Methods, transformation constructs, and transgenic animals for identifying anti-tumor agents and anti-tumor drug targets are described. The transformation constructs are used to generate transgenic animals that have altered expression of an oncogene or tumor suppressor gene in a target tissue that is dispensable for viability and reproduction. In some embodiments, the altered expression results in abnormal proliferation of the target tissue and normal proliferation in all other tissues. Anti-tumor drug targets can be identified by generating progeny of the transgenic animals that have mutations in various genes. Gene mutations that result in a specific reduction or killing of the target tissue are identified as possible anti-tumor drug targets and are further evaluated. Anti-tumor agents are identified that mimic the effect of the gene mutations that result in specific reduction of the target tissue. Alternatively, anti-tumor agents can be identified by administering various compounds directly to the transgenic animals, or their progeny, and selecting as putative therapeutic agents, compounds that result in target-tissue specific antiproliferation.

The invention concerns genetic engineering and screening methods useful for the identification of gene targets for anti-cancer agents.
Cancer is a complex and devastating group of diseases that kills one in five adults in developing countries. Although cancers arise from a wide variety of cells and tissues in the body, there are unifying features of this group of diseases. Cancer is predominantly a genetic disease, resulting from the accumulation of mutations that promote clonal selection of cells that exhibit uncontrolled growth and division. For example, by the time a tumor reaches a palpable size of about one centimeter, it has already undergone about thirty cell doublings, has a mass of approximately one gram, and contains about one billion malignant cells. The result of such uncontrolled growth of tumor cells is the formation of disorganized tissue that compromises the function of normal organs, ultimately threatening the life of the patient. Obviously, methods for prevention, early detection and effective treatment of cancer are of paramount importance.
The past twenty years of research on the mechanistic basis of carcinogenesis have resulted in a revolution in our understanding of the molecular nature of genetic changes that initiate tumor formation. Specific genes have been identified that are frequently mutated in tumor cells, many of which have been grouped into two main classes termed oncogenes and tumor suppressor genes. A few key genes have been identified that are very commonly mutated in a large number of different tumors, such as the oncogene ras and the tumor suppressor genes p53 and Rb. Furthermore, genes that are mutated in tumor cells tend to have functions that cluster in one of the following categories: DNA repair, chromosomal integrity, cell cycle control, growth factor signaling, apoptosis, differentiation, angiogenesis, immune response, and cell migration. Thus, it is clear that there are specific mutations in certain genes that distinguish cancer cells from normal cells.
Despite the fundamental significance of these discoveries, they have not been paralleled by the development of highly selective drugs to treat cancer. This lag in the development of practical therapeutic applications from these discoveries is due to several factors. An ideal chemotherapeutic must selectively kill or block the proliferation of tumor cells without having a deleterious effect on normal growing cells in the body. Most of the genetic alterations found in tumors cells that distinguish them from normal cells are either gain-of-function mutations in oncogenes, which result in increased expression or activity of the gene product, or loss-of-function mutations in tumor suppressor genes, which result in underexpression or lack of activity of the gene product. The protein products of oncogenes having gain-of-function mutations are technically difficult drug targets, due to the lack of effective strategies to selectively inhibit solely the excessive activity of the protein in tumor cells, without deleteriously affecting necessary levels of protein activity in normal cells. Conversely, tumor suppressor genes with loss-of-function mutations are also problematic as drug targets, as it is technically very difficult to develop small molecule drugs that restore the function of a missing or defective protein.
Thus, there is a need for systematic methods to identify highly selective drugs and their cognate targets for killing or inhibiting the proliferation of cancer cells by exploiting the specific genetic alterations that characterize tumor cells. Genetic screening in model organisms offers one possible solution to this challenge. Large-scale, systematic genetic screens in model organisms provide a technically feasible strategy for functionally analyzing nearly all genes and gene products within an organism that relate to a physiological process of interest, and are robust and efficient enough to identify extremely rare genetic mutations. This approach has been used routinely to dissect physiologically important pathways in a number of genetically facile species including the baker""s yeast Saccharomyces cerevisiae, the nematode Caenorhabditis elegans, the fruit fly Drosophila melanogaster, the zebrafish Danio rerio, and the mouse Mus musculus. With respect to using these model organisms for analyzing processes that relate to human disease, each model organism has its own advantages and disadvantages which generally reflect a balance of technical ease of manipulation versus direct relevance to human genetics and physiology. Factors affecting technical ease of use in each system include generation time, cost of growth and maintenance, genome size, and availability of tools for genetic engineering, mutagenesis, gene mapping, and gene cloning. Consequently, the unicellular yeast S. cerevisiae offers perhaps the greatest technical facility for genetic screens with a short generation time of only 2 hours, a haploid phase of the life cycle, and a small genome size less than {fraction (1/100)} that of human; however, this system suffers from the fact that baker""s yeast is a unicellular organism and many genes and pathways involved in intracellular communication, differentiation, and growth control in humans are completely absent in S. cerevisiae. Conversely, as a mammal the mouse is clearly the most similar model organism in genome organization and physiology to human, but suffers from that fact that growth, maintenance, and manipulation of mice is relatively cumbersome, time consuming and expensive. Accordingly, the invertebrate animal model organisms, C. elegans and Drosophila, have found favor for large scale genetic screens because they have provided an especially effective comprise between ease of manipulation and functional relevance to human physiology.
Beyond the issues of the technical feasibility of performing large scale genetic screens with model organisms, properly designed genetic screening strategies provide an efficient and logically rigorous method to identify ideal drug targets. Most drugs act by specifically inhibiting the activity of the target proteins with which they associate. And, most mutations generated by mutagenesis in genetic screens are loss-of-function mutations which reduce the expression or activity of the protein products of those genes. Thus, it follows that a loss-of-function mutation can be considered a surrogate for the effect of a drug that specifically inhibits the activity of the protein product of that gene; and further a loss-of-function mutation in a gene which produces a phenotype in vivo that mimics a desired therapeutic effect therefore identifies as a potential drug target the protein product of that mutant gene. So, the challenge in using genetic screens to identify novel drug targets for a particular disease is to carefully design the screen such that the desired loss-of-function mutations, which simulate the ideal therapeutic effect of a drug in vivo, can be readily and efficiently selected by virtue of a specific, easily scored phenotype.
In fact, large scale genetic screens in model organisms have been extensively employed to dissect genetic and biochemical pathways that relate to fundamental aspects of cancer biology. For example, genetic analysis of yeast has proven to be a very valuable approach to identify genes and proteins involved in DNA repair (Friedberg, Micrbiol Rev (1988) 52:70) and control of the cell cycle (Hartwell, J. Cell Biol. (1980) 85:811-822). Genetic analysis in the nematode C. elegans has led to important discoveries regarding growth factor signaling, for example through the ras pathway (Kayne and Sternberg, Curr Opin Genet Dev (1995) 5:38-43), and factors involved in controlling apoptosis (Ellis and Horvitz, Cell (1986) 44:817-829). Similarly, large scale genetic screens in the fruit fly Drosophila have also led to the discovery of novel components of cancer associated signal transduction pathways, including the ras (Karim et al., Genetics (1996) 143:315-329), notch (Go and Artavanis-Tsakonas, Genetics (1998) 150:211-220), dpp (Raftery et al., Genetics (1995) 139:241-254), and hedgehog (Hooper and Scott, Cell (1989) 59:751-765) pathways. Indeed, gene mutations in Drosophila that affect tumor formation in this simple invertebrate organism were identified as long as 80 years ago (Stark, J. Cancer Res. (1918) 3:279-299; Gateff and Schneiderman, Natl. Cancer Inst Monogr (1969) 31:365-397). The physiological relevance of Drosophila tumors to those of mammals has been convincingly demonstrated by studies of the lats tumor suppressor gene. Mutations in the lats gene in Drosophila were first discovered in genetic screens specifically designed to identify tumor suppressor-like genes in this organism (Xu et al., Development (1995) 117:1223-1237). In these studies, genetically mosaic Drosophila were generated containing clones of cells with homozygous mutations in the lats gene, and these clones of mutant cells were found to develop into large tumors. Most importantly, human