For the transmission of variable length coded data blocks, a threshold arithmetic calculation circuit (9) obtains a threshold from an average of the bit lengths of the variable length coded data blocks for each group of such block, and the judgment circuit (10) makes a judgment as to whether or not those variable length coded data blocks have bit lengths exceeding the threshold of the block group to which such data blocks belong. Then, a block divider circuit 11 divides the variable length coded data blocks having bit lengths exceeding the threshold into blocks having small bit lengths. Each block thus obtained is fixedly equalized in bit length to an average length level and transmitted in that condition.

This invention relates to a variable length coded data transmission device for pseudo-fixing various bit lengths of data blocks, which are obtained by variable length coding, to a constant length level and transmitting the data blocks in that condition.
The variable length coding is a coding method, in which codes having different bit lengths are assigned respectively to various data in accordance with frequency of appearance of each data item, in order to reduce the quantity of code. Therefore, although the end locations of the codes, which codes were subjected to variable length coding processing, are different from each other, it will still be possible that the individual codes are correctly decoded and the ends of the individual codes are correctly recognized only if the bit string is correctly read because the decoding is made at the time point when the bits are read on equivalent to the length of the specific code.
If code errors should occur during the transmission of the variable length coded data, the coded data would be decoded incorrectly as if they had a different code length. As a consequence, an out-of-synchronization occurs and therefore, decoding is carried out in a wrong manner for a long period of time even after the recovery of code errors. This, in fact, significantly deteriorates the quality of decoded signals. As one method for prevent possible adverse effects from such out-of-synchronization attributable to code errors, there is known a method as discussed in a printed material written by David Redmil under the heading of "Robust Architectures for Image and Video Coding" 2nd International Workshop on Mobile Multimedia Communications (MoMuC), April 1995, in which bit lengths of variable length coded data blocks are averaged for each group of data blocks so that the bit length of each data block in any selected group will become equal. The bit length of each block thus averaged is fixed so that each block has a pseudo fixed bit length, and then each data block is transmitted in that condition. In this printed material, the variable length coded data are properly divided into several blocks taking advantage of the nature or characteristic of the variable length codes during the transmission of data such that each divided data item has a predetermined length. Such divided coded-data are used to detect the ends of the codes during the decoding process by judging whether or not the codes can be decoded and then returned to their original variable length codes.
This method will now be described with reference to FIG. 9.
Now, presume that there are a number, N, of variable length coded data blocks and that a bit length of each variable length coded data block i satisfies b.sub.i (0.ltoreq.i.ltoreq.N-1). It should also be noted that any numerical value including i is hereinafter supposed as a mod N.
First, prior to transmission of the number, N, of variable length coded data blocks, an average s.gtoreq.(1/N) sum b.sub.i (where the sum is an operator indicating a sum of i=0 to N-1) is obtained.
Then, a number, N, of slots each having a bit length s is imagined. Various stages of operation to be described hereinafter are made with respect to those slots. On the first stage, as indicated by S1, each bit constituting the variable length coded data block i (0.ltoreq.i.ltoreq.N-1) is filled in each bit location constituting each slot i (0.ltoreq.i.ltoreq.N-1). At that time, with respect to the block i which satisfies bi<s, the slot i has excessive bits (namely, the slot i has extra space to receive additional bits). On the other hand, with respect to the block i which satisfies bi>s, all of the bits cannot be filled into the slot i. If some blocks have too many bits to fill therein, the process proceeds to the second stage. On second stage, with respect to those bits, which could not be filled in the block i, a judgment is made as to whether or not they can be filled in the following slot (namely, adjacent slot) as indicated by S2. If the bit length of the block i+1 to be assigned to the following slot i+1 satisfies b.sub.i+1 <s, the slot i+1 has an empty area behind the bits of the block i+1 and therefore, the excessive bits, which could not be filled in the slot i and overflowed, are filled in this empty area. In case there still remains a block having bits, which could not be filled in the empty area of the slot i+1, the process proceeds to the third stage where the remaining excessive bits are filled in the following slot i+2 of the slot i+1 as indicated by S3. If such a filling operation is repeated by N-times at the most, the bits of the number, N, of the blocks can all be filled in the slots. The resultantly obtained data can be handled as the number, N, of pseudo-fixed length codes (hereinafter referred to as the "fixed length data block") having bit lengths as indicated by S4.
In this way, each variable length coded data block is caused to have a pseudo fixed length, then each coded data block having such a pseudo fixed length is transmitted in that condition and decoded on the receiver side. Here, the fixed length data blocks arriving, one after another, at the receiver side include the variable length coded data blocks. In order to detect the end of a variable length coded data block, it is necessary to finish the decoding of the block. However, as is apparent from the hereinbefore description, a top portion of the variable length coded data block necessarily occupies a top portion of the fixed length data block received. Accordingly, on the receiver side, decoding of the received code is started always at the start timing of the fixed length data block.
When decoding is over with respect to a number, one, of the variable length coded data block, decoding is started with respect to the following variable length coded data block. However, with respect to the variable length coded data block which is astride a plurality of slots and transmitted in that condition, decoding is not finished even after the decoding was made with respect to the bits of the last s-th slot. In the light of this fact, therefore, with respect to such a variable length coded data block which is received in a fashion astride a plurality of slots, a required number of slots (namely, those slots over which the data block is astride) are prepared to receive all bits of the variable length coded data block so that decoding can be performed. That is, for decoding, the procedures at each stage are performed in the following manner. First, suppose the number, N, of slots having a bit length s are present and presume that the received fixed length coded data blocks are filled respectively in these slots. On the first stage, decoding is performed from the top bit location of each slot. At that time, if there is present a slot, whose decoding is not yet finished, in a location somewhere before the s-th bit, the process proceeds to the second stage. On the second stage, the slot i whose decoding is not yet finished is checked as to whether or not decoding was finished in the following slot i+1 and a judgment is made as to whether or not a block i+1 satisfying b.sub.i+1 <s is obtained. If the judgment result is affirmative, the bits of the remaining area in the slot i+1 are added to the slot i and decoding is further performed with respect to the slot i. If the decoding is not yet finished in spite of the addition of the bits in the slot i+1, the process proceeds to the third stage where the bits in the following slot i+2 of the slot i+1 are added. If this bit-adding operation is repeatedly performed by the same number of times as at the time of transmission of data, the original number, N, of variable length code blocks can be obtained.
As discussed hereinbefore, the variable length coded data blocks are formed as pseudo-fixed length codes having s*N bits, and transmitted together with the value of s. With respect to each block to be transmitted at the start timing of the slot, even if transmission errors occurred to the preceding block, no out-of-synchronization, which would otherwise occur due to transmission errors, will occur and decoding is performed at the normal timing. That is, even if errors occur in the midway, a correct synchronization can be obtained for each block at the time for decoding. Thus, an occurrence of decoding errors on a large scale can be prevented.
On the other hand, aside from the method for obtaining a correct synchronization in the manner as just mentioned, an idea of an application of error correction code may come across the mind as one of the methods for effectively preventing deterioration of the quality of decoded signals due to signal errors during the time for transmission of data. As a method for applying an error correction code, aside from the method for applying a constant error correction code to all data, a bit selective error correction is effective in which error correcting ability of the error correction code is partly varied. This method is particularly effective to data which have different sensitivity for code error (error sensitivity) depending on part of the data. This bit selective error correction is known in the name of BS-FEC (Bit Selective Forward Error Correction) or UEP (Unequal Error Protection) (hereinafter simply referred to as "BS-FEC"). The details are described, for example, in a printed material written by H. Suda and T. Miki, "An Error Protected 16 kbit/s Voice Transmission for Land Mobile Radio Channel" IEEE J-SAC, vol. 6, No. 2, pp. 346-352, 1988.
Now, presume that there is found a variable length coded data block j having a remarkably longer bit length than the rest of the variable length coded data blocks when there is employed the method for causing the variable length coded data blocks to have a pseudo-fixed length and transmitting the data blocks in that condition, as previously mentioned. The various bits constituting such a variable length coded data block j are distributed to many other slots than the slot j. Since those bits are filled in the rear empty area of each slot instead of being filled in the leading end area of each slot, they are subjected to adverse effects of the out-of-synchronization caused by code errors occurred in each fixed length data block during the time for transmission of data. As apparent from the discussion made hereinbefore, the above conventional transmission method has such a vital disadvantage in that in case there are some variable length coded data blocks having a remarkably longer bit length than the rest of the blocks, adverse effects to the variable length coded data blocks due to the code errors are even increased.
Also, presume a case where an error correction code is applied when data are to be transmitted in the state that the data has a pseudo-fixed length. In this case, it is not desirable to apply a constant correction code to all data because error sensibility is sometimes different depending on part of the data. In such a case, some data become unduly redundant, thus degrading the transmission efficiency. In case the BS-FEC is applied, it becomes necessary for such data whose code length and code configuration are varied due to variable length coding applied thereto to simultaneously transmit application patterns of the error correction codes as additional data which application patterns correspond to the data and error sensibility of the data. Moreover, if error sensibility is different depending on minor data items, it will be necessary to change the error correction codes more frequently.
As discussed above, the conventional technology is encountered with a problem in that when error correction codes are applied, effective operation is difficult to make in case the error sensibility is different depending on part of the data.

Pseudo fixed data transmission device and method


The invention provides a BIOS management device and a method for managing a BIOS setting value. The invention determines whether to shut down a computer and to restore the BIOS setting value to a default state by detecting whether a restoring event occurs. In addition, the computer is shut down and the BIOS setting value is restored to the default state when the restoring event occurs. Therefore, the fault caused by the improper setting of the BIOS is eliminated.

