which is a reference iron compound for food fortification in humans in terms of high absorption, causes sensory changes in the food vehicle in the presence of polyphenols or high amounts of unsaturated lipids. In contrast, more stable iron sources, which are typically water-insoluble (e.g. ferric (i.e. Fe(III)) pyrophosphate), have relatively low bioavailability compared to water-soluble compounds.
A number of approaches have been taken during attempts to improve iron fortification of foods. Encapsulated ferrous sulphate has been considered, because it could provide a bioavailable iron source while maintaining stability through encapsulation of the formulation. However, bioavailability is highly dependent on the coating used and in many cases bioavailability of the coated iron source is reduced. Encapsulation also increases production costs. Moreover, most coatings used for encapsulation, which are often lipid based, give rise to problems associated with melting during the different heat treatment stages of the manufacture of many food products.
Alternative approaches have used iron-containing nanoparticles that have been stabilised with biopolymers (EP 1743530), or ferric sodium EDTA (ethylenediaminetetraacetic acid), which has good bioavailability and stability (US 2005/0053696), for iron fortification. However, the use of nanoparticles and EDTA in food products is meeting with increased consumer resistance. Furthermore, sodium iron EDTA is expensive and not stable in all food matrices (e.g. chicken bouillon).
Accordingly, there remains a significant need for compositions and methods that enable fortification of foods and beverages with iron. In particular, there remains a need for compositions and methods that provide a soluble, preferably bioavailable source of iron that has minimal effect on the organoleptic properties of foods.
Any reference to prior art documents in this specification is not to be considered an admission that such prior art is widely known or forms part of the common general knowledge in the field. As used in this specification, the words "comprises", "comprising", and similar words, are not to be interpreted in an exclusive or exhaustive sense. In other words, they are intended to mean "including, but not limited to".


A method and circuit for eliminating input voltage offset in an amplifier circuit are provided. An exemplary offset correction circuit is configured with DC restoration to eliminate the DC input voltage offset by suitably providing a correction voltage to correct an input voltage offset during operation of the amplifier circuit, without realizing recovery time problems associated with AC coupling. An exemplary offset correction circuit is configured with DC restoration and comprises a timing circuit, a sample and hold circuit, and a feedback circuit to provide a correction voltage signal to correct input voltage offset. The timing circuit is configured to determine a “dead time” and “live time” for operation of the amplifier circuit. During the “dead time” period the sample and hold circuit will sample a differential signal across the DC coupling and provide a feedback signal through feedback circuit to correct input offset voltage. During the “live time” operation of the amplifier circuit, the sample and hold circuit operates to hold the level of correction voltage provided by the feedback circuit to suitably maintain a low input voltage offset.

Amplifiers are commonly used to provide gain to an input signal. For example, if a voltage amplifier has a voltage gain of 10, then an input signal of 50 millivolts ("mV") applied to the voltage amplifier results in an output signal of 500 mV. An amplifier typically has a range in which the amplifier operates in a linear manner. For example, a voltage amplifier connected to a 5-volt power supply may be linear for outputs up to 4.5 volts. However, driving output voltages greater than 4.5 volts may force the amplifier into non-linearity, resulting in overload of the amplifier and thus potential inaccuracy. In addition to linearity and noise concerns that can affect accuracy, many amplifier circuits can also be susceptible to input offset. For example, even an input offset of a few millivolts can greatly affect the accuracy of the amplifier circuit.
Many amplifier circuits, such as instrumentation amplifiers, generate a current signal between two amplifier devices through a direct connected resistor. For a direct connection of the resistor between the amplifier devices using DC coupling techniques, such amplifier circuits can generally operate without difficulty so long as the gain of the amplifier circuit is low. However, if the gain in the amplifier circuit is high, then large offset can occur to decrease accuracy of the amplifier circuit.
To address large voltage offset, AC coupling is often implemented, such as through capacitive coupling with the addition of a capacitor configured between the amplifier devices. In many instances, the capacitor is provided external to the integrated circuit chip containing the amplifier circuits, particularly if the capacitor exceeds 200 pF in value. As a result of an additional bond pad that is utilized and the accumulated stray capacitance, mainly due to the need to configure the bond pad to allow for the connection of the external capacitor, the capacitive loading of the external wiring connections becomes unequal. When the capacitive loading becomes unequal, the ability to achieve low, even harmonic distortion and/or operate within the linear region becomes extremely difficult to obtain.
Unfortunately, even in an instance when the amplifier circuit utilizing AC coupling is able to operate within the linear region, the AC coupling can still cause difficulty in the recovery time of the amplifier circuit, such as difficulty in the identification of a closely-coupled in time small signal following a large pulse signal. Moreover, in high-gain, if the voltage offset is too high, the voltage offset may be amplified to such unacceptably large values that AC coupling techniques cannot restore the amplifier to proper function. Thus DC coupling techniques may be more desirable in many instances due to the close signal interaction and improved recovery time. Unfortunately, conventional DC coupling techniques are limited in their ability to eliminate input offset voltage.

Method and circuit for input offset correction in an amplifier circuit


A plurality of calibration structures facilitate calibration of a probing system that includes a differential signal probe having a linear array of probe tips.