and mouse homologs of the Drosophila lats gene were identified, and knockout mice genetically engineered to contain homozygous mutations in the Lats gene developed soft-tissue sarcomas, ovarian stromal cell tumors, hyperplastic changes in the pituitary, and were highly sensitive to carcinogenic treatments (St. John et al., Nat Genet (1999) 21:182-186) thereby validating the physiological relevance of tumor suppressor genes in Drosophila with counterparts in mammals. The technical obstacles posed by mammalian model systems such as the mouse have made it more costly and less practical to pursue large scale mutagenesis schemes by comparison with the simpler invertebrate organisms; nonetheless, recent progress has provided tools to perform in vivo mutagenesis in the mouse efficiently enough to enable phenotype-based genetic screens (McDonald, Proc Soc Exp Biol Med (1995) 209:303-308; Beddington, Curr Biol (1998) 8:R840-R842; Schimenti and Buchan, Genome (1998) Res 8:698-710). With respect to applications to cancer, a genetic screen in the mouse using the chemical mutagen ethylnitrosourea was used to identify a dominant mutation that predisposes to spontaneous intestinal cancer (Moser et al., Science (1990) 247:322-324). Subsequent characterization of this particular mutation revealed that the mutant mice contained a genetic lesion in the murine homolog of the human APC gene, a gene mutated in patients afflicted with familial adenomatous polyposis which predisposes to colorectal cancer, and which is also mutated in sporadic colorectal cancers (Su et al., Science (1992) 256: 668-670). As a further variation beyond ordinary phenotype-based forward genetic screening in the mouse, methods for genetic modifier screens have been proposed based on the identification of mutations that enhance or suppress a starting index phenotype of interest, such as modification of the predisposition to intestinal cancer caused by mutations in the murine homolog of the APC gene (U.S. Pat. No. 5,780,236).
Although all of the genetic screening approaches in model organisms described above have proven their utility in the context of basic research, it is significant to note that the general object of such screens is to systematically identify as many components as possible of biological pathways of interest, for example those biological pathways linked to cancer. Importantly, such screens are not designed to selectively identify genes encoding proteins having properties expected for ideal anti-cancer drug targets. Thus, much time and effort must be invested to carry out functional analysis and validation on the genes arising from such screens to identify those few which are most promising as practical drug targets. More recently, a type of genetic screen directly aimed at identifying drug targets for the treatment of cancer has been described (PCT WO9924603; Hartwell et al., Science (1997) 278:1064-1068; Friend and Oliff, New Eng. J. Med. (1998) 338:125-126). This directed genetic screen has been most well-defined in its application in the yeast S. cerevisiae, and is actually based on a well-established method in yeast genetics termed a xe2x80x9csynthetic lethal screenxe2x80x9d which has been commonly employed as a tool to investigate redundant genetic functions in yeast (Botstein, Harvey Lectures (1987) 82:157-167; Doye and Hurt, Trends Genet (1995) 11:235-241). As a directed strategy to identify anti-cancer drug targets using yeast genetics, the standard synthetic lethal screening strategy has been modified slightly by starting with a yeast strain that contains a primary mutation in a yeast gene that is homologous to a human or mammalian gene mutated in cancer cells, for example a mutant yeast strain modified in the DNA repair genes MLH1 or MSH2 (PCT WO9924603; Hartwell et al., supra). As a consequence, this variation of a synthetic lethal genetic screen specifically selects for secondary mutations which result in a lethal phenotype in yeast only in the context of a primary mutation within a yeast homolog of a human cancer-associated gene (such as MLH1 or MSH2), but not in the context of the wildtype form of the cancer-associated gene.
The underlying logic of using a synthetic lethal screen in yeast to identify anti-cancer drug targets is sound, but it poses serious limitations with respect to ultimate applicability to human cancer. In particular, homologs of many of the genes and pathways that are the most commonly mutated in human cancer are completely missing in yeast and are beyond the scope of these screensxe2x80x94including Rb, p53, growth factor signaling, and apoptosis pathways. It is these genes that clearly represent the most desirable starting points for such a screen as the resulting drug targets would have the broadest clinical applicability across different forms of cancer. The absence of these most common cancer associated genes and pathways in yeast reflects that fact that S. cerevisiae is a very simple unicellular organism. This leads to the question of whether the methods of the yeast synthetic lethal screen to identify anti-cancer drug targets can be directly transferred to a more complex multicellular metazoan animal, such as the nematode C. elegans, the fruit fly Drosophila or the mouse, where the common cancer-associated pathways are present. Unfortunately, this is not feasible as the yeast genetic screening method relies on plasmid manipulation techniques that are not applicable in metazoans. Also, the screening methods in yeast take advantage of the haploid life cycle in this organism, where there is just a single copy of each yeast gene, to efficiently identify genes where loss-of-function mutations would otherwise be recessive.
Although synthetic lethal genetic interactions have long been known in metazoan animal genetics (Dobzhansky, Genetics (1946) 31:261-290), a genetic screen based on identification of an organismal synthetic lethal phenotype would be extremely inefficient in metazoans, due to the inability to directly recover the secondary mutation from the dead animals for further analysis and characterization. As a result, other forms of genetic screens to selectively identify anti-cancer drug targets have been proposed for use in metazoans as substitutes for a true synthetic lethal screening strategy. Specifically, it has been suggested that a genetic modifier screen in Drosophila based on identifying mutations that act as enhancers of a rough eye phenotype induced by ectopic expression of dmyc (a homolog of the human myc oncogene) would be the xe2x80x9cconceptual equivalentxe2x80x9d of synthetic lethal mutations; hence, the genes having the enhancer mutations would have the properties of ideal anti-cancer drug targets (WO 99/24603). Actually, this is not the case; enhancer mutations arising from such a dmyc misexpression modifier screen would generally identify genes whose normal role is to down-regulate the activity of the dmyc pathway, and these enhancer mutations would not necessarily exhibit the desired property of a mutation in a gene encoding an ideal anti-cancer drug target, i.e. specifically killing or inhibiting the proliferation of only those cells were the dmyc oncogene is abnormally overexpressed.
In view of the foregoing, it is apparent that improved methods for identifying anti-cancer drug targets are highly desirable.
The invention provides highly selective methods for the identification of anti-cancer drug targets. One method comprises recombinantly modifying a non-human metazoan animal to mis-express a tumor gene or an oncogene (collectively referred to as xe2x80x9csensitizer genesxe2x80x9d) in a target tissue. Preferably the non-human animal is one that is commonly used in genetic studies (e.g. Drosophila, C. elegans, or mouse). The target tissue is dispensable for viability and reproduction of the animal. In some embodiments, mis-expression of the sensitizer gene results in abnormal proliferation of the target tissue, while non-targeted tissues of the recombinantly modified animal exhibit normal proliferation. Progeny of the recombinantly modified animal are generated that have mutations in putative xe2x80x9cinteractorxe2x80x9d genes that may result in sensitizer gene-specific antiproliferation or killing of the target tissue. The interactor gene mutations may be specifically targeted, for example using RNA interference to knock out gene function, or may be randomly generated using chemical, radiation, or transposon mutagenesis. Progeny are identified that have a reduction in size or absence of the target tissue, but have normal non-target tissues. These animals, which are said to exhibit sensitizer gene-specific antiproliferation phenotypes, are further evaluated to determine whether they have mutatations in interactor genes that cause the phenotype. Interactor genes and homologues and orthologs thereof, are isolated and used to identify anti-tumor compounds.
In an alternative embodiment of the invention, the recombinantly modified animals and their progeny are used to directly screen anti-tumor compounds. Test compounds are administered to the animals in varying doses. Compounds that cause a reduction in size of the target tissue and have no adverse effects on non-target tissues are further evaluated as putative anti-tumor compounds.
The invention also provides various novel transformation constructs that can be used to generate novel transgenic animals that have altered expression of a sensitizer gene in a target tissue. The constructs are diagrammed in FIGS. 2, 6, and 8, and are described in detail in the specification.
In another alternative embodiment of the invention, RNA interference (RNAi) is used in cell culture-based screens to identify interactor genes that exhibit sensitizer gene-specific antiproliferation phenotypes, or as confirmation screens of interactor genes identified in the progeny of the recombinantly modified animals.
The entire contents of all references, including patent applications, cited herein are incorporated by reference in their entireties for all purposes. Additionally, the citation of a reference in the preceding background section is not an admission of prior art against the invention described herein.