1. Field of the Invention
The invention relates to a management technology for a basic input output system (BIOS) and, more particularly, to a BIOS management device and method for managing a BIOS setting value.
2. Description of the Related Art
Along with the popularity of the self-assembly computer technology, a user often makes a computer have preferred performance by the overclock technology. The common method is that the operating frequency of the computer is controlled by setting the BIOS of the computer. Generally speaking, the BIOS of the computer can be set only when the computer is in a normal working state. If the BIOS is improperly set, the computer not only can be caused to crash, but also even cannot be booted after the computer is shut down, and therefore, the user cannot restore the BIOS by the common method of setting the BIOS.
The improper setting of the BIOS can cause the crash of the computer, and along with the increase of crash time, interior components of the computer are possible to be further badly damaged. The conventional method is that the user needs to press the power button of the computer for four seconds to shut down the computer. Next, the user needs to open the housing of the computer. Finally, the user makes a jumper electrically connected to a specific pin in the front panel area of the motherboard to clear (or restore) BIOS setting values in the BIOS. The actions are usually called actions of clearing the setting values of a complementary metal oxide semiconductor (COMS) (Clear CMOS). Persons having ordinary skill in the art should know that steps of clearing the BIOS setting values in the BIOS are very complicated, and the jumper is very small and is often lost.

BIOS management device and method for managing BIOS setting value


The present invention provides a shock absorbing structure made of a rubber-like elastic material having a hardness in the range of 5 to 60, according to a JIS-A type hardness meter and being composed of a base and a plurality of ridges or projections spaced apart in parallel on said base. The shock absorbing structure according to the present invention is suitable as a shock absorbing material, especially, for shoes.

1. Field of the Invention
The present invention relates to a shock absorbing structure. More particularly, it relates to a shock absorbing structure suitable for shoes to be used in daily life, sports shoes for jogging, tennis, and golf shoes and the like, shoes for medical usage, mattresses for beds, cushioning sheets for chairs, floor coverings, packing or wrapping materials for protecting products and other shock absorbing materials.
2. Description of the Related Art
Heretofore, there have been used, as shock absorbing materials for shoes, foamed sheets from an ethylene-vinyl acetate copolymer (hereinafter referred to as "EVA"), natural rubber, synthetic rubber, polyurethane and the like, resin structures constructed like a branched tree as disclosed in Japanese Kokohu Publication (examined) 43224/1972, polyurethane solid elastomers having a high shock-damping capacity, bags filled with viscous materials or gas, and the like. These materials, however, have defects in absorbing shock which occurs when the foot contacts the ground, supporting the body or receiving impact force at the time of striking the ground with the foot without restricting motion of the body in walking and exercising.
It is ideally required that the shock absorbing material absorb the impact force which occurs in walking or exercising. It is also required against back and forth motion or right and left motion which occur in exercising, that the material firmly fix the foot on the ground and prevent the right and left motion as far as possible, and that the material simultaneously produce a reacting force for the next motion. It is further required that the shock absorbing material protect the ankle. These requirements are contrary to each other. For example, if a soft material is employed as the shock absorbing material, it often twists the ankle and may often injure it. Accordingly, conventional shock absorbing materials are poor in durability, cushioning characteristics, producibility of reaction force, protection of an ankle and a combination thereof.
For example, in view of durability, the EVA foam and the tree-like resin structure are too high in change rate in comparison with the other materials, such as, synthetic rubber, natural rubber, polyurethane, synthetic rubber foams and the polyurethane rubber foams (See Table 3). They are also poor in appearance after a compression test. These results indicate that the EVA foam and the tree-like resin structure reach a permanent compression set of an early stage and are poor in durability. Thus, they are not suitable in long time usage. The polyurethane foam and the synthetic rubber foam has a small change rate in comparison with the EVA foam and has good durability. They, however, are not good in change rate in comparison with non-foamed materials and are poor in appearance. They, therefore, are not adequate in view of durability.
In view of shock absorbing properties, the EVA foam, as shown in FIG. 10, has a high stiffness at an initial (light) weight load, but has a smaller stiffness at a heavy weight load. Thus, the foam exhibits good shock absorbing properties in heavy load conditions, e.g. in running, but poor in light load conditions, e.g. in walking. The polyurethane and synthetic rubber foams show shock absorbing properties, as shown in FIG. 11. If the foams have a high stiffness, the degree of deformation at an initial (light) weight load is very small to result in low shock absorbing properties when walking. In order to enhance the shock absorbing properties, if the foams having a low stiffness are employed, then their deformation degrees are inherently too large to protect the ankle in running. The tree-like resin structure, as shown in FIG. 12, is low in initial stiffness and high in stiffness at a heavy weight load due to its structure. Thus, this structure is preferred, because the shock absorbing properties are good in walking and the deformation degree is small in a heavy weight load condition, such as in running. This structure, however, has defects in that the foot is not fixed and moves in the shoe in which the foot is put, in such sports as need an accelerated speed, i.e. track events and tennis. It is also necessary that the structure be made from a hard resin, in order to fully enjoy its technical effects. Shoes thus made, however, have a bad feeling when the foot is put in them. When the tree-like structure is incorporated in the shoes, flashes which occur from cut portions have to be removed and the resulting structure also has to be covered with cloth. Accordingly, this structure has some difficulties in producibility.
The polyurethane solid elastomers having a high shock-damping capacity and the bags filled with viscous fluid have excellent shock absorbing properties, but are short of reaction forces necessary for the next motion and insufficient to protect the ankles. The bags filled with gas have a defect that the gas gradually leaks out after a long time.
In order to resolve the above mentioned defects, it is also proposed to combine two or more materials mentioned above. The combination makes a toe and a heel of a shoe thick, which makes it heavy. The process for preparing the shoes is also complicated.
As discussed above, the conventional shock absorbing materials have the following defects: (1) durability is poor, and (2) Each one of the materials does not have fully satisfactory shock absorbing properties. For example, the material has proper shock absorbing ability even in a light weight load in walking but, if in a heavy weight load in running, it has an increased stiffness and a little deformation. Further, reaction forces necessary for the next motions are produced and twist of the ankle does not occur. (3) In the case where two or more of the materials are combined to obtain desirable properties, weight and thickness increases and its production process becomes complicated. It often has a defect in durability.


An electronic device and a payment processing method in the electronic device are provided. The electronic device includes a memory configured to store first payment means information corresponding to a first payment means and second payment means information corresponding to a second payment means, and a processor electrically connected with the memory, wherein the processor is configured to execute a first application associated with the first payment means by activating the first payment means information, obtain a request to execute a second application associated with the second payment means, while the first application is executed, and deactivate the first payment means information based on at least the request.

1. Field of the Disclosure
The present disclosure relates to payment processing, and more particularly, to a mobile payment processing method for an electronic device including a mobile card (or a smart card) as a mobile payment means.
2. Description of the Related Art
Recently, an electronic device such as a smartphone supports a mobile payment function. For example, a user of an electronic device registers a mobile card (or a smart card) usable as a credit card, a debit card, a transit card, or the like with the electronic device and may use the registered mobile card in a payment method (hereinafter referred to as a payment means).
A mobile payment function may include, for example, a payment mode using a physical secure element (SE), a payment mode which does not use a physical SE, or the like. A mobile payment function may include, for example, a one time password (OTP) mode, a host card emulation (HCE) mode, an embedded secure element (eSE) mode, or the like.
The OTP mode is, for example, a mode of authenticating a user using an OTP randomly generated without using a fixed password and performing a payment. The HCE mode may use near field communication (NFC) and is a mode of communicating with a payment terminal through execution of an application without using a physical SE and performing a payment. The eSE mode is a mode of performing a payment based on an SE embedded in an electronic device in the form of a separate integrated circuit or chip.
In the eSE mode, a point of sale (POS) terminal randomly selects a mobile card to be used as a payment means among mobile cards installed in an eSE based on a pre-determined condition and may proceed with a payment. For example, if an electronic device sends a list of mobile cards installed in an eSE to a POS terminal, the POS terminal selects a mobile card based on a type of a mobile card supported by the POS terminal from the sent list of the mobile cards and may perform a payment in the eSE mode. In this case, if there are a plurality of mobile cards supported by a POS terminal on a list of mobile cards, the POS terminal may randomly select a mobile card based on a pre-determined condition.
It is difficult for a user to select a certain mobile card as a payment means among mobile cards installed in an electronic device in an eSE.

Payment processing method and electronic device supporting the same


The present invention refers to a method for controlling undesired vegetation at a plant cultivation site, the method comprising the steps of providing, at said site, a plant that comprises at least one nucleic acid comprising a nucleotide sequence encoding a wild-type or a mutated protoporphyrinogen oxidase (PPO) which is resistant or tolerant to a benzoxazinone-derivative herbicide by applying to said site an effective amount of said herbicide. The invention further refers to plants comprising wild-type or mutated PPO enzymes, and methods of obtaining such plants.