The present invention relates to integrated circuits and, more particularly, to structures for calibrating probing systems that utilize differential signals to inspect integrated circuits and other microelectronic devices.
Integrated circuits (ICs) are economically attractive because large numbers of often complex circuits, for example microprocessors, can be inexpensively fabricated on the surface of a wafer or substrate. Following fabrication, individual dies, including one or more circuits, are separated or singulated and encased in a package that provides for electrical connections between the exterior of the package and the circuit on the enclosed die. The separation and packaging of a die comprises a significant portion of the cost of manufacturing the integrated circuit device and to monitor and control the IC fabrication process and avoid the cost of packaging defective dies, manufacturers commonly add electrical circuits or test structures to the wafer to enable "probing", on-wafer testing to verify the characteristics of the integrated circuits, before the dies are singulated.
A test structure typically includes a device-under-test (DUT), a plurality of metallic bond or probe pads that are deposited at the wafer's surface and a plurality of conductive vias that connect the probe pads to the DUT which is typically fabricated beneath the surface of the wafer. The DUT typically comprises a simple circuit that includes a copy of one or more of the basic elements of the marketable integrated circuits fabricated on the wafer, such as a single line of conducting material, a chain of vias or a single transistor. The circuit elements of the DUT are typically produced with the same process and in the same layers of the die as the corresponding elements of the integrated circuit. The ICs are typically characterized "on-wafer" by applying a test instrument generated signal to the test structure and measuring the response of the test structure to the signal. Since the circuit elements of the DUT are fabricated with the same process as the corresponding elements of the integrated circuit, the electrical properties of the DUT are expected to be representative of the electrical properties of the corresponding components of the integrated circuits.
At higher frequencies, on-wafer characterization is commonly performed with a network analyzer. The network analyzer comprises a source of an AC signal, commonly, a radio frequency (RF) signal, that is used to stimulate the DUT of a test structure. A forward-reverse switch directs the stimulating signals to one or more of the probe pads of the test structure. Directional couplers or bridges pick off the forward or reverse waves traveling to or from the test structure. These signals are down-converted by intermediate frequency (IF) sections of the network analyzer where the signals are filtered, amplified and digitized for further processing and display. The preferred interconnection for communicating the signals between the signal source and the signal sink of the network analyzer and the test structure is coaxial cable. The transition between the coaxial cable and the probe pads of the test structure is preferably provided by a movable probe having one or more conductive probe tips that are arranged to be co-locatable with the probe pads of the test structure. The network analyzer and the test structure can be temporarily interconnected by bringing the probe tips into contact with the probe pads of the test structure.
The probe functions as an adapter enabling the signals to transition between the coaxial cable connecting the probe to the network analyzer and the coplanar waveguides of the probe pads. As a result of the transitions from one form of transmission line to another, the probe will perturb high frequency signals transmitted to and from the network analyzer. Relatively accurate measurements can be made with a network analyzer and probe system if the system is calibrated to remove the signal perturbations caused by the interconnection of the network analyzer and the test structure and, in some cases, perturbations caused by components of the test structure. Probing systems are typically calibrated by interconnecting the network analyzer and a calibration structure and stimulating the calibration structure with a test signal. Calibration structures typically comprise one or more conductive contact areas or probe pad regions arranged to spatially conform to the probe tips of the probe(s) to be calibrated. The probe pad regions are interconnected, in various combinations, by a conductive or non-conductive calibration element. Deviations from the ideal response to the stimulating signal are stored in the network analyzer. In a process known as "de-embedding," the data is used to mathematically compensate for the effect of the probe, or, in some cases, elements of the test structure, when probing a test structure on a wafer.
Most test instrumentation utilizes ground referenced or single ended signals for stimulating the test structure and measuring the response to the stimulation. At higher frequencies noise and interference induced by adjacent circuitry and uncertainty concerning the ground potential often make the integrity of single ended signals inadequate. For example, integrated circuits typically have a ground plane at the lower surface of the substrate on which the active and passive devices of the circuit are fabricated. The terminals of transistors fabricated on a semi-conductive substrate are typically capacitively interconnected, through the substrate, to the ground plane. The impedance of this parasitic interconnection is frequency dependent and at higher frequencies the ground potential and the true nature of single ended signals becomes uncertain.
Differential signals, on the other hand, are transmitted on two conductors which carry inverted copies of the signal waveform and the value of the signal is the difference between the waveforms on the respective conductors. Noise typically effects both conductors equally and this common mode noise or signal is cancelled when the value of the signal is determined from the difference between the waveforms. In addition, the two waveforms are mutual references enabling greater certainty in determining the transition from one value to the other in binary devices and enabling a faster transition between binary values with a reduced voltage swing for the signal. Differential signaling enables a reduction in signal power, an increase in data rate and greater immunity from noise from sources such as power supplies, adjacent circuitry and external sources.
Test structures comprising differential gain cells require five connections to the test instrumentation. The two components of the differential input signal or a common mode signal is transmitted by the network analyzer to two of the probe pads of the test structure and the two components of the differential output signal are transmitted from two other probe pads of the test structure to the network analyzer. At least one additional probe pad of the test structure enables biasing of the transistors of the differential gain cell. Test structures for differential signal probing are, typically, interconnected to the network analyzer with two probes and, correspondingly, calibration structures for differential signal probes provide for simultaneous contact by the tips of two probes. However, a test structure and probe comprising a linear array of probe pads and probe tips permits a differential test structure to be fabricated in a saw street between dies increasing the surface area of the substrate available for the fabrication of marketable ICs.
What is desired are calibration structures for calibrating a differential signal probe having a linear array of contact tips.