Methods for identifying anti-cancer drug targets


A method of analyzing a sample comprising directing a beam of light to a spot on the surface of a microarray treated with the sample using a digital micromirror device, and observing the SPR spectral shift due to a chemical binding event. The digital micromirror device can be, for example, that used in Digital Light Processing (DLP). Such a device can selectively place a pixel of light onto a microarray such that each spot can be observed at millisecond intervals and the whole microarray can be sequentially scanned over a relatively short period. The SPR spectral shift for each spot can be measured as a function of time, thus producing SPR detection of molecular binding in an array format.

All patents, patent applications, and publications cited within this application are incorporated herein by reference to the same extent as if each individual patent, patent application, or publication was specifically and individually incorporated by reference.
The invention relates to detecting molecular binding events as well as photochemical spectral emission and/or absorption in a two-dimensionally discriminated manner such as, for example, in an array. The observation of molecular binding and affinity is a key element in biochemical and pharmaceutical research and development and analytical assays. In this field, the use of arrays is desirable in order to increase assay throughput and decrease the amount of expensive reagents consumed. Microarray technologies are commonly used in fluorescence, electrochemical, and mass spectrometry analytical instruments. However, microarray technologies based on surface plasmon resonance (SPR), which is a powerful method used for the detection of molecular affinity and binding, have developed more slowly. Array capable SPR systems are being developed that observe the angular shift in SPR upon binding using a charge couple device (CCD) camera and dual angular goniometers. In this approach, the change in reflectivity of the SPR sensor surface during a binding event is observed using the CCD output, which can be displayed as video gray level. Unfortunately, the use of dual goniometers to adjust the system to the resonance condition angle as well as to the linear portion of the SPR curve can produce a cumbersome and costly instrument. The other method of observing SPR is by wavelength absorption spectroscopy. In this approach, a molecular binding event is observed by a wavelength shift of the SPR absorption maximum. The observation of spatially discriminated or array organized binding/affinity events can be achieved by monitoring the spectra displayed at each position of a two-dimensional matrix or grid. However, there is still a need for simpler SPR sensing methods and instruments that will allow wide deployment in bioanalytics, biopharmaceutics, and proteomics with relatively compact size at low cost.


An apparatus and process for detecting rotor position for improved motor start-up. The apparatus detects a target equilibrium position of the rotor using a fixed gain amplifier, window comparator and slope detector circuitry. The window comparator circuitry qualifies the peaks of the back EMF signal. Slope detector circuitry pinpoints the peak of the back EMF signal qualified by the window comparator. The technique utilizes the steps of energizing the phase windings of said motor, detecting the target equilibrium position, and then accelerating the motor through a commutation process.

Brushless DC motors generally include rotor position detectors, such as Hall sensors, positioned on the motor stator. Such devices sense the magnetic field of permanent magnets on the rotor as such magnets move over the sensors. By detecting the magnitude and polarity of the magnetic field, Hall sensors provide angular position information which is employed to switch current to the proper motor windings at the correct time through a process known as commutation. Such position information is critical for efficient motor start up in the desired direction. Failure to achieve start-up in the proper direction or to minimize reverse rotation of the rotor could cause damage to the heads when utilized in magnetic storage disc drive devices.
Motor construction typically includes a rotor formed of one or more pairs of magnetic pole pieces which rotate relative to a phase stator. Frequently, brushless DC motor construction consists of a three phase stator winding. Individual motor phases can be energized separately or in combination. The energizing of such phase or phases is typically predetermined. The resulting torque developed due to an electrical current in a motor winding is a function of the angular position of the rotor. Generally, the function can be approximated by a sinusoidal curve. Over one electrical cycle, one permanent magnetic pole pair, half of the torque developed is positive and the other half is negative. The magnitude and sign of the developed torque depends on the angular position of the rotor relative to the windings. Without rotor position information, maximum torque and correct rotation direction can not be guaranteed.
The requirement for smaller and lower cost brushless DC motors has required the removal of Hall or similar sensors from the motors. Reverse rotation of DC motors in disc drives can result in head or medium damage. Therefore, alternative methods are necessary for obtaining angular position for motor start up.

Apparatus and method for detecting rotor position in a sensorless and brushless DC motor


A laundry machine and a control method thereof are provided in which laundering ability may be improved while also improving efficiency and noise/vibration. The laundry machine employs a plurality of drum motions by varying drum rotational speed, drum rotational direction, and drum starting and stopping point, to provide different motion of laundry items in the drum.

1. Field
This relates to a laundry machine and a control method thereof.
2. Background
Laundry machines are machines which are typically used to wash and/or dry fabric articles. Laundry machines may include a drum rotatably installed in a cabinet, with the drum being configured to receive laundry items therein for treatment. In a top loading laundry machine, the drum may be oriented substantially vertically, with an opening at a top end thereof through which the laundry items may be received. In a front loading laundry machine, the drum may be oriented substantially horizontally, or at a slight incline, with an opening at a front end thereof through which the laundry items may be received. Movement of the drum and friction between the laundry items, wash water and wash agents, and the interior of the drum, may facilitate contaminant removal from the laundry items.


A circumcision clamp system and related methods of use. The clamp system includes an inner ring that is placed under the foreskin proximate to the corona of the glans penis, and an outer ring that clamps the foreskin against the inner ring. In an embodiment suitable for necrotic circumcisions, the inner and outer rings include one or more break-off sections that enable a clinician to adjust the diameter of the clamp accordingly. The inner ring includes a key and lock arrangement that ensures the inner ring maintains a circular shape by denying all degrees of freedom to the joined sections thereof. The outer ring includes a plurality of clamping members extending radially inward from an inner surface thereof. In some embodiments, the outer ring includes castellations that work in cooperation with longitudinal grooves in the inner ring to aid in suture placement.