Herbicides that inhibit protoporphyrinogen oxidase (hereinafter referred to as Protox or PPO; EC:18.104.22.168), a key enzyme in the biosynthesis of protoporphyrin IX, have been used for selective weed control since the 1960s. PPO catalyzes the last common step in chlorophyll and heme biosynthesis which is the oxidation of protoporphyrinogen IX to protoporphyrin IX. (Matringe et al. 1989. Biochem. 1. 260: 231). PPO-inhibiting herbicides include many different structural classes of molecules (Duke et al. 1991. Weed Sci. 39: 465; Nandihalli et al. 1992. Pesticide Biochem. Physiol. 43: 193; Matringe et al. 1989. FEBS Lett. 245: 35; Yanase and Andoh. 1989. Pesticide Biochem. Physiol. 35: 70). These herbicidal compounds include the diphenylethers {e.g. lactofen, (+−)-2-ethoxy-1-methyl-2-oxoethyl 5-{2-chloro-4-(trifluoromethyl)phenoxy}-2-nitrobenzoate; acifluorfen, 5-{2-chloro-4-(trifluoromethyl)phenoxy}-2-nitrobenzoic acid; its methyl ester; or oxyfluorfen, 2-chloro-1-(3-ethoxy-4-nitrophenoxy)-4-(trifluorobenzene)}, oxidiazoles, (e.g. oxidiazon, 3-{2,4-dichloro-5-(1-methylethoxy)phenyl}-5-(1,1-dimethylethyl)-1,3,4-oxadiazol-2-(3H)-one), cyclic imides (e.g. S-23142, N-(4-chloro-2-fluoro-5-propargyloxyphenyl)-3,4,5,6-tetrahydrophthalimide; chlorophthalim, N-(4-chlorophenyl)-3,4,5,6-tetrahydrophthalimide), phenyl pyrazoles (e.g. TNPP-ethyl, ethyl 2-{1-(2,3,4-trichlorophenyl)-4-nitropyrazolyl-5-oxy}propionate; M&B 39279), pyridine derivatives (e.g. LS 82-556), and phenopylate and its O-phenylpyrrolidino- and piperidinocarbamate analogs. Many of these compounds competitively inhibit the normal reaction catalyzed by the enzyme, apparently acting as substrate analogs.
Application of PPO-inhibiting herbicides results in the accumulation of protoporphyrinogen IX in the chloroplast and mitochondria, which is believed to leak into the cytosol where it is oxidized by a peroxidase. When exposed to light, protoporphyrin IX causes formation of singlet oxygen in the cytosol and the formation of other reactive oxygen species, which can cause lipid peroxidation and membrane disruption leading to rapid cell death (Lee et al. 1993. Plant Physiol. 102: 881).
Not all PPO enzymes are sensitive to herbicides which inhibit plant PPO enzymes. Both the Escherichia coli and Bacillus subtilis PPO enzymes (Sasarmen et al. 1993. Can. J. Microbiol. 39: 1155; Dailey et al. 1994. J. Biol. Chem. 269: 813) are resistant to these herbicidal inhibitors. Mutants of the unicellular alga Chlamydomonas reinhardtii resistant to the phenylimide herbicide S-23142 have been reported (Kataoka et al. 1990. J. Pesticide Sci. 15: 449; Shibata et al. 1992. In Research in Photosynthesis, Vol. III, N. Murata, ed. Kluwer:Netherlands. pp. 567-70). At least one of these mutants appears to have an altered PPO activity that is resistant not only to the herbicidal inhibitor on which the mutant was selected, but also to other classes of protox inhibitors (Oshio et al. 1993. Z. Naturforsch. 48c: 339; Sato et al. 1994. In ACS Symposium on Porphyric Pesticides, S. Duke, ed. ACS Press: Washington, D.C.). A mutant tobacco cell line has also been reported that is resistant to the inhibitor S-21432 (Che et al. 1993. Z. Naturforsch. 48c: 350). Auxotrophic E. coli mutants have been used to confirm the herbicide resistance of cloned plant PPOs.
Three main strategies are available for making plants tolerant to herbicides, i.e. (1) detoxifying the herbicide with an enzyme which transforms the herbicide, or its active metabolite, into non-toxic products, such as, for example, the enzymes for tolerance to bromoxynil or to basta (EP242236, EP337899); (2) mutating the target enzyme into a functional enzyme which is less sensitive to the herbicide, or to its active metabolite, such as, for example, the enzymes for tolerance to glyphosate (EP293356, Padgette S. R. et al., J. Biol. Chem., 266, 33, 1991); or (3) overexpressing the sensitive enzyme so as to produce quantities of the target enzyme in the plant which are sufficient in relation to the herbicide, in view of the kinetic constants of this enzyme, so as to have enough of the functional enzyme available despite the presence of its inhibitor. The third strategy was described for successfully obtaining plants which were tolerant to PPO inhibitors (see e.g. U.S. Pat. No. 5,767,373 or 5,939,602, and patent family members thereof.). In addition, US 2010/0100988 and WO 2007/024739 discloses nucleotide sequences encoding amino acid sequences having enzymatic activity such that the amino acid sequences are resistant to PPO inhibitor herbicidal chemicals, in particular 3-phenyluracil inhibitor specific PPO mutants.
To date, the prior art has not described benzoxazinone-derivative herbicide tolerant plants containing at least one wild-type or mutated PPO nucleic acid. Nor has the prior art described benzoxazinone-derivative herbicide tolerant crop plants containing mutations on genomes other than the genome from which the PPO gene is derived. Therefore, what is needed in the art is the identification of benzoxazinone-derivative herbicide tolerance genes from additional genomes and species. What are also needed in the art are crop plants and crop plants having increased tolerance to herbicides such as benzoxazinone-derivative herbicide and containing at least one wildtype and/or mutated PPO nucleic acid. Also needed are methods for controlling weed growth in the vicinity of such crop plants or crop plants. These compositions and methods would allow for the use of spray over techniques when applying herbicides to areas containing crop plants or crop plants.

This patent is subject to a terminal disclaimer.

Plants having increased tolerance to herbicides


A pharmaceutical composition and method for treating injury to or diseases which result in neuronal degeneration resulting from stroke, brain, retina or spinal cord injuries and other brain disorders and possible trauma associated with neurosurgical procedures is disclosed. The composition consists of glutamine synthetase (GS), analogues and derivatives thereof and a pharmaceutical carrier which when administered to a patient prevents or reduces neuronal degeneration.

1. Technical Field
The present invention relates to compositions for and a method of treatment of neuronal degeneration due to stroke, brain, retina or spinal cord injuries and other brain or retinal disorders by glucocorticoids or glutamine synthetase.
2. Background Art
Neuronal degeneration as a result of stroke, brain, retina or spinal cord injuries, ischemia and reperfusion and other brain or retinal disorders is an enormous medical and public health problem by virtue of both its high incidence and the frequency of long-term sequelae. The pathophysiology of neuronal degeneration has been shown to be directly related to the neurotransmitter glutamate. Upon injury or upon ischemic insult, the damaged neurons release massive amounts of the neurotransmitter glutamate, which is excitotoxic to the surrounding neurons Choi, 1988; Rothman and Olney, 1986; Choi and Rothman, 1990; David et al., 1988; Drejer et al., 1985!. See also U.S. Pat. No. 5,135,956 issued Aug. 4, 1992 particularly columns 1-8 and U.S. Pat. No. 5,395,822 issued Mar. 7, 1995 columns 1-3 for a review, incorporated herein in their entirety by reference.
Under normal conditions, accumulation of glutamate in the extracellular space is prevented by the operation of a recycling mechanism which serves to maintain neuronal glutamate levels despite continual loss through transmitter release Van der Berg and Garfinkel, 1971; Kennedy et al., 1974!. Glutamate, released by glutaminergic neurons, is taken up into glial cells where it is converted into glutamine by the enzyme glutamine synthetase L-glutamate: ammonia ligase (ADP-forming; EC 22.214.171.124)! (GS); glutamine reenters the neurons and is hydrolyzed by glutaminase to form glutamate, thus replenishing the neurotransmitter pool. This biochemical pathway may also serve as an endogenous neuroprotective mechanism, which functions by removing the synaptically released glutamate from the extracellular space and converting it to the nontoxic amino acid glutamine before toxicity occurs. This neuroprotective mechanism fails, however, to prevent glutamate neurotoxicity after insult.
Massive release of glutamate to the extracellular fluid stimulates a cascade of events that amplifies the initial trauma and causes the damage to spread to the neighboring cells Mattson, 1990a; Olney, 1989; Olney, 1994a!. This biochemical cascade of induction and progression may continue for hours or days and causes delayed neuronal death. The object of medical therapy is to break or eliminate this cascade process and thus prevent spread of the secondary damage.
Involvement of glutamate in neuronal degeneration is supported by three major lines of evidence.
I. Neuronal insult leads to accumulation of relatively high levels of glutamate in the extracellular fluid Drejer et al., 1985; Waniewski and Martin, 1986!. PA1 II. Administration of glutamate (systematically or in vitro) leads to neuronal cell death Mattson, 1990b; Michaels and Rothman, 1990!. PA1 III. Glutamate receptor antagonists can protect from neuronal degeneration Clifford et al., 1998; Mosinger et al., 1991; Olney, 1994b; Olney et al., 1991!.
The mechanism responsible for the glutamate mediated cellular damage and death is not fully understood. However, accumulating evidence supports the hypothesis that glutamate neurotoxicity is mediated through NMDA and non-NMDA-type glutamate excitatory receptors Simon et al., 1984; Tecoma et al., 1989; Mosinger et al., 1991; Olney et al., 1991! and entails sustained depolarization of postsynaptic dendrosomal membranes, increased membrane permeability and impaired ion homeostasis Olney, 1989; Moudy et al., 1994; Waniewski and Martin, 1984; Olney et al., 1986; Dubinsky and Rothman, 1991; Choi, 1995! and lead to either an apoptotic or a necrotic type of death Bonfoco et al., 1995; Ankarcrona et al., 1995!. Although definitive evidence implicating specific ions has been lacking, several studies proposed that excessive calcium influx into the postsynaptic neuron may be responsible for activating signaling pathways and possibly endonucleases which cause neuronal cell death Olney, 1994; Michaels and Rothman, 1990; Dubinsky and Rothman, 1991!.
Several studies have shown the involvement of glutamate in the pathophysiology of Huntington's disease (HD) Coyle and Schwarcz, 1976!, Alzheimer's disease (AD)Maragos et al, 1987!, epilepsy Nadler et al, 1978!, lathyrism Spencer et al, 1986!, amyotrophic lateral sclerosis (ALS) and Parkinsonian dementia of Guam Calne et al, 1986! as well as in the neuropathology associated with stroke, ischemia and reperfusion Rothman, 1984; Dykens et al, 1987!.
U.S. Pat. No. 5,135,956 discloses treating neuronal degeneration by treating with a long-chain fatty alcohol which has cytoprotective effect. U.S. Pat. No. 5,395,822 discloses treating neuronal degeneration with a salt of pyruvic acid. Further U.S. Pat. Nos. 5,444,095, 5,428,069, 5,162,375 and 5,013,558 disclose other compounds for the treatment of neuronal degeneration. However, none of these approaches utilizes glutamine synthetase to block the cascade resulting in neurotoxicity at the initiation step by directly neutralizing the activity of its trigger: glutamate.

Method and composition for treating neuronal degeneration

Ramot-University Authority for Applied Research and Industrial Development, Ltd.