Calibration structures for differential signal probing


A photoelectric conversion device including a substrate having opaque interconnection layers, an insulating film formed on the substrate, and having a plurality of openings, light-emitting elements formed of the openings, each light-emitting element having an upper electrode layer, and light-receiving elements formed of the openings, each light-receiving element having an upper electrode layer, wherein a semiconductor material is different in the light-emitting element and the light-receiving element, the upper electrode layer both of the light-emitting element and the light-receiving element are formed as common electrodes, and each interconnection layer is formed on a region outside a region specified by the opening.

In recent years, a light source-sensor integrated type photoelectric conversion device used in a sensor which irradiates a living body with light, and detects its response, a sensor which optically detects a surface state of a display device, and the like has been proposed.
For example, a light source integrated type solid-state imaging device has been proposed as a document reading device of a copying machine. In this solid-state imaging device, a thin-film light-emitting element and a solid-state imaging element (light-receiving element) are independently formed on non-overlapping regions on a substrate. An object is irradiated with light from the light-emitting element, which is extracted on the side opposite to the substrate, and reflected light from the object is detected by the light-receiving element. Since the light-emitting element and light-receiving elements are formed on a single substrate, a state of the object can be accurately detected.
However, in the device of this type, since the light-emitting element and light-receiving element are independently formed on the substrate, their structures are restricted, and much labors are required to manufacture the device. For example, when the light-emitting element is formed after the light-receiving element is formed, an upper layer of the already formed light-receiving element may be damaged upon formation of the light-emitting element, resulting in deterioration of element characteristics. Especially, this problem is conspicuous when organic semiconductor materials are used. Furthermore, when the light-emitting element and light-receiving element are formed on the single substrate, some light rays from the light-emitting element are reflected by respective layers in the device, and enter the light-receiving element, thus causing an increase in detection noise.
As a near-infrared spectroscopy which irradiates a living body with near-infrared light and detects its response to obtain information in the living body, for example, a pulse oximeter has been put into practical use. However, near-infrared light in the living body is easier to be transmitted than visible light, but it is largely scattered. Hence, an amount of reflected light is several percentages or less with respect to incident light. Therefore, detection at a high sensitivity is required. However, in a PIN photodiode of microcrystalline Si, which is popular as a light-receiving element, it is insufficient to obtain a light-receiving element which has a high sensitivity to near-infrared light in terms of a band gap.

Light-source sensor integrated photoelectric conversion device


A data distributor in a computational unit of an integrated circuit is enclosed. The data distributor receives data from a network and distributes the data to a plurality of components within the computational unit. The data distributor includes an input mechanism for receiving the data from the network, and distributes the data to a selected component of the plurality of components, a control mechanism responsive to a control signal for distributing the data to the selected component using a data distribution selected between a look-up table-based memory write and a point-to-point distribution with acknowledgement. The plurality of components comprises a Peek/Poke Module, an Execution Unit, a DMA Engine, and a Hardware Task Manager Message Generator. The selected data distribution type may comprise using an output port number or a direct-memory address transfer or an interrupt to distribute the data.

This invention relates in general to digital data processing and more specifically to a uniform interface for transferring digital information to and from a computational unit in an adaptive computing engine (ACE) architecture.
A common limitation to processing performance in a digital system is the efficiency and speed of transferring data and other information among different components and subsystems within the digital system. For example, the bus speed in a general-purpose Von Neumann architecture dictates how fast data can be transferred between the processor and memory and, as a result, places a limit on the computing performance (e.g., million instructions per second (MIPS), floating-point operations per second (FLOPS), etc.).
Other types of computer architecture design, such as multi-processor or parallel processor designs require complex communication, or interconnection, capabilities so that each of the different processors can communicate with other processors, with multiple memory devices, input/output (I/O) ports, etc. With today's complex processor system designs, the importance of an efficient and fast interconnection facility rises dramatically. However, such facilities are difficult to design to optimize goals of speed, flexibility and simplicity of design. Also, a uniform interconnection, or interface, is desirable to reduce the overall complexity of a system, improve programmability and to reduce design and manufacturing costs.

Data distributor in a computation unit forwarding network data to select components in respective communication method type


A small, light and portable sensor for detecting and quantifying a harmful high molecular weight substance present in a sample gas in trace amounts is herein disclosed. In the sensor, light and heavy ions are formed by ionizing molecules of the sample gas components in an ionization region. The heavy ions are formed through an ion-molecule reaction. The passage of ions through an ion-passage control region is controlled by directly or indirectly controlling the electric field established between a central electrode and a counter electrode The ions which pass through the control region are collected on a collector electrode. The high molecular weight substance is detected and quantified on the basis of the output from the collector electrode.