1. Technical Field
The present disclosure generally relates to the field of circumcision, and more particularly, the present disclosure relates to apparatus and methods for reducing hemorrhaging, improving suture placement, and improving surgical outcomes during male circumcision procedures. Fixed size and adjustable size apparatus are presented with related methods of use.
2. Background of Related Art
The foreskin, or prepuce, is the retractable sheath of skin that covers the head, or glans, of a penis. The outside of the foreskin is a continuation of the skin on the shaft of the penis, while the inner foreskin includes mucous membrane, similar to the inside of the eyelid. Male circumcision is a procedure whereby the foreskin is removed, typically for health, religious, or cultural reasons.
Conventional circumcision may be performed by applying a local anesthetic to the penis, applying an appropriately-sized clamp to the foreskin, removing the foreskin using a scalpel or scissors, and suturing the wound. Alternatively, the foreskin may be clamped in a necrosing device such as a Shang Ring, whereby the foreskin is drawn over a first ring, a second ring is positioned on the foreskin outside the first ring, and the foreskin is crushed between the two rings, which in about a week results in necrosis of the foreskin. In each case, the penis must first be measured, or sized, to determine which diameter clamp to use during the procedure.
Conventional circumcision techniques may have drawbacks. In one respect, conventional devices require the practitioner to have considerable skill in order to avoid complications such as excessive hemorrhaging, infection, and/or permanent insult to the penis. In another respect, a variety of clamp sizes need to be inventoried to accommodate differently-sized penises. This may create logistical challenges, particularly in rural or remote regions where access to supply chains are limited. In another respect, necrotic techniques and clamps typically require a follow-up visit to a medical facility so that the device may be removed. The need for follow-up visits can be problematic in rural or remote areas, where lack of transportation, harsh terrain, or long distances may hinder or preclude a patient from returning to the doctor.

Clamp for male circumcision and related method of use


A method of making an electric lamp with high torque threaded base having lamp envelope, threaded base, and light source is disclosed. The electric lamp with high torque threaded base may be formed by making a lamp envelope with a ring of depressions extending around the lamp opening. A threaded brass base may then be rolled into the depressions, locking the threaded base to the lamp envelope. High temperature melting of the glass is then unnecessary, and expensive, or messy glues are unnecessary.

A few years ago, tungsten halogen technology was adapted for use in standard lamps. The new tungsten halogen standard lamps have an inner capsule that contains the tungsten halogen process, and an outer envelope that guards against possible non-passive fracture of the inner capsule, and shields the user from the high surface temperature of the inner capsule. The inner capsule is then mounted on a frame inside the outer envelope, with the frame acting as one of the electrical connections for the inner capsule. Tungsten halogen lamps can produce a higher quality light, be more efficient, and have a longer life than ordinary filamented lamps.
During assembly, the frame and inner capsule are inserted in the outer envelope, and the base is screwed on. The threaded base pinches the exterior arms of the frame against the envelope neck to make electrical contact and hold the frame in place. To make good electrical contact, and to ensure the base is not unthreaded, the frame to base contact has been made by a sharp point, aimed in the threading direction. As the base threads over the frame, the frame points dig progressively deeper into the base. In final position, the frame points are well embedded in the base, ensuring electrical contact, and are pointed against the unthreading of the base to prevent removal of the base. Because of variations in the pointed ends, the lengths of the frame components, molded glass dimensions and similar causes, the frame ends do not always contact the base equally. The frame can then be twisted in the outer envelope, leaving the inner capsule misaligned. This is a cosmetic problem. The misalignment can also be a mechanical problem. The misaligned inner capsule can knock against the outer envelope during shipment and break. The life of the inner capsule may also be affected by the irregular heat flow around the adjacent outer envelope. There is then a need for a support frame that consistently centers the inner capsule in the outer envelope.
The double envelope, tungsten halogen lamps are assembled by hand threading the base to the lamp neck. The torque characteristic of lamps with pointed frame ends is not a linear force, but is an increasing and perhaps even an accelerating force. The high torque need to thread the base to its final position may lead to injuries from repeated high stress of the assemblers, fingers, hands or wrists. By reducing the diameter of the support frame wire, the wire may be made more flexible, but a more flexible wire allows greater sway in the assembled lamp. Greater flexibility in the support frame is also likely to result in a bent, or distorted support frame. There is then a need for a double envelope electric lamp with a low assembly torque support frame for the internal capsule that is unlikely to sway or be distorted.
Standard lamps have frequently been sealed by cementing or epoxying the threaded metal base to the outer glass envelope. Fluid or paste glues and cements are not easy to work with in an assembly line operation. Inadequate gluing may occur, allowing the base to open. While excessive gluing may leave the lamps cosmetically unacceptable. Glues and cements are also usually relatively expensive materials. There is then a need for a method of coupling the metal base to the outer envelope of a capsule lamp without glue or cement.
The small portions of the threaded base have also been peened into slots formed in the lamp envelope in the past. Peening requires the lamp be properly oriented, so the peenings properly hit the preformed envelope slots. Alignment takes time, and machinery to properly execute the test. Peening regularly results in broken product, where the peening strike is excessive. Alteratively, using less peening force, yields lamps with bases that can come loose. There is then a need for a lamp with a mechanically sealed envelope and base, that does not use glue or cement.
Hand assembly of lamps does not usually lead to strong mechanical couplings between bases and envelopes. On the other hand, a lamp envelope, being made of glass is usually fragile, and a mechanical coupling made by a machine can lead to fracture of the lamp envelope, and wasted product. There is then a need for a machine made mechanical coupling between the outer envelope of a capsule lamp and a threaded metal base.
Examples of the prior art are shown by the following U.S. patents.
U.S. Pat. No. 3,194,625 issued to G. K. Danko on Jul. 13, 1965 for an Electric Lamp with Unitary inner Envelope and Stem Assembly and Manufacturing thereof shows a threaded base lamp with an internal capsule integral with an outer envelope. The threaded base is cemented to the outer envelope.
U.S Pat. No. 3,243,634 issued to F. A. Mosby on Mar. 3, 1966 for an Electric Lamp and Support Web shows a threaded base lamp with an internal capsule supported from the threaded base. The threaded base is cemented to the outer envelope with an epoxy.
U.S. Pat. No. 4,647,809 issued to R. G. Blaisdell et al. Mar. 3, 1987 for Electric Lamp with Self Mounting Frame Assembly and Method of Constructing Same, shows a threaded base lamp with an internal capsule. The internal capsule is supported on a wire frame that was spiked ends bent around the opening of the outer envelope. The threaded base is threaded to the outer envelope causing the spiked ends to be compressed and pointed into the base. The spikes then resist unthreading of the base from the outer envelope.
U.S. Pat. No. 4,959,583 issued to Vito J. Arsens et al on Sep. 25, 1990 for a Reflective Lamps Having An Improved Light Source Mounting Arrangement shows a threaded base lamp with an internal capsule. The threaded base is coupled to the outer envelope a high temperature resistive adhesive.

Method of making an electric lamp with a high torque threaded base


Differential amplifiers comprise a differential input stage, first, second, third, and fourth fixed current sources, a first resistive element, and a current-folding element. Due to topology thereof, the differential amplifier converts the difference between the input voltages to the voltage difference between the source voltages of the transistors in the differential pair, and a current is induced through the first resistive element, thereby generating two currents. The current-folding element folds the two currents to generate output voltages.