The laser decontamination device includes: a laser oscillator; a scanning device provided with an XY axis scanner and a Z axis scanner to condense the laser beam emitted from the laser oscillator onto the surface of the contaminated article without the intervention of any compound lens such as an f θ lens so as to optically scan the surface; and a surface shape measuring device to measure the surface shape of the contaminated article, the Z axis scanner being provided with a focus position controlling section to automatically adjust a focus position in accordance with an irradiation position such that a focus of the laser beam comes on the surface of the contaminated article based on a shape data obtained at the surface shape measuring device.

Conventionally, such decontamination method by laser is known as irradiating substantially parallel light pulse laser beams of lower average power output onto the surface of the objects contaminated by the RIs with such objects linearly or planarly scanned, the device employing which method is characterized in that the contaminants deriving from RIs, which are black and others in color and higher in photoabsorption, are vaporized for removal without doing damage on the base metal and as such.
However, according to the above method by which the pulse laser beams are rendered into parallel light, making the condensed area smaller for the purpose of enhancing the power density (irradiation intensity) unavoidably leads to causing uneven irradiation, so that the same spot shall be irradiated several times. On the other hand, enlarging an irradiation area of one pulse causes the power density to be lowered (in the order of some MW/cm2 or less) so that the irradiated beams result in being reflected from the lustrous metallic surface, with the result that the RIs advanced deeply into the microscopic cracks on the metallic surface cannot be removed at all.
Further, conventionally, besides the above-mentioned laser decontamination, such decontamination employing a sandblast, a sander and a grinder is carried out, according to which mechanical methods in order to remove the attached RIs, it is general that a portion of the surface of the object contaminated by them is scraped off by the thickness ranging from 0.05 mm to 0.1 mm or more
However, according to the above-mentioned mechanical methods, during the grinding not only the RIs are ready to reenter the surface so as to cause recontamination, but also the grinding device (such as the nozzle of the sandblast) is secondarily contaminated by the grinding particles of the sandblast, the grinding belt of the sander or grinder or the grinding disk that are used repeatedly.
Further, providing that the sandblasts and sanders secondarily contaminated by the grinding particles or belt are exchanged with new ones every time the decontaminations are carried out, it makes the cost incurred for exchanging such mechanical devices and their parts so bulky that not only the decontamination cost goes overboard, but also a large volume of secondary wastes are produced, which is unfavorable in view of the cost-saving aspect and the eco-friendly trend.
On the other hand, conventionally, such method is known as the objects contaminated by the RIs being clipped into the solution containing an oxidant and a reductant so as to make the contaminants solved into the solution, according to which chemical method it requires a lot of disposal cost to dispose with a large volume of ion-exchange resins used for separating the RIs from the wasted solution, which resins are burnt so as to be reduced in volume and stabilized with concrete and the like for storage.
Further, in recent years, such technique is proposed as the pulsed laser beams whose peak output is 10 MW or higher (for instance, refer to Document 1) being employed, according to which technique it is unable to focus the laser beams on the surface of the object contaminated by the RIs with precision, so that the power density (irradiation intensity) in the order of GW/cm2 cannot be secured. Moreover, uneven irradiation density might happen on the surface of the object with irregularities.
Furthermore, where such high-output pulsed laser beams are employed, it requires that the thermally induced diffusion and reattachment of the RIs be taken into due account, besides, with the method by which the laser beams are irradiated with the laser head moved, because there is limit in the scanning velocity for the low-velocity motion even when it might be automatically scanned, the thermally induced diffusion of the RIs is aggravated in which the portions onto which the beams are irradiated result in being extensively and deeply fused and thermally affected. Such method is also known (refer to non-patent literature 1) as fusing the surface of the object by CW (Continuous Wave) laser beams of high output power and removing the fused portions by a pressurized gas, which method is also subjected to aggravated thermal effect so as to make the thermally induced diffusion of the RIs further aggravated.
On the other hand, a laser machining device in which a focal length is adjusted with a beam expander in use is also well known (refer to Patent Literature 2), but with such device, the condensing optical system including compound lenses are disposed posterior to the XY scanner, so that it often happens that measuring a surface shape with a laser range finder fails because the reflected light from the object is under the influences of such compound lenses and as such. Further, passing the machining and measuring laser beam through the compound lenses and as such makes such beam greatly attenuated, so that the available machining laser beam unavoidably results in being smaller in output power.


Touch regions in a diamond configuration in a touch sensitive device are disclosed. Touch regions can include drive regions of display pixels to receive stimulation signals and sense regions of display pixels to send touch signals based on a touch or near touch. The drive regions and sense regions can be disposed diagonally adjacent to each other to form a diamond configuration. In an example diamond configuration, diagonal drive regions can be separate and unconnected from each other, while diagonal sense regions can be electrically connected to each other via their sense lines. The diagonal sense region connections can be in a forward diagonal direction, a backward diagonal direction, or a combination thereof. In an alternate example diamond configuration, diagonal drive regions can be electrically connected to each other via their drive lines, while diagonal sense regions can be electrically connected to each other via their sense lines. The diagonal drive and sense region connections can be in a forward diagonal direction, a backward diagonal direction, or combinations thereof. An exemplary touch sensitive device having a diamond configuration can be a touch screen.

Many types of input devices are available for performing operations in a computing system, such as buttons or keys, mice, trackballs, touch sensor panels, joysticks, touch pads, touch screens, and the like. Touch screens, in particular, are becoming increasingly popular because of their ease and versatility of operation as well as their declining price. Touch screens can include a touch sensor panel, which can be a clear panel with a touch sensitive surface, and a display device such as a liquid crystal display (LCD) that can be positioned behind the panel so that the touch sensitive surface can substantially cover the viewable area of the display device. Touch screens can generally allow a user to perform various functions by touching or near touching the touch sensor panel using one or more fingers, a stylus or other object at a location dictated by a user interface (UI) including virtual buttons, keys, bars, displays, and other elements, being displayed by the display device. In general, touch screens can recognize a touch event and the position of the touch event on the touch sensor panel, and the computing system can then interpret the touch event in accordance with the display appearing at the time of the touch event, and thereafter can perform one or more actions based on the touch event.
Touch screens that integrate touch circuitry with display circuitry are described in U.S. patent application Ser. No. 11/760,080, entitled "Touch Screen Liquid Crystal Display," and Ser. No. 12/240,964, entitled "Display with Dual-Function Capacitive Elements," the contents of which are incorporated herein by reference in their entirety for all purposes. In these touch screens, display pixels can be grouped into drive regions to receive a stimulation signal and sense regions to transmit a touch signal based on a touch or near touch. These regions can generally be disposed in a rectangular configuration with, from left to right, some drive regions aligning vertically, a sense region extending vertically along the lengths of the drive regions, more drive regions aligning vertically, another sense region extending vertically along the lengths of the drive regions, and so on.
Because of this rectangular configuration, horizontal drive lines for transmitting the stimulation signal and vertical sense lines for transmitting the touch signal can cross numerous times in the sense regions, creating parasitic capacitance that can interfere with the ability of the touch screen to effectively sense the touch or near touch. However, to reduce the effects of this parasitic capacitance, more expensive and powerful sensing circuitry may be needed to improve the signal-to-noise ratio of the touch signal.


A method and apparatus for the storage and transfer of medical material includes a syringe having a rodless piston magnetically coupled to an actuator that is positioned along the syringe independent of the rodless piston. The syringe may also include a medical material stored in a cartridge.

1. Field of the Invention
The present invention is directed to an apparatus and method for use in medical injection technology. More particularly, the present invention is directed to improved hypodermic syringe assemblies and methods for using the same.
2. Description of the Related Art
For generations, people all over the world have received injections (or fluid withdrawals) utilizing a piston driven device commonly referred to as a hypodermic syringe. Hypodermic syringe designs have not really changed much since their first inception in which a plunger formed from a piston and piston rod is manually operated to drive fluid, from a cylindrical chamber in the syringe into, or out of, a living body through a needle.
Similarly, unchanged is the way that a dosage of medicine is stored such as in an ampoule or a vial in which the period of drug shelf life is limited only by the drug stability and/or by opening of the storage vessel and introducing air and other impurities therein. One change has been in the form of a pre-filled and/or cartridge syringe in which a cylindrical drug chamber is pre-filled with a drug and sealed with a piston with an opening to receive a piston rod from the syringe at one end. However, the drug shelf life is limited by the quality of the fill and the seal between the piston and the wall of the cartridge in the opening left for the piston rod to connect with the piston.
Except in the instance of current cartridge designs, the present technological method for injecting drugs includes filling of ampoules and vials in order to store the drug for a period of time and then filling of the syringes, when needed, from these ampoules and vials. Filling of ampoules and vials is the most labor intensive and, therefore, the most expensive part of the process. In order to fill ampoules and the vials, the pharmaceutical company has to set up the clean-room operations, purchase and set up specific equipment, maintain supply of ampoules and the vials, employ operators, administration, technicians, engineers, quality control and the quality assurance personnel dedicated to this process. Ampoules and vials have to be stored and, therefore, the warehouse space is required. Inspections, handling and shipping add to the cost of the final product by adding the manpower required to handle all these operations, rejects and damages, and the cost of extra storage, logistics and the shipping containers. And, in addition to all that, the syringes are needed to inject the drug.
Some of these issues have been addressed with pre-filled syringes. The pre-filled syringes do not need ampoules and vials, but are not very popular and common. The presently available pre-filled syringes cannot maintain sterility for a long time and, therefore, have a very short shelf life. The shelf life of the modern common pre-filled syringes is a couple of months if that much. The reason for that is that the syringe is not perfectly sealed and air, germs and bacteria can work itself in while the drug can leak out. Plastic is not an ideal material to store some of the drugs for an extended period of time. The extended plunger of the pre-filled syringe could be accidentally pushed in or pulled out changing the volume of the drug inside or letting the air in. Pre-filled syringes cannot be shipped far unless specially designed containers are used (expensive). Therefore, pre-filling has to be done locally by qualified personnel just before the distribution. This option requires the qualified personnel and the necessary equipment to be present and one still cannot store it for any extensive period of time. Therefore, it cannot be pre-filled in advance at a medical production facility adding to the high cost of shipping.
All above adds to the logistics and the expense of the drug manufacturing process. Such shortcomings are even more appreciated when considering situations such as mass vaccinations, personal insulin injections, on-location pain relievers for the military, in sporting events and remote areas. A storage vessel easily convertible into a syringe without the shortcomings discussed above would solve these problems.
Thus, the need exists for a way to provide a storage vessel that easily converts into a syringe.