1. Field of the Invention
The present invention relates to a sensor for detecting a high molecular weight substance present in a low molecular weight gas such as air, and more particularly to a sensor which can be used in environmental and medical measurements or semiconductor manufacturing processes for monitoring a trace amount of a harmful high molecular weight substance present in air or other low molecular weight gas, the sensor being highly sensitive, compact and lightweight and being convenient for portable use.
2. Description of the Prior Art
An example of an apparatuses used for detecting high molecular weight substances present in the air is disclosed in U.S. Pat. No. 4,769,540. The apparatus disclosed in this patent is based on the atmospheric ionization mass spectrometric method. This method comprises the steps of ionizing molecules of the air to yield light ions, ionizing a polymeric substance present in the air through an ion-molecule reaction between the light ions and the high molecular weight substance to thus yield heavy ions, and then guiding these light ions and heavy ions to a mass spectrometer to quantitatively analyze the heavy ions. In this first conventional apparatus, however, the path through which these ions are transported must be maintained at a high vacuum in order to separate the ions from each other and obtain correct mass spectra. Since a high vacuum pump is needed, such an apparatus cannot be installed at any desired place, and furthermore carrying the apparatus and using it for onsite measurements is cumbersome.
Another known method comprises the steps of forming light and heavy ions as in the foregoing conventional apparatus, extracting ions by applying a pulse voltage to a grid disposed perpendicularly to the direction of flow of the air containing these ions, and separating and determining the heavy ions according to the atmospheric ionization flight time measuring method. This method makes use of the difference in time for the light and heavy ions to arrive at the grid after the application of the pulse voltage, since the flight velocity of the light ions differs from the that of the heavy ions. In this method, however, the effective flight time separation of masses is ensured only when the ionization chamber is as small as possible so as to restrict, to a narrow region, the flight-initiation position of the ions attracted to the grid through the application of the pulse voltage. For this reason, it is necessary to use only radiation emitted toward a specific direction obtained through the collimation of the radiation emitted from a source such as .sup.63 Ni, which emits radiation having a short trajectory. This greatly restricts the resulting ionization efficiency. In addition, the effective time which is available for the measurement is greatly limited by the time interval of the pulse-voltage application. Furthermore the use of a source (e.g., .sup.63 Ni, 50 mCi) which emits very strong radiation would be severely restricted by regulations on the handling of radioactive substances.
GB 2,228,139A discloses an improved ion-mobility-detector based on the atmospheric ionization flight time measuring method. This detector comprises an ion source disposed at a position branching off from a ion reaction region, at least two drift regions which communicate with the ion reaction region, an electrical ion injection shutter disposed between the ion reaction region and each drift region, and an ion detector positioned at the end of each drift region far apart from the ion reaction region. In each drift region, a potential gradient is established so as to define the drift direction of the ions. The detection of ions in a sample gas is performed on the basis of the lapse of time from the opening of the ion injection shutters till the ions are detected by the ion detectors, or on the basis potential applied to the ion source and the timing of an opening pulse applied to the ion injection shutters is adjustable. This apparatus makes it possible to perform separation and detection or quantitative analysis for every drift mobility or for approximately every ionic species, but to this end, it is necessary to adjust the timing of the application of a potential to the ion source and the timing of the application of an opening pulse to the ion injection shutters for every ionic species, and a high speed-high resolution pulse measuring circuit must be used.
Further, U.S. Pat. Nos. 3,835,328 and 4,238,678 disclose other apparatuses for detecting trace amounts of impurity gas components in gaseous samples operated at atmospheric pressure.
The apparatus disclosed in U.S. Pat. No. 3,835,328 is mainly provided with a recombination region positioned downstream from an ionization region which is equipped with a radiation source. This recombination region comprises electrically insulating washers fitted into a shaft at proper intervals, each having a hole of a different diameter to form a tortuous path through which the impurity gas ions can pass. The impurity ions pass through the tortuous path while the recombination of the ionic main components of the sample gas is promoted during transfer therethrough. The ions are detected by a screen of an electrically conducing material in a collection region positioned downstream from the recombination region. The shaft is electrically connected to the conductive screen through a DC voltage source and an ammeter arranged in series, and a DC voltage is applied between the shaft and the screen to permit an electric current which corresponds to the concentration of the impurity to be read out.
The detecting apparatus disclosed in U.S. Pat. No. 4,238,678 comprises a first drift region which is defined by a grid and a shutter and which is positioned downstream from an ionization region, and a second drift region which is defined by the shutter and a collector electrode and which is positioned downstream from the shutter. The grid comprises a plurality of conducting materials arranged parallel to one another and is positioned perpendicularly to the flow direction of a sample gas stream. An electric voltage is alternatively applied to the plurality of conducting materials so that each pair of neighboring conducting materials have different potentials at each instance. Thus, the grid serves to collect light ions having a high drift mobility among the ions present and to conduct heavy ions having a low drift mobility to the first drift region. Moreover, the shutter has the same structure and arrangement as the grid and serves to guide specific ions or discrete packets of ions among the low mobility ions which drift through the first drift region to the second drift region. A conductive ring is arranged around the periphery of the first and second drift regions, through which an electric field is established. The field has a desired potential gradient which is parallel to the direction of the sample gas stream containing ions. The drift velocities of ions in the first and second drift regions depend on the foregoing electric field and the ions which drift through the second drift region are collected and detected by a collector electrode positioned at the downstream end of the second drift region.
U.S. Pat. No. 4,119,851 discloses an apparatus for detecting impurities in a gaseous sample which comprises a recombination tube as disclosed in U.S. Pat. No. 3,835,328 and a drift tube as disclosed in U.S. Pat. No. 4,238,678 which are connected in series.
The recombination tube disclosed in U.S. Pat. No. 3,835,328 allows the recombination of main ionic components of a sample gas as soon as possible to remove the same and thus serves to guide only the impurity ions to a detector, while the drift tube disclosed in U.S. Pat. No. 4,238,678 serves to separate and detect impurity ions for all drift mobilities, approximately corresponding to their molecular weights, or for every species of the impurities.
As has been discussed above in detail, all of the conventional apparatuses for detecting impurities in a gas sample are designed in such a manner that only impurity ions are guided to detectors such as collector electrodes. In these apparatuses, it is sufficient that only a part of the impurity ions are involved in the detection, but the ions of the main components of the gas obstruct the detection of the impurity ions.
Furthermore, the grid and shutter disclosed in U.S. Pat. No. 4,238,678 are both realized by arranging a plurality of conductive materials perpendicularly to the flow direction of a sample gas containing ions so that there does not occur any warping in the distance between neighboring pairs of conductive materials and so that a desired electric field can thus be established therebetween. This makes the production of these apparatuses very difficult.