The invention relates to differential amplifiers, and more particularly, to differential amplifiers with a large and predictable linear gain over a wide input range.
Differential amplifiers are widely used in analog and digital circuits to amplify differential voltage between two input signals. Ideally, a differential amplifier amplifies only the difference between the input signals while rejecting common-mode input changes such as noise. Differential amplifiers have found important applications where signals are contaminated by noise. For example, digital signals transmitted over a long cable may pick up miscellaneous noise signals during the signal transmission. The differential amplifiers reject the noise signals while amplifying the digital signals, thereby leading to the recovery of the original signals.
Unfortunately, conventional differential amplifiers present several drawbacks. For example, fully differential amplifier circuits often suffer from limited linear operating ranges. As a result, the differential amplifier circuits can only receive a narrow range of input voltages to produce a linear output. If the input voltages venture outside of the narrow input voltage range, the differential amplifier circuits produce a non-linear output.
In addition, the gain of conventional differential amplifiers may vary in response to changes in temperature. This is because base-emitter voltages of individual transistors in the differential amplifiers are highly sensitive to temperature variation. Since base-emitter voltages affect the transconductance of a transistor, the gain of the differential amplifier may not be constant or linear when such temperature variation occurs. In such cases, the gain of the conventional differential amplifiers may not be predictable due to the temperature variations.
Furthermore, the conventional differential amplifiers may not provide sufficient gain for state of the art low current or low voltage applications. For example, such high speed analog or digital circuits often employ low currents and/or low voltages to speed operation of the circuit while reducing power requirements for continuously decreased die sizes. At such low currents and/or voltages, the conventional differential amplifiers may not provide enough gain to operate properly in high speed applications.
Thus, what is needed is a differential amplifier that provides a large and predictable linear gain over a wide input range.


Disclosed herein is a piezoelectric actuator drive system for forward or backward driving a piezoelectric actuator for zooming and/or focusing in a camera module. The piezoelectric actuator drive system comprises a power supply for supplying an operating voltage, a drive controller for controlling generation of a forward/backward drive signal for a piezoelectric actuator in response to an operation ON select signal and a forward/backward driving select signal, a clock generator for generating a first clock signal in response to the operating voltage from the power supply, and a drive signal generator for generating and supplying the forward or backward drive signal to the piezoelectric actuator in response to the first clock signal from the clock generator and the operating voltage from the power supply under the forward/backward drive signal generation control of the drive controller.

1. Field of the Invention
The present invention relates to a system for driving a piezoelectric actuator which is applied to a camera module of a mobile phone or the like for focusing and/or zooming therein, and more particularly to a piezoelectric actuator drive system which is capable of driving a piezoelectric actuator for zooming and/or focusing in a camera module forward or backward using a phase shift of two drive waves forming a drive signal, and selectively driving two such piezoelectric actuators, thereby reducing power consumption and improving efficiency.
2. Description of the Related Art
Generally, piezoelectric actuators are transducers that convert electrical energy into a mechanical displacement or stress using a piezoelectric effect. These actuators may be, for example, a motor for zooming and focusing in a camera module of a mobile phone or the like, a cylinder, etc.
The piezoelectric actuators are driven in various manners according to the purposes and methods of use of systems to which they are applied.
Recently, such a piezoelectric actuator has been applied to a small-size camera module of a mobile phone or the like for zooming and focusing therein, resulting in a need for a drive system to drive the actuator.
FIG. 1 is a circuit diagram of a conventional piezoelectric actuator drive circuit, which is denoted by the reference numeral 2.
In the conventional piezoelectric actuator drive circuit 2 shown in FIG. 1, the reference numeral 20 denotes an initial storage unit which stores energy to drive a piezoelectric actuator 3. The initial storage unit 20 is implemented with an inductor. The reference numeral 4 denotes a voltage detector which detects a voltage across the piezoelectric actuator 3 at a predetermined time after transfer of the energy stored in the initial storage unit 20 to the actuator 3. The reference numeral 5 denotes a storage controller which compares the voltage detected by the voltage detector 4 with a voltage desired for the piezoelectric actuator 3 and, on the basis of a result of the comparison, controls the amount of energy to be stored in the initial storage unit 20 in the next driving period such that the voltage detected by the voltage detector 4 is equal to the desired voltage in the next driving period.
In FIG. 1, when a switch SW1 is turned on, energy is stored in a primary coil L1 of a transformer in the initial storage unit 20. If the switch SW1 is turned off after the lapse of a certain time, the energy stored in the initial storage unit 20 drives the piezoelectric actuator 3, which is a capacitive element, through a secondary coil L2 of the transformer and a diode D2, thereby causing a voltage Vp to be generated across the actuator 3 and then maintained at a constant level after the lapse of a predetermined time.
When a switch SW2 is turned on after the lapse of the predetermined time, the energy stored in the piezoelectric actuator 3 is discharged, so that the voltage Vp drops to 0. While the voltage Vp across the piezoelectric actuator 3 is maintained at the constant level, the voltage detector 4 detects the voltage Vp and the storage controller 5 compares the detected voltage Vp with a voltage Va desired for the piezoelectric actuator 3. The storage controller 5 then determines the amount of energy for the next driving period according to a result of the comparison and then whether to make the ON time of the switch SW1 in the circuit of FIG. 1 longer or shorter than that in the previous driving period. As a result, the desired voltage Va is rapidly applied to the piezoelectric actuator 3 by repeating the driving operation a minimum number of times.
In other words, by detecting a voltage across the piezoelectric actuator 3 which is driven at intervals of the predetermined time and determining the amount of energy to be stored in the next driving period, it is possible to maintain the voltage across the actuator 3 at a constant level and cope with capacitive variation of the actuator 3.
Details of such a piezoelectric actuator drive circuit are disclosed in Japanese Patent Laid-open Publication No. Heisei 06-62585.
However, the aforementioned conventional piezoelectric actuator drive circuit is disadvantageous in that it cannot be applied for forward or backward driving of the piezoelectric actuator and cannot selectively drive two such piezoelectric actuators.


In an autogenous generator (1) in which electrical energy is generated by a linkage between fixed windings (2) and permanent magnets which move integrally on the alternating motion of one or more pistons of a two-stroke internal combustion engine, the cylinders (5) coupled to the pistons (4) have a conical precombustion chamber (10) opening towards the cylinders (5), the engine runs with variable compression strokes, and the magnets (3) and windings (2) are designed such that the ratio between the quantities of mechanical energy used to generate electrical energy for two different strokes of the magnets (3) is equal to the ratio between the two compression ratios obtained in the cylinders (5) in relation to the two different strokes performed by the pistons (4) integral with the said magnets (3) multiplied by the ratio between the two overall efficiency values of the engine in relation to the said compression ratios.

The present invention concerns the autogenous electrical energy generator sector, and more particularly generators in which the mechanical energy supplied by the alternating movement of pistons in an internal combustion engine without a crankshaft is transformed into an electrical current by the interaction of permanent magnets, integral with the aforesaid pistons, with fixed windings which are immersed cyclically in the magnet's magnetic field.
This type of generator is suitable for the production of electrical current which can then be used either directly, for example, for lighting or heating, as well as indirectly to supply electric motors that can be used for different types of locomotion on land, water, in the air or for other applications.
In any use, the generator is required to provide good performance in terms of output and adjustment with minimum environmental and noise pollution.