A computer-implemented method for performing a search on a data backup system is disclosed, where at least a portion of the method is performed by a computing device comprising at least one processor. The method includes receiving a search query, performing a search of indexed information stored in the data backup system based on the search query, determining non-indexed information stored in the data backup system related to the search query, and returning results of the performing and the determining.

Conventionally, data backup applications store target images of data from a particular computer system onto a backup server. The target images may be retrieved via the data backup application over communication mediums, and may be written to the backup server. During write cycles, a plurality of options may be available for backup storage. For example, one option may be to index the target images for future searching on the backup server. Generally, not all target images are indexed, and therefore, not all backup data is searchable.
For example, in some data backup systems, users must explicitly request backup image data be indexed. In others, some or all of backup image data is indexed, but only during non-peak computing times to conserve system resources. Still in others, only essential or flagged backup image data is indexed.
It follows then, that if backup image data on any particular data backup system is searched, only a portion of actual information stored may be retrieved. Therefore, if a particular search operation is considered vital, there is no conventional method for increasing the confidence of the returned search results as compared to all available data which cannot be searched.
Therefore, there is a need in the art for a solution which overcomes the drawbacks described above.


A medicine bag, which includes a bag body having a medicine storage chamber that stores a medicine in such a way that the medicine is visually confirmed through a light-transmission portion provided in at least one part of the bag body, the bag body having a weak seal portion that divides the medicine storage chamber into a plurality of division spaces, and the sealing of the weak seal portion adjacent to a specific division space being removed by increasing the internal pressure of that division space, including: a cover sheet which is peelably attached to the bag body; and a requisitely-used portion which is used in the process shortly before the medicine is administered, in which the cover sheet includes: a light-shielding portion which shields from the light the medicine stored in at least one division space by covering a predetermined part of the light-transmission portion; and a continuously-formed portion which is continuously formed in the light-shielding portion and is placed so that the requisitely-used portion is prevented from being used with the cover sheet kept attached.

1. Field of the Invention
This invention relates to a medicine bag which is used in the medical field or the like, specifically, a medicine bag which is used by providing a weak seal portion that divides its bag body into a plurality of division spaces, removing the sealing of the weak seal portion adjacent to a specific division space by increasing the internal pressure of that division space, and mixing a medicine stored in a predetermined division space.
2. Description of Related Art
As the medicines which are administered to patients by intravenous injections or the like, some are mixed and used with other such medicines. Some of those medicines are unstable, and thus, if mixed beforehand, they may deteriorate as time passes. In the case where such unstable medicines are stored, therefore, a medicine bag is generally used conventionally which has the following configuration. Specifically, several division spaces are formed which store those medicines separately before mixed. When the medicines are used, the division spaces are allowed to lead to each other to mix the medicines stored in each division space.
Some medicines deteriorate as they have been exposed to the light for many hours. If such photo-variable medicines are stored in the above described division spaces, a medicine bag is often used in which the division spaces are covered with a light-shielding layer portion such as an aluminum-foil layer portion.
In such a medicine bag which has the light-shielding layer portion, for example, as disclosed in European Patent Publication No. 0639364A1 or Japanese Design Registration No. 1107140, a weak seal portion which can be peeled divides its bag body into a liquid-medicine storage space that stores a liquid medicine and a medicine storage space that stores a photo-variable dried medicine. The inner wall of this medicine storage space is formed by a transparent flexible sheet. A cover is attached to the bag body so that it can be peeled. Herein, it includes a light-shielding layer portion which is formed by an aluminum film or a colored film that covers the inner wall so that a medicine inside of the inner wall can be shielded from the light.
When this medicine bag is used, usually, the liquid-medicine storage space is pressed by hand to apply pressure to the inside of the liquid-medicine storage space. Then, the weak seal portion is peeled using the pressure of the liquid medicine generated at this time. This allows the liquid-medicine storage space to lead to the medicine storage space, thus mixing the medicines in each storage space. Next, an operation is conducted such as a hole formed in the bag body is hung on a hanger of a bag stand. In order to display the remaining quantity of the medicines mixed in such a way as described above, the total quantity of the medicines before administered are confirmed using a remaining-quantity displaying portion (such as a calibration) which is provided in the bag body. Finally, a tube or the like for injecting a patient with a medicine is connected to a port of the medicine bag, and the medicines mixed in the medicine bag are administered to the patient. On the other hand, in addition to the above described series of operations shortly before administered, the cover is peeled, and then, the state of the medicines, such as how properly they have been mixed and how well they are preserved, is visually confirmed, so that the medicine can be properly administered.
However, in the case where the medicine bag of European Patent Publication No. 0639364A1 is used, even though the need for visual confirmation as described above is called, for example, a user may not peel the cover as the user grows accustomed, or the user may forget carelessly to peel the cover under a complicated situation. In this case, the user may conduct the series of operations without visually confirming medicines in the medicine storage chamber. As a result, the medicines to be essentially mixed may be administered to a patient without mixed, or the medicines which have undergone changes in their outside appearances may be administered to a patient as they are after mixed.


The invention relates to water-soluble nanoparticles and methods for making such nanoparticles. Specifically, the invention relates to dendrimerization to enhance the solubility of nanoparticles.

Colloidal up-converting nanoparticles (UCNPs) are capable of converting near-infrared excitation into visible emission via mutiphoton up-conversion processes. These processes involve long-lived excited electronic states of dopant lanthanide ions—antennae (e.g. Yb3+), admixed to the crystal lattices of host materials (e.g. NaYF4). The host crystals also contain emissive lanthanide ions—emitters (e.g. Er3±). The antenna ions transfer excitation energy onto the emitter ions by way of multi-exciton annihilation/sensitization process. The overall up-conversion scheme consist of the following steps: 1) excitation of two or more antenna ions by low energy photons, 2) diffusion of the excitons mediated by energy transfer/exchange between the antenna ions, 3) formation of multi-exciton antenna/emitter complexes; 4) exciton annihilation and sensitization of excited states of the emitter ions within these complexes, followed by 4) emission of a higher energy photon. These processes, occurring at the core of the UCNP, are responsible for its photophysical properties, which are relatively insensitive to the environment. On the contrary, the periphery of the particle, which remains in constant contact with the environment, determines the UNCP biocompatibility and bio-analytical functionality.
UCNPs offer a number of advantages for biological imaging, including high photostability, narrow emission bands, near infrared excitation wavelengths for depth-resolved imaging and potentially reduced risk of photodamage. Compared to conventional multiphoton excitation, sequential absorption of photons by UCNPs occurs via population of real as opposed to virtual states; and, therefore, multiphoton excitation cross-sections of UCNPs are much higher than those of regular organic dye molecules. In fact, multiphoton excitation and emission of UCNPs can be induced by low power continuous wave (cw) sources. Such sources excite virtually zero auto-fluorescence and cause no photodamage.
There have been many efforts to utilize UCNPs in biological sensing. UCNPs can be effectively detected at cm's depths in the tissue, including applications in optical tomography, as well as provide opportunities for single-particle detection. Multicolor nature of UCNP emission has been recently demonstrated as a valuable tool for in vivo imaging. Nonetheless, all so far reported experiments capitalize on the advantage of near-infrared excitation to induce emission of UCNPs, whereas very few specific biological analytes have been addressed, e.g. lectin. Furthemore, in spite of the fact that the multiphoton-nature of UCNP excitation is a natural prerequizite for multiphoton microscopy applications, no high-resolution depth-resolved imaging using UCNPs has yet been performed.
UCNPs can be synthesized by a variety of methods. In the majority of these synthetic schemes, and especially in those schemes that yield the maximally emissive nanoparticles (vide infra), UCNPs are stabilized by coats of the so-called supporting ligands, such as oleic acid, polyethyleneamine etc, or even by secondary inorganic shells (e.g. mesoporous silica).
The role of this layer is to control the formation of nanocrystals, keep the UCNPs in solution during the synthesis and maximize the yield of a particular crystalline phase (β- or hexagonal phase), which is characterized by the highest up-conversion efficiency. The supporting organic ligands are attached to the UCNP surfaces by their polar head groups (carboxyls or amines). The long hydrophobic tails support crystals in non-polar solutions, but make them completely insoluble in aqueous environments. For biological applications these ligands shoul be replaced by hydrophilic coats to ensure high aqueous solubility.
Solubilization of UCNPs in aqueous environments has been attempted by several methods, including solvothermal, hydrothermal, ionothermal methods and the method of thermal decomposition. These methods differ in their efficiency and generality, but presently there is no universal approach to the synthesis of truly water-soluble UCNPs with surface groups suitable for functionalization and linking to biological targets.
Accordingly, there exits a need for improved nanoparticles that would provide enhanced solubility in water.

THE TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA


A combination of: a first tetracycline (TC) component; and a second component capable of releasing nitric oxide (NO) or a nitrate capable of mimicking NO effects in vivo (NO mimetic). The combinations of the invention advantageously act as more effective MMP modulators with selective reductions in circulating MMP-9 levels in-vivo and inhibitory effects on MMP-2 and MMP-9 levels in-vitro. The combinations of the invention also advantageously act as modulators of inflammation mediators. The co-existence of abnormalities of MMP enzymes and inflammation in many diseases make these characteristics advantageous. Therefore, the various combinations of the invention find utility in medical applications where MMPs and/or inflammation is implicated.