Sensor for detecting a high molecular weight substance using ionization effects


A memory card connector includes an insulating housing having a base board defining longer cavities thereon. Each longer cavity has a guiding cavity having two first mounting grooves. The guiding cavity extends rearward to form a connecting cavity being wider than the guiding cavity. The bottom of the connecting cavity extends rearward at one side to form a first receiving cavity, and the other side of the connecting cavity extends rearward to form a second receiving cavity. Longer terminals received in the longer cavities have a base portion having two restraining portions protruding from two sides of the base portion. The rear end of the base portion stretches rearward to form a connecting portion wider than the base portion. One side of the connecting portion extends rearward to form a fixed portion, and the other side extends rearward to form a contacting portion spaced away from the fixed portion.

1. Field of the Invention
This invention generally relates to a memory card connector, and more particularly to a memory card connector having improved electric terminals.
2. The Related Art
Recently, more and more compact and multi-functional electronic apparatuses such as digital cameras, mobile phones or the like have been displayed on the market. In order to add a variety of sub-functions, an integrated circuit card is inserted in the electronic apparatus with a built-in CPU or a memory card such as a SIM card, a MMC card, a SD card and so on. Many different kinds of memory card connectors are provided for connecting such cards to the electronic apparatuses.
Conventionally, a memory card connector includes a plurality of commonplace terminals which are located inside terminal slots of the memory card connector respectively for electrically connecting a memory card to an electronic apparatus. The terminal is a slender metallic sheet, and the side of the terminal is mounted in a groove defined in the side of the terminal slot for being located in the memory card connector. However, it can be seen that the commonplace terminals are fabricated in the terminal slots not steadily enough. Therefore, the stability of the connection between the terminals and the memory card is not fine.


A system and method for securing input signals when using input interfaces such as touch-screens and other input interfaces that are suitable for handheld, mobile, computing and other devices, by generating fake signals. In accordance with an embodiment, the technique can be used to protect input signals from, e.g. a touch-screen keyboard, and make it more difficult for malicious software applications to intercept and understand such input signals. The technique can also be implemented without requiring significant changes to the underlying operating system (OS) or graphical user interface (GUI). In accordance with an embodiment, a security enhancer or security enhancing application injects fake signals into the OS/GUI input signals queue. The security enhancer or security enhancing application is also associated with a communication channel that allows it to establish a cryptographic signature or key with authorized or sensitive application receivers that are authorized to receive the input signals. The fake signals can later be removed from the input signal stream only by the authorized receivers of the input signals. Unauthorized application listeners may be able to intercept a signal, but are unable to determine the original input.

Nowadays, many handheld, mobile, computing and other devices, for example smartphones, personal digital assistants (PDA) and handheld computers, use an input interface such as a touch-screen as the default input and output method for human/user interaction. This allows for efficient use of the physical real estate of the device, since the same physical area (e.g. the display screen) can be used both for input and output depending on the state of the software running on the device.
At the same time, handheld computing devices have become increasingly more powerful, so that they now rival the capabilities of full-fledged personal computers. A consequence of this is that most modern devices no longer use older-style, limited and locked down operating systems (OS), but instead use slightly reduced versions of full-blown operating systems, such as GNU/Linux or Berkeley Software Distribution (BSD) Unix, which are necessary to make full use of the computing power in these devices.
This progress has made it significantly more difficult for software programmers to establish a safe environment for entering secure data into the device, for example user passwords, personal identification numbers (PIN), bank account numbers, and social security numbers. In older-style, limited handheld devices, the more limited hardware and operating system made it possible to control the entire handheld device from a single application, and so an application for communicating with a bank could be reasonably sure that it was running alone on the device, and that no other application could intercept the data traffic. However, this is not the case with modern handheld computing devices, which offer a modern operating system that allows several applications to be running at the same time.
Additionally, the graphical user interface (GUI) is usually provided as a separate library outside of the operating system. This GUI library is typically quite large and complex, and is not always designed to prevent different applications from examining the graphical state of other applications. Even if it was designed to prevent applications from accessing each others graphical state, there can be mistakes in the design or bugs that allow this to happen anyway. Larger, more complex, operating systems also make it easier for potential mistakes in the application programmer interfaces (API) or bugs to slip into the operating system. These mistakes can also make it easier for unauthorized or malicious applications, such as computer viruses, trojan software, and other malware, to monitor the input and output of other, authorized, applications.
Furthermore, since modern handheld computing devices offer the possibility of downloading and installing many different applications onto the device, for example through purchasing additional applications, this makes it easier for malicious intruders to acquire sensitive data or information from the device. The user simply has to be tricked into installing a malicious application. Such an application might otherwise perform a valid service—however, unbeknownst to the user, the malicious application can acquire sensitive data or information from the user, not by hacking the other applications or the OS/GUI, but simply by interacting with the graphical state available to it through the standard OS/GUI API. This form of threat has existed for some time on desktop computers as well; however in those environments the problem can be somewhat mitigated by installed anti-virus software. Handheld computing devices are generally not yet powerful enough to run such anti-virus software regularly.
The problems are compounded in that many handheld computing devices use an input interface such as a touch-screen as the default input and output method. Since the only input that arrives from the touch-screen hardware are display coordinates, the operating system can no longer see the difference between drawing a point in a drawing program and entering a number as part of a PIN—it depends entirely on what image is drawn on the touch-screen. Thus the operating system can no longer assist in protecting input signals from the keyboard, because there is no physical keyboard. This risk could allow intruders to acquire sensitive data or information from users of computing devices with touch-screens by intercepting the signals from the touch-screen, either inside the OS, or by listening to the same signal stream from the GUI. These are the areas that embodiments of the invention are intended to address.