A method for making semicrown stacked capacitors for DRAM devices is achieved. A first insulating layer, a second insulating etch-stop layer, and a high-etch-rate third insulating layer are sequentially formed on a substrate over the memory cell areas having FETs with source/drain areas. Recesses are etched in the third and second insulating layers for bottom electrodes, aligned over device areas. Node contact openings are plasma etched in the first insulating layer exposed in the recesses to one of each source/drain area. A first polysilicon layer is deposited to form node contacts and the bottom electrodes. A high-etch-rate fourth insulating layer is used to fill the recesses. The fourth insulating layer and the first polysilicon layer are etched or chem/mech polished back to form the array of bottom electrodes having oxide plugs. The plugs and third insulating layer are wet etched to the etch-stop layer to form the semicrown bottom electrodes. A thin dielectric layer is deposited, and a patterned second polysilicon layer is formed for top electrodes. The etch-stop layer, retained in the final structure, supports the bottom electrodes to reduce mechanical damage during subsequent processing and to also reduce the nonuniformity across the substrate for an improved photolithographic process window.

(1) Field of the Invention
This invention relates to an integrated circuit semiconductor device, and more particularly to a method for fabricating an array of memory cells for dynamic random access memory (DRAM) devices with semicrown-shaped capacitors having increased capacitance.
(2) Description of the Prior Art
The integrated circuit density on chips formed on semiconductor substrates has dramatically increased in recent years. The increase in density is the result of scaling down the individual semiconductor devices built in and on the substrate.
One circuit type experiencing this demand for increased circuit density and the need for an essentially planar surface is the dynamic random access memory (DRAM) chip (or devices) made on a semiconductor substrate. The DRAM chip areas on the substrate consist of an array of closely spaced memory cells with address and read/write circuits along the periphery of the chip. Currently in production there are 64 million memory cells on a DRAM chip with minimum features sizes less than a half micrometer. The individual memory cells are formed from a single access transistor, typically a field effect transistor (FET), and a storage capacitor with a node contact to one of the two source/drain areas of the FET. The capacitor is used for storing information in binary form (0's and 1's) as electrical charge, and the second source/drain area is connected to a bit line that is used to read and write information via peripheral circuits on the DRAM chip. Word lines that also form the FET gate electrodes are used to randomly access (address) the individual memory cells.
Both trench capacitors formed in the substrate and stacked capacitors formed on the substrate surface over the FET are currently being pursued for DRAM applications. However, the stacked capacitor has received considerable attention in recent years because of the various ways its shape can be changed in the vertical direction to increase capacitance without increasing the area it occupies on the cell area. However, as the cell density increases and the cell size shrink to accommodate more cells, it is necessary to increase the vertical dimension of the stacked capacitor. This is to provide sufficient capacitance to maintain the necessary charge for acceptable sign-to-noise levels and to provide a reasonable refresh cycle times.
Unfortunately, as the stacked capacitors are increased in height the topography across the chip becomes rougher, and the problem associated with reliably exposing the photoresist and etching high-aspect-ratio patterns in the material layers are made more difficult. Although the spaces between the closely spaced capacitors in the memory cell area can be easily filled with an insulator to provide a relatively planar surface, the topography at the perimeter of the array cell near the periphery of the chip can be considerably greater than 1.0 micrometer in height. Another problem is when freestanding bottom electrodes are formed, subsequent processing, such as cleaning and the like, can result in mechanical damage.
Numerous methods for making the stacked capacitors are described in the literature. One approach to forming stacked capacitors is described by Kim et al., U.S. Pat. No. 5,444,005. The method shows a sequence of process steps for forming a multiwalled cylindrical freestanding bottom electrode using multiple sidewall spacers. Another approach for making stacked capacitors is described by Liaw et al. in U.S. Pat. No. 5,543,345, which also uses sidewall spacers for forming freestanding sidewalls for the bottom electrode of a crown capacitor. Still another approach is described by Tseng in U.S. Pat. No. 5,604,146 for an E-shaped crown capacitor using sidewall spacers and a second photoresist mask to etch freestanding bottom electrodes. Dennison et al., U.S. Pat. No. 5,270,241, show a method for forming container stacked capacitors in the node contacts etched in an insulating layer. The insulating layer is then partially etched back, without an etch-stop layer, to leave portions of the insulating layer as a protective layer over the underlying devices.
There is still a need in the semiconductor industry to develop a method for making stacked capacitors that are less susceptible to mechanical damage. There is also a need to provide a process that forms a more planar surface over the substrate for improved high-resolution lithography and residue-free anisotropic etching.

Method of forming semicrown-shaped stacked capacitors for dynamic random access memory

Vanguard International Semiconductor Corporation


An instrument for surface analysis includes a gun for selectively focusing an electron beam on an anode spot, or rastering the beam across an array of such spots, to generate x-rays. A concave monochromator focuses an energy peak of the x-rays to a specimen surface, in a spot on a selected pixel area or across an array of pixel areas on the surface to emit photoelectrons. An analyzer with a detector provides information on the photoelectrons and thereby chemical species in the surface. A second detector of low energy photoelectrons is cooperative with the rastering to produce a scanning photoelectron image of the surface, for viewing of a specimen to be positioned, or for imaging an insulator surface. The monochromator is formed of platelets produced by cutting an array of platelets from a single crystal member, and bonding the platelets to a concave face of a base plate juxtaposed in crystalline alignment in a positioned array identical to that of the initial array.

A variety of electron microscopes and associated surface analyzers have evolved in recent years. One approach to chemometric surface analysis is electron spectroscopy for chemical analysis (ESCA) which involves irradiating a sample surface with ultraviolet or preferably x-rays and detecting the characteristic photoelectrons emitted. The latter method is also known as x-ray photoelectron spectroscopy (XPS). The photoelectrons are filtered by an electrostatic or magnetic analyzer which allow only electrons of a specified narrow energy band to pass through to a detector. The intensity of the detected beam typically represents the concentration of a given chemical constituent on or near a specimen surface. U.S. Pat. No. 3,766,381 (Watson) describes such a system, including an electrostatic hemispherical type of analyzer.
Another method for analyzing surfaces utilizes secondary Auger electrons generated at a small area of sample surface by a focused primary electron beam. Surface mapping of elements is accomplished by scanning with the primary electron beam. An example of a scanning Auger microprobe utilizing a cylindrical type of electrostatic electron analyzer is provided in U.S. Pat. No. 4,048,498 (Gerlach et al).
A more commonly known instrument is a scanning electron microscope (SEM) in which a focused electron beam is rastered over a surface. Secondary electrons emitted from the surface are detected in correlation with rastering positions. The secondary electron signals are processed electronically to provide a picture or image of topographical features of the surface. An SEM itself does not provide chemometric analysis. Another limitation of the SEM is imaging the surface of some insulators, because of rapid charge buildup from the incident beam of electrons. Conductive coatings or other techniques are used to alleviate charging, but at the loss of surface details, time and cost of extra preparation, and loss of ability to remove surface layers during analysis. U.S. Pat. No. 5,118,941 (Larson) discloses that insulator specimens can be imaged with a single frame of SEM rastering, but at the expense of resolution.
The latter patent also discloses a system for locating target area for microanalysis of a specimen surface, using an SEM in conjunction with the microanalyzer. Backscattered electrons from the SEM electron beam are passed through the analyzer for producing a further image that is superimposed on the SEM image, such that the further image represents the target area for microanalysis.
Thus systems involving electron beam impingement on a specimen surface have evolved into high sensitivity instruments, in which very small areas may be selected for analysis. Rastering can be used to provide images or chemical mapping of the surface. However, similar small-area sensitivity and raster mapping has been elusive for x-ray photoelectron spectroscopy (XPS).
X-rays from an anode target have been focused onto the specimen by means of a concave crystal monochrometer, as taught in U.S. Pat. Nos. 3,567,926 (Siegbahn) and 3,617,741 (Siegbahn et al).
A method of construction of a concave monochrometer for focusing x-rays is disclosed in U.S. Pat. No. 3,772,522 (Hammond et al), in which a quartz crystal disk is brazed with a metal film onto a concave spherical surface of a substrate. Because of a tendency of the disk to break during mounting to the curvature, a number of platelets may be bonded to the surface, for example in a monochrometer used in a PHI model 5600 instrument sold by Perkin-Elmer. Bonding techniques include brazing, optical contacting, epoxy and the like. The platelets are cut sequentially from the end of a single crystal rod of quartz.
A second approach to reduced area analysis has been to use an x-ray beam that floods the specimen surface, combined with a small-area objective lens for the photoelectrons, such as taught in U.S. Pat. No. Re. 33,275 (Wardell et al) for an electrostatic objective lens. Direct XPS imaging of a surface flooded with x-rays, using a type of magnetic lens variously known as an immersion lens, single pole piece lens or snorkel lens, is taught in U.S. Pat. Nos. 4,810,880 (Gerlach) and 4,810,879 (Walker).
Scanning for XPS may be effected by rastering the sample or the lens mechanically, which is cumbersome. Scanning is also achieved by electronic deflection in the objective lens to receive electrons from off-axis, in a manner as described in an article "A Wide-angle Secondary Ion Probe for Organic Ion Imaging" by C.C. Grimm, R.T. Short, and P.J. Todd, J. Am Soc. Mass. Spectrum 1991, 2, 362-371. Such scanning for photoelectrons is disclosed in an article "AXIS: An Imaging X-Ray Photoelectron Spectrometer" by I.W. Drummond, F.J. Street, L.P. Ogden, and D.J. Surman, SCANNING 13, 149-163 (March-April 1991).
A more precision type of x-ray microscope utilizes zone plates and mirror techniques. This requires a very intense source of x-rays such as from a synchrotron, and so is not practical for general use.