The prevalence of heart failure (HF) is increasing in the developed world and the cost of providing medical care for an expanding HF population imposes an increasingly heavy burden on healthcare systems throughout the world. Most commonly, HF is associated with impaired left ventricular (LV) systolic function. However, at least half of all patients with typical symptoms of congestive HF have a normal or slightly reduced left ventricular ejection fraction (LVEF) (>50%). The predominant cause of heart failure with preserved ejection fraction (HFpEF) is diastolic heart failure (DHF). Heart failure (HF) with preserved ejection fraction (HFpEF) is predominantly caused by hypertension, is often preceded by asymptomatic left ventricular diastolic dysfunction (ALVDD) and has few defined therapies. The predominant aetiological cause of DHF is myocardial fibrosis as a result of long standing hypertension and metabolic abnormalities associated with diabetes and obesity. The rising prevalence of metabolic disease due to the obesity and diabetic epidemics means that DHF is a major public health problem. DHF, similar to systolic HF has a five-year mortality rate of 65%. In many of these patients, diastolic dysfunction caused by hypertensive heart disease (HHD) is implicated as a major contributor, if not a primary cause. Furthermore, the prevalence of asymptomatic diastolic dysfunction in the community is significant with approximately 25-30% of individuals >45 years of age being affected. There are no proven, life-saving therapies for treating DHF. Many of the well-established drug therapies for systolic heart failure have been directed at DHF without success. The diagnosis of DHF can present a challenge in routine clinical practice. The major limitation in the diagnosis of DHF is the identification of diastolic dysfunction (DD), which at present is predominantly reliant on Doppler echocardiographic studies. Echocardiography has been used for many years to provide structural correlates to the clinical picture of HF. It can also measure multiple clinically important parameters of cardiac function, including hemodynamic status and LVEF, volumes and mass. The pathophysiology of DHF includes delayed relaxation, impaired LV filling and/or increased stiffness. These conditions result in an upward displacement of the diastolic pressure-volume relationship with increased end-diastolic, left atrial and pulmo-capillary wedge pressure leading to symptoms of pulmonary congestion. Diagnosis of DHF requires three conditions; (1) presence of signs or symptoms of HF; (2) presence of normal or slightly reduced LVEF (>50%) and (3) presence of increased diastolic filling pressure. Data indicate that the underlying pathophysiology in diastolic dysfunction and DHF is related to myocardial interstitial disease. Collagen is a stable protein and its balanced turnover is estimated to be 80-120 days. Alteration of collagen turnover by various mechanisms can lead to adverse accumulation of collagen in the myocardial interstitium leading to fibrosis, increased tissue stiffness, reduced myocardial compliance and impaired diastolic function. The successful neurohumoral-based approach to pharmacotherapy in HF with systolic dysfunction has not resulted in similarly impressive results in HFpEF, implicating additional pathophysiological signals. Changes in the extracellular matrix (ECM), known as myocardial remodeling, are central abnormalities in many patients with HFpEF and are characterized by inflammation, increased ECM turnover and myocardial fibrosis. Key mediators of inflammation are pro-inflammatory cytokines including interleukins (IL) (IL-1β, IL-6, IL-8) and tumor necrosis factor (TNF)α. Key regulators of the turnover of collagen and extracellular matrix (ECM) in the myocardium are the matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs). MMPs in particular have been found to play an important role in both inflammation and fibrosis. MMPs also contribute to collagen degradation and remodeling of the ECM after myocardial infarction. ECM turnover is regulated by matrix metalloproteinases (MMPs), especially the "gelatinases", MMP-2 and MMP-9, and their tissue inhibitors (TIMPs). MMP-2 and MMP-9 knockout models are associated with reduced aortic elastin degradation and protection from pressure overload hypertrophy, fibrosis and dysfunction. In the clinic, independent associations between ALVDD and HFpEF have been identified with markers of inflammation, fibrosis and MMP-9. During ischemic cardiomyopathy, neutrophil proteinase activates latent myocardial MMP, which can degrade the ECM. If unchecked by TIMPs, the ECM continuously degrades, leading to ventricular dilatation and diastolic dysfunction. Despite the emerging awareness of the potential role of collagen metabolism in the pathogenesis of diastolic HF there are as yet no effective therapies for this form of HF. Pharmacological modulation of MMPs may present an opportunity. However, all MMP synthetic inhibitors developed to date have either been ineffective or demonstrated dose- and duration-dependent drug-related side-effects, most which were musculoskeletal-related. Despite some promising animal studies of MMP inhibitors showing attenuation of cardiovascular remodeling in chronic pressure-overload models, the approach of direct inhibition of MMP enzymes has proven too toxic or ineffective in the clinic. An alternative approach in cardiovascular disease would inhibit production and/or secretion of inducible myocardial MMP-9. As well as classic inflammatory diseases such as rheumatoid arthritis, hay fever, periodontitis, inflammation plays an important role in the development and progression of diabetes and a variety of cardiovascular conditions, most notably coronary atherosclerosis and congestive heart failure. The term "Diabetic cardiomyopathy" was coined 4 decades ago and describes a "silent, stiffening" of the heart tissue which can lead to heart failure. There are no symptoms until heart failure occurs. It is present in half of people with diabetes and is more prevalent than well-recognised "silent pumping problem" which has good treatment available. This silent stiffening of the heart is linked to overweight, diabetes, high blood pressure and there are no specific therapies. Over the past 20 years, basic and human research has shown that enzymes in the heart called matrix metallproteinases or MMPs are involved in the stiffening process. They also affect large and small blood vessels and cause eye and kidney damage in diabetes. For example, in patients with diabetic retinopathy, increased MMP-9 activity was observed in retinal microvessels and MMP-9 knockout was protective (Kowluru et al, Abrogation of MMP-9 Gene Protects Against the Development of Retinopathy in Diabetic Mice by Preventing Mitochondrial Damage. Diabetes. 2011 Sep. 20 [Epub ahead of print]). Increased urinary excretion of MMP-9 in patients supports a role for MMP-9 dysregulation in diabetic renal dysfunction (Thrailkill et al., Endocrine. 2010 April; 37(2):336-43). Aortic and coronary arteries of diabetic patients taken at autopsy had higher expression of MMP-9 compared to non-diabetics and were correlated with HbA1c as well as apoptosis (Ishibashi et al., J Atheroscler Thromb. 2010 Jun. 30; 17(6):578-89). Elevated MMP-9 has also been associated with arterial stiffness in patients with diabetes (Chung et al., Cardiovasc Res. 2009 Dec. 1; 84(3):494-504). Furthermore, human genetic polymorphisms associated with MMP-9 elevation support a role for this enzyme in the pathophysiology of vascular disease. The 1562C>T single nucleotide polymorphism (SNP), which affects the promoter region of MMP-9 gene and increases circulating levels of MMP-9, is significantly associated with vascular disease in type 2 diabetes mellitus (Wang et al., Biochem Biophys Res Commun. 2010 Jan. 1; 391(1):113-7). In age and sex matched controls, patients with type 2 diabetes without and with microangiopathy, T allele frequencies were 11.9%, 13.1% and 24.4% respectively (p<0.05). Similarly, in a cohort of asymptomatic hypertensive patients, the 1562C>1 polymorphism is associated with increased T allele frequency, higher plasma MMP-9 and evidence of increased hypertension and vascular stiffness, measured by pulse wave velocity (Zhou et al. J Hum Hypertens. 2007 November; 21(11):861-7). Inflammation is also involved in the development and progression of some cancers (e.g., gallbladder carcinoma). Inflammation is mediated by a complex interplay of mediators such as IL-1 beta, IL-4 and IL-8. IL-1 beta induces COX-2, which causes brain levels of prostaglandin (PG)E2 to rise, thus activating the thermoregulatory center for fever production. In the periphery, IL-1 beta activates IL-1 receptors on the endothelium, resulting in expression of adhesion molecules and chemokines, which facilitate the emigration of neutrophils into the tissue spaces. IL-1 is pro-inflammatory and has been implicated in various pro-inflammatory diseases such as coronary atherosclerosis and congestive heart failure as well as diabetes where recent studies from animals, in-vitro cultures and clinical trials provide evidence that support a causative role for IL-1β as the primary agonist in the loss of beta-cell mass in type 2 diabetes. IL-4 is a TH2 type anti-inflammatory and profibrosis cytokine that stimulates and amplifies the inflammatory response by activation of the synthesis of types I and II collagen by fibroblasts and the promotion of the progression of fibrosis. IL-4 also inhibits the proinflammatory response of TNF-α, IL-1 and IL-6. IL-4 stimulates inflammatory responses, activates collagen synthesis, promotes fibrosis progression, and inhibits the production of inflammatory cytokines. The patients with CHF had higher IL-4 and PIIINP values than the controls. Comparison of the IL-4 values between the patients and controls showed a significantly greater difference in the CHF patients (12 [12] vs 4 [3] pg/mL; P<0.0001). Recent studies have shown that pro-inflammatory cytokines play a significant contributory role in the pathogenesis of acute heart failure. The purpose of this study was to determine whether the serum IL-8 concentration in patients with acute myocardial infarction (AMI), who were undergoing percutaneous coronary intervention (PCI) was related to the subsequent presence or absence of heart failure. A study by Dominguez-Rodriguez 2006, included 50 patients who underwent successful PCI. During their subsequent stay in the coronary care unit, their maximum degree of heart failure was recorded. Serum levels of IL-8 in patients more severe symptoms (Killip class >I) were significantly higher than those of with less severe symptoms (Killip class I) (P<0.001). By multivariante analysis a higher level of IL-8 was a significant predictor of heart failure after PCI. Similarly in HF, the presence of the metabolic syndrome which puts patients at higher risk, plasma levels of IL-8 (p<0.05) were significantly higher in HF patients with MetS than those without MetS.
Tetracyclines, commonly known for their broad-spectrum antimicrobial properties, have been characterized as pleiotropic immunomodulatory agents. In human studies, sub-antimicrobial doses of the tetracycline, doxycycline, have exerted potentially beneficial effects on inflammation that could promote plaque stability in an effort to prevent acute coronary syndrome, as doxycycline therapy has been shown to lead to a powerful reduction of aneurysmal wall neutrophil and cytotoxic T-cell count; two cell types considered crucial for the process of aneurysm formation. Attempts have been made to attenuate MMP expression to inhibit aortic abdominal aneurysm formation using doxycycline, thereby reducing the need for surgery. Doxycycline has been shown to inhibit secretion of MMP-2 and MMP-9 and is the only drug currently licensed for human use that relies on MMP inhibition. It is currently under evaluation in ALVDD and HF patients in our group for its effects on inflammation, MMPs, myocardial structure and function using cardiac MRI [EudraCT number: 2010-021664-16]. However, in several animal and human studies, the efficacy of MMP inhibition with doxycycline has been questioned. This may reflect non-specific inhibition of the wider MMP family with high doses and/or chronic therapy, involving inhibition of both constitutive and inducible enzymes. It prompted our group to create analogues of doxycycline that target over-expression of inducible MMP-9 rather than direct enzyme inhibition as a more effective and safer approach. Evidence is emerging that members of the MMP and/or A disintegrin and metalloproteinase (ADAM) family can serve not only as potential markers for diagnosis and prognosis, early detection, and risk assessment, but also as indicators of tumor recurrence, metastatic spread, and response to primary and adjuvant therapy for breast cancer. MMP-9 levels in tumor tissue as well as serum, plasma, and urine are significantly elevated in patients with breast cancer. Recently, efforts have focused on the use of MMPs and ADAMs as potential biomarkers of early breast cancer. Studies indicate that urinary MMP-9 and ADAM12, in addition to being predictive markers for breast cancer, may also prove useful as noninvasive breast cancer risk assessment tools. Several independent studies have used circulating MMP-9 activity to predict metastatic spread of disease as well as to monitor patient response to primary and adjuvant therapy and to evaluate outcome. High levels of serum MMP-9 and TIMP-1 are associated with increased incidence of lymph node metastasis and decreased relapse-free and overall survival rates. MMPs may also be useful in predicting therapeutic efficacy. Plasma MMP-9 levels decrease after the surgical removal of primary breast tumors and a progressive decrease in plasma MMP-9 was observed in patients who responded well to adjuvant therapy. Importantly, in all patients who suffered a relapse of disease there was a gradual increase of plasma MMP-9 activity 1 to 8 months before the clinical diagnosis of recurrence. Serum and tissue