System and method for securing input signals when using touch-screens and other input interfaces


A therapeutically useful compound of formula I ##STR1## or pharmaceutically acceptable salts thereof where A and B are oxygen, sulfur or CH.sub.2, X is an amine moiety as defined herein and R.sub.1 and R.sub.2 are as defined herein having 5HT.sub.1A neuronal activity and/or dopamine receptor activity useful in the treatment of central nervous system and cardiovascular system disorders.

The present invention is related to new heterocyclic compounds containing both an indole and a 1,4-dioxan portion, processes for preparing such compounds, pharmaceutical preparation of such compounds and the use of such compounds in manufacture of a pharmaceutical preparation.
Psychiatric diseases are thought to be due to dysfunctions in monoaminergic neuronal systems, particularly those involving serotonin (5-HT) and dopamine (DA).
Anxiety is associated with increased activity in 5-HT systems. In animals where 5-HT has been depleted, benzodiazepine anxiolytics are not active in anti-anxiety assays that they otherwise are effective in. Seronotin neurons have autoreceptors that, when activated by agonists, depress firing rates of 5-HT cells. These receptors are of the 5-HT1A subtype. Because they depress 5-HT neuronal activity, it can be expected that 5-HT1A agonists will be anxiolytic.
Depression is a psychiatric condition thought to be associated with decreased 5-HT release. Most anti-depressants potentiate the effects of 5-HT by blocking the termination of activity through reuptake into nerve terminals. Since some 5-HT1A receptors are activated postsynaptically by 5-HT, 5HT1A agonists may also be anti-depressants. Since the postsynaptic 5-HT1A receptor may be less sensitive than the autoreceptor, high doses of 5-HT1A agonists, particularly very effective ones (i.e., those causing greater stimulation of the 5-HT1A receptor, a parameter referred to as "efficacy"), can be expected to be effective anti-depressants.
5-HT1A agonists are known to depress sympathetic nerve discharge and thus lower blood pressure. Thus, they may be useful in treating hypertension, congestive heart failure (by reducing cardiovascular afterload) and heart attack (be removing sympathetic drive to the heart). 5-HT1A agonists may also be useful in treating overeating and sexual dysfunction. These compounds have been shown to alter feeding and sexual behavior in animals.
Schizophrenia is thought to be due to hyperactivity in DA systems. Thus, currently available anti-psychotics are DA antagonists. Dopamine autoreceptors depress DA neuron firing rates, DA synthesis and release. Thus DA autoreceptor agonists can also be expected to be anti-psychotics. DA agonists are also useful for treating Parkinsonism, a disease caused by degeneration of DA neurons, and hyperprolactinemia, since DA agonists depress prolactin release.
Dopamine autoreceptor antagonists are a new class of drug that increase release of DA by releasing the DA neuron from autoreceptor control. Thus, these drugs can be expected to be useful in conditions treatable with amphetamine and other similar stimulants which directly release DA. However, DA autoreceptor agonists will be much milder stimulants because, rather than directly releasing DA, they simply increase the release associated with the normal DA activity by releasing the cell from autoreceptor control. Thus, DA autoreceptor antagonists can be expected to be useful in treating overeating, attention deficit disorders, psychiatric, cognitive and motor retardation in demented and elderly patients, and in treating nausea and dizziness with space travel.
The compounds of the present invention have a variety of effects at 5-HT1A and DA receptors, and offer a variety of utilities associated with those activities.
Clinically, 5-HT1A agonists have also demonstrated anxiolytic properties. These compounds antagonize dopamine receptors at the same dose they stimulate 5-HT1A receptors.
The search for new CNS active compounds is focused on finding compounds with selective 5-HT1A receptor agonist effects without detrimentally influencing central dopamine receptors.
Drugs acting on central dopamine transmission are clinically effective in treating a variety of central nervous system disorders such as parkinsonism, schizophrenia, and mano-depressive illness. In parkinsonism, for example, the nigro-neostriatal hypofunction can be restored by an increase in postsynaptic dopamine receptor stimulation. In schizophrenia, the condition can be normalized by achieving a decrease in postsynaptic dopamine receptor stimulation. Classical and-psychotic agents directly block the postsynaptic dopamine receptor. The same effect can be achieved by inhibition of intraneuronal presynaptic events essential for the maintenance of adequate neurotransmission, transport mechanism and transmitter synthesis.
In recent years a large body of pharmacological, biochemical and electrophysical evidence has provided considerable support in favor of the existence of a specific population of central autoregulatory dopamine receptors located in the dopaminergic neuron itself These receptors are part of a homeostatic mechanism that modulates nerve impulse flow and transmitter synthesis and regulates the amount of dopamine released from the nerve endings.
Direct dopamine receptor agonists, like apomorphine, are able to activate the dopamine autoreceptors as well as the post synaptic dopamine receptors. The effects of autoreceptor stimulation appear to predominate when apomorphine is administered at low doses, whereas at higher doses the attenuation of dopamine transmission is outweighed by the enhancement of postsynaptic receptor stimulation. The anti-psychotic and anti-dyskinetic effects in man of low doses of apomorphine are likely due to the autoreceptor-stimulator properties of this dopamine receptor agonist. This body of knowledge indicates dopamine receptor stimulants with a high selectivity for central nervous dopamine autoreceptors would be valuable in treating psychiatric disorders.