Scanning and high resolution x-ray photoelectron spectroscopy and imaging


The level of the harmonics of oscillation signals for synchronous detection to be inputted to a mixer circuit for converting frequencies is suppressed low. A first integrated circuit component formed with a first mixer circuit for converting frequencies; a second integrated circuit component formed with a second mixer circuit for synchronously detecting intermediate frequency signals and an oscillator transistor circuit; a resonant circuit coupled to the oscillator transistor circuit and forming an oscillator circuit for synchronous detection; an intermediate frequency tuning circuit interposed between the first mixer circuit and the second mixer circuit; and a circuit board for mounting the first integrated circuit component, the second integrated circuit component the intermediate frequency tuning circuit and the resonant circuit in a predetermined block area are provided, wherein the resonant circuit is mounted on the side opposite to the side where the first integrated circuit component and the intermediate frequency tuning circuit are mounted as the second integrated circuit component is sandwiched.

1. Field of the Invention
The present invention relates to a television tuner, particularly to a television tuner in which mutual interference is reduced between circuits to be mounted on a circuit board.
2. Description of the Related Art
In regard to a traditional television tuner, the layout of circuit components to be mounted on a circuit board is shown in FIG. 3. FIG. 3 is a plan view illustrating the inside of a television tuner, depicting a circuit board 32 mounted in a rectangular frame 31 and the layout of circuits disposed on the circuit board 32. The frame 31 is formed of a first side plate 31a bent in a horseshoe shape and a second side plate 31b for connecting two sides facing each other in the first side plate 31a in which the circuit board 32 is mounted in the rectangular area surrounded by the two side plates 31a and 31b. Then, a connector 33 for taking in television signals is mounted on the first side plate 31a, and a plurality of terminals 34 to be connected to the circuit board 32 is mounted on the second side plate 31b.
The circuit board 32 is separated into three block areas 32a, 32b and 32c as shown in the drawing, and shield plates, not shown, are erected along the borders (indicated by dotted lines) between the block areas adjacent to each other. Then, an input tuning circuit (not shown) is formed in the first block area 32a disposed on the connector 33 side, and a high frequency amplifier circuit and an interstage tuning circuit (both not shown) are formed in the second block area 32b disposed inbetween. In addition, an intermediate frequency circuit for converting the inputted television signals to intermediate frequency signals and for detecting intermediate frequency signals is formed in the third block area 32c most separated from the connector 33.
The intermediate frequency circuit has the configuration as shown in FIG. 4, and a first oscillation signal is fed from a first oscillator circuit 42 to a first mixer circuit 41 for converting frequencies. The first oscillator circuit 42 is formed of a first oscillator transistor circuit 42a and a first resonant circuit 42b coupled thereto. Then, the first mixer circuit 41 and the first oscillator transistor circuit 42a are formed in a first integrated circuit component 40. An intermediate frequency tuning circuit 43 is connected to the subsequent stage of the first mixer circuit 41, and an intermediate frequency amplifier circuit 44 is connected to the subsequent stage of the intermediate frequency tuning circuit 43. The intermediate frequency amplifier circuit 44 is also formed in the first integrated circuit component 40. A SAW filter 45 is connected to the subsequent stage of the intermediate frequency amplifier circuit 44.
A second mixer circuit 47 for synchronous detection is connected to the subsequent stage of the SAW filter 45. A second oscillation signal is fed to the second mixer circuit 47 from a second oscillator circuit 48. The second oscillator circuit is formed of a second oscillator transistor circuit 48a and a second resonant circuit 48b connected thereto. Among them, the second oscillator transistor circuit 48a is formed in a second integrated circuit component 46 along with the second mixer circuit 47.
And, when a television signal to be received is inputted to the first mixer circuit 41, it is mixed with the first oscillation signal outputted from the first oscillator circuit 42 and converted to an intermediate frequency signal. The intermediate frequency signal is inputted to the second mixer circuit 47 through the intermediate frequency tuning circuit 43, the intermediate frequency amplifier circuit 44 and the SAW filter 45. Then, it is mixed with a second oscillation signal (the same frequency as a video intermediate frequency in an intermediate frequency band) outputted from the second oscillator circuit 48 and is synchronously detected to obtain a video signal.
Next, the detailed layout of the intermediate frequency circuit formed in the third block area 32c will be described. The third block area 32c has a nearly square shape, and the first integrated circuit component 40 and the second integrated circuit component 46 are disposed in small areas diagonally splitting the square area. Additionally, the first resonant circuit 42b is formed adjacent to the first integrated circuit component 40, and the second resonant circuit 48b is formed adjacent to the second integrated circuit component 46. Furthermore, the intermediate frequency tuning circuit 43 is formed in the area between the area formed with the first integrated circuit component 40 and the area formed with the second resonant circuit 48b, and the SAW filter 45 is formed in the area between the area formed with the second integrated circuit component 46 and the area formed with the first resonant circuit 42b. The first resonant circuit 42b, the second resonant circuit 48b and the intermediate frequency tuning circuit 44 are formed of components such as coils and condensers, and these components are mounted on the circuit board 32.
Power source voltage is fed to the first integrated circuit component 40 and the second integrated circuit component 46 by a power supply line 49 made of a conductor formed on the circuit board 32. A terminal 34a applied with the power source voltage is disposed at the position corresponding to the second block area 32b. On this account, a common power supply line 49a connected to a terminal 34a is disposed from the second block area 32b to the third block area 32c, and is connected to two power supply lines 49b and 49c in the third block area 32c. The power supply line 49b, one of them, is disposed between the area formed with the intermediate frequency tuning circuit 43 and the area formed with the second resonant circuit 48b, and the power supply line 49c, the other of them, is disposed in the area opposite to the power supply line 49b as the second resonant circuit 48b is sandwiched. Then, current is fed to the first integrated circuit component 40 through the power supply line 49b, one of them, and is fed to the second integrated circuit component 46 through the power supply line 49c, the other of them.