levels of MMP-9 are significantly higher in patients with pancreatic ductal adenocarcinoma than in patients with chronic pancreatitis and healthy controls. Active MMP-2 levels are upregulated in the pancreatic juice of patients with cancer (100%) as compared with patients with chronic pancreatitis (2%) or normal controls (0%). Several studies have reported that plasma and/or serum levels of MMP-9 and TIMP-1 are elevated in patients with stage III or IV lung cancer when compared with those in patients with nonmalignant lung diseases. Urinary MMP-2 and MMP-9 levels correlate with presence of bladder cancer as well as stage and grade of disease. Several MMP species have been reported in urine from patients with primary tumors in the bladder and prostate including MMP-2, MMP-9, MMP-9/neutrophil gelatinase-associated lipocalin complex and MMP-9 dimer. Each urinary MMP species was detected at significantly higher rates in urine from patients with cancer as compared with controls. The difference in detection of MMP species in the urine of the two types of cancers studied may serve as a tumor-specific fingerprint that can indicate both the presence of a tumor as well as its location. Increased levels of MMP-9 and MMP-2 in urine correlate with increased expression of these proteases in bladder tumor tissue as well. Urinary MMP-9 levels when combined with telomerase analysis of exfoliated cells from voided urine could also increase the sensitivity of cytology, a commonly used method for bladder cancer detection and monitoring. MMP-2 and MMP-9 have been studied as potential prognostic biomarkers of colorectal cancer. Enhanced MMP-9 staining in primary tumors was found to be an independent marker of poor prognosis in a study with T3-T4 node-negative patients. Plasma MMP-2 and MMP-9 levels were significantly elevated in patients with colorectal cancer and those with adenomatous polyps, and significant reduction in both were observed after tumor resections, suggesting their potential as markers for therapeutic efficacy. These MMPs may not be prognostic markers for tumor recurrence, however, since plasma proMMP-2 and -9 activities did not correlate with disease relapse after surgery. Tutton and colleagues investigated whether plasma MMP-2 and MMP-9 levels could be used as a surrogate for tumour expression in colorectal cancer patients and they found significant correlations between plasma levels and tumor pre- and post-op. MMP-2, -9, and -14 are among the most studied MMPs as biomarkers for ovarian cancer. MMP-9 activity in tissue extracts was significantly increased in advanced ovarian cancers (International Federation of Gynecology and Obstetrics stage III) compared with benign tumors and was found to be an independent prognosticator of poor survival. In another study of invasive epithelial ovarian cancer, high stromal expressions of MMP-9 and -14 were significantly correlated with cancer progression and were independent prognostic markers. Tissue MMPs have also been shown to distinguish different histotypes of ovarian cancer, which is a significant finding given that different histotypes have different prognoses. A recent study showed that more than 90% of clear-cell carcinomas expressed moderate to high levels of MMP-2 or MMP-14, compared with 30% to 55% of the other ovarian cancer histotypes (serous, endometroid, and mucinous), whereas MMP-9 was expressed more widely in other histotypes. Importantly, the cellular source of MMPs must be considered when evaluating MMPs as ovarian cancer biomarkers. For example, strong MMP-9 levels in cancer cells were associated with longer survival whereas strong stromal MMP-9 was associated with shorter survival, suggesting a dual role for MMP-9 during ovarian cancer progression. MMP-2, -9, -15, and -26 expression in tissue or serum have been positively correlated with Gleason score in prostate cancer. Among these MMPs, the activities of plasma MMP-2 and -9 increased significantly in metastatic prostate cancer. Analysis of MMP-2 and -9 levels in radical prostatectomy specimens revealed these two as significant predictors of cancer recurrence. These two enzymes may also be markers of therapeutic efficacy, since both the levels and activities of plasma MMP-2 and -9 decreased significantly in metastatic patients after therapy. In addition, increased urinary MMP-9 activity has been shown to distinguish between prostate and other types of cancer (e.g. bladder cancer). MMPs can also be combined with other markers to increase their predictive capability. For example, the mRNA ratio of gelatinases to E-cadherin in biopsy samples independently predicted prostate cancer stage. Elevated tissue levels of MMP-2 and MMP-9 have been reported in aggressive brain tumors. Both latent and activated forms of MMP-2 and MMP-9 have been detected in the cerebrospinal fluid of patients with brain tumors. In studies of primary glial tumors and other central nervous system tumors, we have recently shown that detection of MMP-2, MMP-9, MMP-9/neutrophil gelatinase-associated lipocalin complex, and/or vascular endothelial growth factor in the urine predicted disease status and therapeutic efficiency of patients with brain cancer. Importantly, these studies showed that the upregulation of MMP-2 and -9 in the source tumor tissue was also reflected in CSF as well as in urine of these patients. Tumor cells overexpress proteases and/or induce expression of these enzymes in neighboring stromal cells in order to degrade the basement membrane and invade the surrounding tissue. Several MMPs have been implicated in the ECM degradation associated with tumor growth and angiogenesis. This proteolytic activity is also required for a cancer cell to invade a nearby blood vessel (intravasation) and then extravasate at a distant location and invade the distant tissue in order to seed a new metastatic site. MMPs have been shown to promote angiogenesis through their release of angiogenic factors stored in the ECM such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF; 3). Stroma-derived MMP-9 can facilitate the liberation of ECM-sequestered VEGF during tumor angiogenesis. MMPs play complex and sometimes conflicting roles in regulating angiogenesis. Remodeling of the ECM during angiogenesis is accomplished largely through the activity of MMPs. Angiogenic mitogens, such as bFGF and VEGF, can stimulate the production of MMPs by capillary endothelial cells. Studies have also demonstrated that MMPs are involved in the angiogenic switch, one of the earliest stages of tumor growth and progression. It has been shown that MMP-9 can be a regulator of the angiogenic switch in a pancreatic tumor model, further confirming the pro-angiogenic role of MMPs. These findings strongly suggest that MMP activity is critical, not only to the initiation of angiogenesis, but to the maintenance of the growing vascular bed, which in turn supports tumor growth and metastasis. MMP activity can, however, result in the production of negative regulators of angiogenesis as well. ECM degradation products display unique biologic properties that can trigger a variety of cellular signals. MMPs have also been implicated in the epithelial to mesenchymal transition (EMT), a hallmark of cancer progression to metastasis. Activation of growth factors and cleavage of adhesion molecules are some of the proposed mechanisms underlying MMP-induced EMT. Recent studies point to an emerging role for MMPs in modulating aspects of immunity and inflammation during tumorigenesis. A variety of cytokines, cytokine receptors, and chemokines have been found to undergo MMP-mediated cleavage. In breast cancer, MMP-9 expression is upregulated in tumor-associated stromal cells including neutrophils, macrophages, and lymphocytes and may play a role in tumor-associated inflammation. Several members of the MMP and ADAM family can regulate cellular proliferation by modulating the bioavailability of growth factors or cell-surface receptors. Ligands for several growth factor receptors are processed by MMP/ADAM family members as well. There are known clinical benefits of MMP inhibition in cancer management (for example Neovastat (AstraZeneca) is currently under evaluation in phase II renal cell carcinoma). However, most MMP inhibitors are too toxic for use in the clinic and adverse effects of MMP inhibitors (e.g. musculoskeletal adverse effects) limit their use. Furthermore, there may be problems with potent, broad spectrum, MMP inhibition. For example, there are some data suggesting that tumour progression is inversely proportional to MMP-3. Accordingly, it is not known if MMP-3 sparing or MMP-3 inhibiting effects are preferable. Recent developments in anti-cancer agents targeting the matrix metalloproteinases have been reviewed (Li, et al., Recent Patents on Anti-Cancer Drug Discovery 2010, 5: 109-141) and show that MMP inhibitors are classified into three main pharmacologic categories: Collagen peptidomimetics, non-peptidomimetics and tetracycline derivatives. Collagen peptidomimetics can be further subdivided into hydroxamates, carboxylates, aminocarboxylates, sulfhydryls, phosphoric acid derivatives. Most MMP inhibitors in clinical development are hydroxamate derivatives, e.g. batimastat and marimastat, illomastat. The lead compounds have been largely unsuccessful because of toxicity and or lack of efficacy. For example, Batimastat can only be administered intraperitoneally and intrapleurally and further development has been suspended. In the case of Marimastat, no benefit over placebo was seen in patients with breast and lung cancer. Severe musculoskeletal pain occurred in 18% of patients and quality of life worsened with marimastat therapy. Development of this drug has also been discontinued. Several members of the non-peptidomimetics class of compounds are undergoing evaluation in Phase III studies in cancer patients. However, the majority are no longer in development because of an adverse efficacy/toxicity profile (including AG3340/Prinomastat (Agouron), BMS-275291 (Bristol-Myers-Squibb), CGS27023A/MMI270 (Novartis), Bay12-9566/Tanomastat (Bayer Inc). Neovastat/AE-941 (Aetherna Zentaris) has MMP-2, MMP-9 and VEGF inhibitory properties and is being evaluated as a potential treatment of renal carcinoma and Phase II clinical trials are underway. Some tetracycline derivatives, such as doxycycline and COL-3 have been evaluated in preclinical cancer models and G31 have entered early clinical trials in patients. Doxycycline has been shown to substantially reduce the tumor burden from breast cancer metastasis in nude mice. It exerts diverse inhibitor effects on MMP production and activity, inhibits tumor cell proliferation. However, it accumulates at high concentrations in bone, and can therefore be used for the treatment of bone metastasis. Inhibition of mitochondrial protein synthesis by doxycycline has significant anti-tumor effects in several tumor systems. Continuous doxycycline treatment combined with intermittent administration of adriamycin or 1-beta-D-arabinofuranosyl cytosine on the growth of rat leukemia resulted in the delay of tumor relapse. Treatment with zoledronic acid in combination with doxycycline may be very beneficial for breast cancer patients at risk for osteolytic bone metastasis, according to the fact that administration of a combination of zoledronic acid and doxycycline resulted in a 74% decrease in total tumor burden compared to untreated mice. In addition, doxycycline significantly enhances the tumor regression activity of cyclophosphamide, a widely used chemotherapeutic drug in neoplasias, on xenograft mice model bearing MCF-7 cells, suggesting that such combination chemotherapeutic regimen may lead to additional improvements in treatment of breast cancer. In vivo, the inhibitory effects of doxycycline on breast cancer tumor matastasis formation was potentiated by the addition of batimastat, confirming that targeting MMPs through multiple distinct pathways may improve treatment efficacy. However, in a Phase I evaluation of cancer patients, oral doses of 400 mg administered twice a day resulted in dose-limiting toxicity that consisted of fatigue, confusion, nausea, and vomiting. At the maximum tolerated dose of 300 mg twice a day, mean through plasma concentrations were comparable to those associated with antiangiogenic effect in vivo.
Nitric oxide is a gaseous molecule that is unsuitable for oral administration. However, there are several pharmacologically relevant nitric oxide-donor groups than are known to release nitric oxide in response to conditions found in the human body after administration. Exemplary nitric-donor groups are described in "Nitric Oxide Donors: For Pharmaceutical and Biological Applications"; Peng George Wang, Tingwei Bill Cai, Naoyuki Taniguchi, Wiley (2005), the contents of which are incorporated herein by reference. The effects of nitric oxide on MMPs are complex. Nitric oxide has been reported to possess inhibitory effects on MMP-9 by destabilization of MMP-9 RNA and through effects on MMP-9 activating cytokines, secondary messengers and transcription factors (AP-1). In contrast higher concentrations of nitric oxide have been shown to cause MMP activation through S-nitrosylation of an inhibitory cysteine on the prodomain.
Abbreviations: ALVDD=Asymptomatic left ventricular diastolic dysfunction, AUC=Area under the curve, cGMP=Cyclic guanosine monophosphate, DMSO=Dimethyl supfoxide, DNA=Deoxyribonucleic acid, ECM=Extracellular matrix, FCS=Fetal calf serum, HCF=Human ventricular cardiac fibroblasts, HF=Heart failure, HFpEF=Heart failure with preserved ejection fraction, IF=Interferon, iNOS=Inducible nitric oxide synthase, IQR=Interquartile range, MCP=Monocyte chemotactic protein, MMP=Matrix metalloproteinase, MRI=Magnetic resonance imaging, mRNA=messenger ribonucleic acid, NHP=Non-human primate, NO=Nitric oxide, PBMC=Peripheral blood mononuclear cells, PCR=Polymerase chain reaction, RAAS=Renin-angiotensin-aldosterone system, RNA=Ribonucleic acid, SEM=Standard error of the mean, TIMP=Tissue inhibitor of matrix metalloproteinase, TNFα=Tumor necrosis factor alpha.