Therapeutically useful heterocyclic indole compounds


A variety of media devices may stream and present content such as movies, music, audiobooks, and so forth. During streaming, data transfer rates may temporarily drop below that needed to maintain presentation. Described herein are techniques and systems for repeating presentation of previously received video frames. This repeated presentation allows for presentation of the content to continue uninterrupted, while providing time for the data transfer rate to regain a level capable of maintaining the presentation.

A wide variety of content is available for streaming delivery to media devices for presentation. The content may include audio, video, or both. The media devices may include televisions, set-top boxes, tablet computers, personal computers, gaming consoles, in-vehicle entertainment systems, portable media players, and so forth.
Traditionally, drops in data transfer rates result in cessation of content presentation or a transition to presentation of lower quality content, such as encoded at a lower bitrate. This cessation or transition to lower quality content may result in an undesirable user experience.
Certain implementations and embodiments will now be described more fully below with reference to the accompanying figures, in which various aspects are shown. However, various aspects may be implemented in many different forms and should not be construed as limited to the implementations set forth herein. Like numbers refer to like elements throughout.

Video presentation using repeated video frames


A time synchronization apparatus, method and system are provided. In one aspect, the apparatus comprises at least a time of day clock, a first port operable to receive at least first time information using a first time protocol, a second port operable to receive at least second time information using a second time protocol, a third port operable to receive at least a timing signal, and a time stamp register operable to at least capture current value of the time of day clock upon receipt of the timing signal from the third port or the first time information from the first port or combination thereof.