Compounds for treatment of heart failure


A process is disclosed for making contact to differently doped regions in a semiconductor device which are disposed in a silicon substrate in different depths, a first region with a first dopant concentration and/or conductivity type and the smaller depth being disposed in a second region with a second dopant concentration and/or conductivity type and the greater depth, and a first metal layer being deposited on the first region. A second metal layer is deposited on a portion of the first metal layer, and the structure is subjected to a heat treatment in which contact is made to the first region through the first metal layer and to the second region through the first metal layer and the second metal layer.

Processes for making contact to differently doped regions in a silicon substrate of a semiconductor device where the doped regions are disposed at different depths in the silicon substrate, and the resulting semiconductor devices are well known in practice. In such processes and devices, the silicon substrate typically includes a first region with a first dopant concentration and/or conductivity type, disposed within a second region with a second dopant concentration and/or conductivity type where the second region extends farther into the silicon substrate than the more shallow first region. In order to make contact to both the regions, a metal layer is deposited on the shallow first region. Through a heat treatment process, contact is established between the shallow first region and the metal layer. To make contact to the more deeply located second region, an additional region is formed in the shallow first region. The additional region is connected to, and is of the same conductivity type as, the deeper second region. Thus, during the heat treatment, contact can also be made to the deeper second region through the metal layer. This process is used, for example, in the fabrication of DMOS transistors. In that case, the semiconductor substrate is lightly doped n-type, the deeper second region is lightly doped p-type, and the shallow first region is heavily doped n-type. To make reliable, low-resistance contact to the lightly p-type doped, second region, the contact region formed in the first region is heavily doped p-type. The formation of this heavily p-type doped region requires an additional masking step in which exact alignment is of great importance, for the position of the additional region determines the size of the remaining portions of the first region, and thus, the properties of the diode formed by this first region and the second region. Accordingly, the deposition of the additional region for making contact to the second region is a very critical step.
It is, therefore, the object of the present invention to provided an improved and simplified process for making contact to differently doped regions in a silicon substrate of a semiconductor device and a semiconductor device which results from such a process.

Process for making contact to differently doped regions in a semiconductor device, and semiconductor device


Test sockets, test systems, and methods for testing microfeature devices with a substrate and a plurality of conductive interconnect elements projecting from the substrate. In one embodiment, a test socket includes a support surface and a plurality of apertures in the support surface corresponding to at least some of the interconnect elements of the microfeature device. The individual apertures extend through the test socket and are sized to receive a portion of one of the interconnect elements so that the substrate is spaced apart from the support surface when the microfeature device is received in the test socket. In one aspect of this embodiment, the individual apertures have a cross-sectional dimension less than a cross-sectional dimension of the interconnect elements so that the apertures receive only a portion of the corresponding interconnect element.

Conventional microelectronic devices are manufactured for specific performance characteristics required for use in a wide range of electronic equipment. A microelectronic bare die, for example, includes an integrated circuit and a plurality of bond-pads and/or redistribution layer (RDL) pads electrically coupled to the integrated circuit. The bond-pads can be arranged in an array, and a plurality of solder balls can be attached to corresponding bond-pads to construct a "ball-grid array." Conventional bare dies with ball-grid arrays generally have solder balls arranged, for example, in 6×9, 6×10, 6×12, 6×15, 6×16, 8×12, 8×14, or 8×16 patterns, but other patterns are also used. Many bare dies with different circuitry can have the same ball-grid array but different outer profiles.
Bare dies are generally tested in a post-production batch process to determine which dies are defective. In one conventional test process, several bare dies are placed in corresponding test sockets of a test tray. FIG. 1 is a schematic side cross-sectional view of a typical test socket 20 carrying a bare die 60 in accordance with the prior art. The test socket 20 includes a body 22 having a recess 24 and a shelf 34 in the recess 24. The shelf 34 supports an outer perimeter region of the bare die 60, and solder balls 68 on the die 60 are positioned within an opening 36 defined by the shelf 34. The test socket 20 is movable relative to a tester interface 90 so that contacts 92 on the tester interface 90 can apply electrical signals to corresponding solder balls 68 for testing the bare die 60.
One problem with conventional test sockets is that debris can accumulate within the sockets, which damages and contaminates the bare dies. More specifically, particles and contaminants from other processes, such as chemical-mechanical planarization, vapor deposition, etc., may be carried to the test socket 20 on the bare dies. This debris can accumulate in the test socket and eventually scratch, impinge, pierce, contaminate and/or otherwise damage subsequent bare dies. For example, during processing, the test socket 20 illustrated in FIG. 1 can collect debris on the shelf 34, and when a bare die is placed into the socket 20, the debris can puncture the soft, protective coating on the surface of the die and damage its internal circuitry.
Another problem with conventional test sockets is that the solder balls may not be aligned with the test contacts. More specifically, if the profile of a bare die is slightly out of tolerance, the solder balls on the die may not align with the test contacts. In the test socket 20 of FIG. 1, for example, the die 60 is aligned with the tester interface 90 by positioning ends 65 of the die 60 against side surfaces 27 of the socket 20. As such, if the profile of the die 60 is out of specification, such as if the length L of the die 60 is too short, the solder balls 68 may not be aligned with the test contacts 92 and the die 60 may fail the test even though the die 60 otherwise functions properly.
Another drawback of conventional test sockets is that the sockets limit the space available on bare dies for ball-grid arrays. For example, because the shelf 34 of the test socket 20 of FIG. 1 supports the outer perimeter region of the die 60, the outer solder balls 68a must be spaced inward at least a distance S from the corresponding ends 65 of the die 60. The reduced area for solder balls is a significant problem on bare dies with small profiles or high solder ball counts.
Accordingly, there is a need for an improved test socket for carrying bare dies and other microelectronic devices.