Mainframe server devices such as the zSeries® eServer®, available from assignee International Business Machines, Inc., use protocols for distributing and synchronising time among the client and server computers, for instance, to provide for system integrity in computer systems. In the past, the Time-Of-Day (TOD) clocks in the timing network were synchronized by means of an external box, the 9037 sysplex timer. Each Central Processing Complex (CPC) in the 9037 timing network stepped its TOD clock to the signals from the 9037. Briefly, a CPC refers to a system that may include one or more central processing units (CPUs) and associated hardware units such as main and expanded storage, TOD clocks, and channels that can be configured to operate under the control of an operating system. The stepping signals broadcast by the 9037 required special point-to-point links (called External Time Reference (ETR) links) from the 9037 to each CPC. A representative system implementing ETR offset values for synchronizing logical partitions of a logically partitioned machine is described in commonly-owned U.S. Pat. No. 6,209,106.
The Server Time Protocol (STP), which may replace the ETR as a time protocol in main server devices such as the zSeries®, implements a timing solution that does not include a common stepping signal. Timing information is communicated by means of messages with time stamps and other timing information, and each CPC must keep its TOD clock in step with the rest of the other CPCs by computing offsets and taking action to adjust the TOD clock. This is similar to the action performed by NTP (Network Timing Protocol), the difference being that NTP is normally implemented in a software layer where time stamps can be generated by the control program. The eServer zSeries® architecture has very stringent requirements on the TOD clock; it can be viewed by any problem program, all timestamps must be different, timestamps must never appear to step backwards, and timestamps must appear to be increasing, even when viewed by programs running on different CPUs in the CPC. To make the adjustments to the TOD clock required by the new timing solution, the stepping rate of the TOD clock must be speeded up or slowed down by very fine adjustments, and these adjustments must by observed simultaneously by all CPUs in the CPC.
The ETR architecture provides a means of synchronizing TOD clocks in different CPCs with a centralized time reference, which in turn may be set accurately on the basis of an international time standard. ETR time can be synchronized to international time by connecting an ETR unit (for example, the 9037) to an external time source (ETS). The Server Time Protocol (STP), however, has no easy way to obtain the same level of accuracy with respect to an international time standard that is achieved by the ETR. On the 9037-1, for example, the ETS was connected to the 9037 console by means of an RS-232 interface and the 9037 console was connected to the 9037-1 by means of a General Purpose Interface Bus (GPIB). This achieved an accuracy of about 5 milliseconds and was not considered acceptable to many customers. On the 9037-2 the ETS was connected directly to the 9037-2 by means of an RS-232 interface and an accuracy of about 1 millisecond was achieved. With the 9037-2, a pulse-per-second (PPS) coaxial connector was also added. When the PPS connection is used in conjunction with the RS-232, the 9037-2 can be synchronized to within about 100 microseconds of the PPS signal.
FIG. 1 shows a known high-availability ETR network with ETS and PPS. To provide for high availability, most ETR timing networks are designed to have no single point of failure. FIG. 1 shows two ETR units 102, 104 each connected to several servers 106, 108, each called a Central Processing Complex (CPC). The output from each ETR 102, 104 referred to as ETR signal is connected to an ETR attachment facility (EAF) port 110, 112, 114, 116 on each CPC 106, 108. To avoid any single point of failure, a high-availability ETR network 100 has two ETRs 102, 104 and each CPC has connections to both ETRs. Some ETR networks do not have all this redundancy. All CPCs, however, have two ETR ports, whether or not they are in a high availability network.
The external time source (ETS) unit 118, 120 obtains coordinated universal time (UTC) by means of dial-out, GPS, or other mechanism. The ETS unit 118 is connected to an ETR unit 102, for example, IBM 9037, by means of two connections RS-232 122, and optional pulse-per-second (PPS) 124. Similarly, the ETS unit 120 is connected to an ETR unit 104 by means of two connections RS-232 126, and optional pulse-per-second (PPS) 128. The RS-232 connection 122, 126 is used to communicate the time information and a special optional pulse-per-second connector 124, 128 is used to get a highly accurate timing pulse. Without the PPS signal, the accuracy is approximately +/−1.0 milliseconds. With the PPS signal, the accuracy is +/−100 microseconds. The ETR units 102, 104 communicate the timing information to each CPC 106, 108 by means of a special ETR interface referred to as the ETR signal. The accuracy of this interface is +/−2.0 microseconds.
FIG. 2 is a block diagram showing details of a known central processing complex (CPC). A CPC 200, for example, includes shared main storage 202, several CPUs 204, a Time of Day (TOD) clock 206, and an ETR attachment facility (EAF) with two ports 208, 210. The TOD clock 206 in each CPC is set to and synchronized to the ETR. The TOD clock may be stepped to either of the two ETRs, or from the local oscillator. The former case is called ETR stepping mode, the latter, local stepping mode.
FIG. 3 is a block diagram showing an ETR attachment facility (EAF) without PPS. It illustrates the EAF in detail for one EAF port. The TOD clock 302 is incremented by the TOD-clock-stepping signal. In the local stepping mode, this signal comes from a local oscillator 304. In the ETR stepping mode, the signal is derived from the ETR signal 306. The ETR signal 306 drives a phase-locked loop (PLL) 308, and a biphase converter 310 converts the ETR signal into a bit stream. At a module shown at 312, the bit stream is deserialized, symbols are recognized, and data is decoded to obtain the four different ETR data words 314 (DW1-DW4). One of the symbols decoded is the on-time-symbol. Recognition of the on-time symbol causes an on-time event (OTE). The OTE causes the contents of the first-level data register 314 to be gated into the second-level data register 316 and also causes the current contents of the TOD clock 302 to be gated into the time stamp register 318.
As described above, time information is communicated from the ETS by means of the RS-232 interface. In the 9037-1, the timing information is sent from the ETS to the 9037 console. In the 9037-2, the timing information is sent from the ETS directly to the 9037-2. With STP, the role of the 9037 console is performed by the Hardware Maintenance Console (HMC). There is no place to connect an RS-232 interface directly to the central processing complex (CPC), so the RS-232 connections must be made to the HMC in the same manner as with the 9037-1. The only interface available from the HMC to the CPC is the service interface. The service interface is designed to be flexible but not fast. It is used for all communication between human operators and the system and is also used by maintenance personnel to install changes to the Licensed Internal Code. This interface has a very high latency and variance. It is estimated, for example, that for HMC-initiated dial-out, an accuracy of about 100 milliseconds is the best that can be obtained, making the accuracy much worse than even the 9037-1.
An alternative solution is to replace the ETR Attachment Facility (EAF) in the CPC with a new interface card that would include RS-232 and PPS interfaces for input and a new protocol to the CPU to access this information. This solution would involve a substantial effort to define and implement such a new interface. Another option that may be considered is to provide a new stand-alone unit that would include RS-232 and PPS interfaces for input and the current ETR signals as output. This approach would require no change to the CPC as the current EAF would remain unchanged. However, design, implementation and manufacturing of such a unit would take a significant effort. Further, the price of a stand-alone unit would represent a significant increase in cost to a customer. Yet another choice is to use a standard input/output (I/O) communication path directly from the CPC to access timing information via Network Time Protocol (NTP) or other timing mechanisms. Like the other options, however, this would also require a significant design effort as there are no I/O paths available to the native machine.
It would thus be desirable to provide a system and method for achieving time of day accuracy in STP preferably without substantial design and implementation efforts.

This patent is subject to a terminal disclaimer.

International Business Machines Corporation