Television tuner having level of harmonics of oscillation signal suppressed low


A system includes a semiconductor substrate having a first cavity. The semiconductor substrate forms a pedestal adjacent the first cavity. A device overlays the pedestal and is bonded to the semiconductor substrate by metal within the first cavity. A plurality of second cavities are formed in a surface of the pedestal beneath the device, wherein the second cavities are smaller than the first cavity. In some of these teachings, the second cavities are voids. In some of these teachings, the metal in the first cavity comprises a eutectic mixture. The structure relates to a method of manufacturing in which a layer providing a mask to etch the first cavity is segmented to enable easy removal of the mask-providing layer from the area over the pedestal.

For many instances of semiconductor manufacturing, and particularly in the manufacture of micro-electromechanical systems (MEMS), it is desirable to bond a separately manufactured device to a semiconductor substrate. MEMS are used in a wide range of applications. For example, MEMS are found in hand held devices (e.g., accelerometers, gyroscopes, digital compasses), pressure sensors (e.g., crash sensors), micro-fluidic elements (e.g., valves, pumps), optical switches (e.g., mirrors), and light detection and ranging (LiDAR).

Segmented pedestal for mounting device on chip

Taiwan Semiconductor Manufacturing Company, Ltd.


A composition and method of cancer chemoprevention is disclosed. The composition and method utilize resveratrol as a cancer chemopreventative agent in mammals, including humans.

Cancer claims over six million lives each year worldwide and is the largest single cause of death in both men and women. Extrinsic factors, including personal lifestyles, play a major role in the development of most human malignancies. Cigarette smoking, consumption of alcohol, exposure to synthetic and naturally occurring carcinogens, radiation, drugs, infectious agents, and reproductive and behavioral practices are widely recognized as important contributors to the etiology of cancer.
A surprising conclusion is that the human diet plays a causative role in more than one-third of human neoplasia. However, the human diet not only contains numerous mutagens and carcinogens, but also contains a variety of chemicals that block carcinogenesis in animal models. Chemoprevention, i.e., the prevention of cancer by ingestion of chemical agents that reduce the risk of carcinogenesis, therefore, is one of the most direct ways to reduce cancer-related morbidity and mortality. See, M. B. Sporn, Fed. Proc., 38, 2528 (1979).
Dietary modifications can modulate cancer risk in various ways. For example, changes in caloric intake, altering the consumption of nutritive and nonnutritive diet components, and providing exposure to numerous minor chemicals that may be genotoxic or protective can increase or decrease the risk of cancer. Modifying the human diet to reduce the risk of cancer requires the identification of dietary carcinogens and chemopreventatives, even though interactions between the factors that modulate cancer risk are complex. Whereas extensive efforts have been made to identify dietary carcinogens and mutagens, the identification of chemopreventative agents has received less attention.
Cancer chemopreventive agents include nonsteroidal antiinflammatory drugs (NSAIDs), such as indomethacin, aspirin, piroxicam, and sulindac, all of which inhibit cyclooxygenase, abbreviated hereafter as COX. A COX inhibitory activity is important in cancer chemoprevention because COX catalyzes the conversion of arachidonic acid to proinflammatory substances, such as prostaglandins, which can stimulate tumor cell growth and suppress immune surveillance. O. J. Plescia et al., Proc. Natl. Acad. Sci. U.S.A., 72, 1848 (1975), and J. S. Goodwin, Am. J. Med., 77, 7 (1984). In addition, COX can activate carcinogens to forms that damage genetic material. T. V. Zenser et al., J. Pharmacol. Exp. Ther., 227, 545 (1983), and D. Wild et al., Carcinogenesis, 8, 541 (1987).
There is a need in the art, therefore, for the identification of specific compounds that have a cancer chemopreventative effect on mammals. Such cancer chemopreventative compounds then can be used in drug compositions or as food additives to reduce the risk of cancer.
Investigators have searched for new cancer chemopreventative agents by evaluating hundreds of plant extracts for a potential to inhibit COX. An extract derived from Cassia quinquangulata Rich. (Leguminosae) was identified as a potent COX inhibitor, and on the basis of bioassay-guided fractionation, resveratrol (i.e., 3,5,4'-trihydroxy--transstilbene) was identified as the active compound. See, E. Mannila et al., Phytochemistry, 33, 813 (1993), and G. S. Jayatilake et al., J. Nat. Prod. 56, 1805 (1993).

Cancer chemopreventative composition and method


A lithographic apparatus is disclosed. The apparatus includes an illumination system that provides a beam of radiation, and a support structure that supports a patterning structure. The patterning structure is configured to impart the beam of radiation with a pattern in its cross-section. The apparatus also includes a substrate support that supports a substrate, a projection system that projects the patterned beam onto a target portion of the substrate, and a debris-mitigation system that mitigates debris particles which are formed during use of at least a part of the lithographic apparatus. The debris-mitigation system is arranged to apply a magnetic field so that at least charged debris particles are mitigated.

1. Field of the Invention
The present invention relates to a lithographic apparatus having a debris-mitigation system, a source for producing EUV radiation having a debris mitigation system, and a method for mitigating debris.
2. Description of Related Art
A lithographic apparatus is a machine that applies a desired pattern onto a target portion of a substrate. Lithographic apparatus can be used, for example, in the manufacture of integrated circuits (ICs). In that circumstance, a patterning device, such as a mask, may be used to generate a circuit pattern corresponding to an individual layer of the IC, and this pattern can be imaged onto a target portion (e.g. comprising part of, one or several dies) on a substrate (e.g. a silicon wafer) that has a layer of radiation-sensitive material (resist). In general, a single substrate will contain a network of adjacent target portions that are successively exposed. Known lithographic apparatus include so-called steppers, in which each target portion is irradiated by exposing an entire pattern onto the target portion in one go, and so-called scanners, in which each target portion is irradiated by scanning the pattern through the projection beam in a given direction (the "scanning"-direction) while synchronously scanning the substrate parallel or anti parallel to this direction.
During use of at least a part of the lithographic apparatus, debris particles may be formed within the lithographic apparatus, for example, when radiation sensitive material is removed from the substrate. However, this is not the only process which may give rise to the production of debris particles. For the generation of EUV radiation, usually an object (or gas) is heated by means of high current pinching or by a laser source of high energy density, for example, of at least 1011 W/cm2, to create a plasma. EUV radiation is produced and undesired particles are released. Also, during production of EUV radiation, which, within the lithographic apparatus is used for providing a projection beam of radiation, debris particles may be produced as a by-product.
The term "debris particles" is meant to encompass particles which are thus formed as a by-product and which need to be mitigated. Debris particles may comprise electrons, ionized particles or neutral particles. The debris particles may have a size in a range varying from the size of an electron towards the size of a micro sized particle. The particles may be part of a plasma and may, within the plasma-environment, comprise fast or slowly moving particles.
These debris particles may have a detrimental effect on the performance of the lithographic apparatus as these debris particles may collect on, for example, optical elements. The debris particles present on these optical elements may hinder the reflection or transmission of the radiation beam. Debris particles with relatively high kinetic energy may even cause serious damage to the apparatus by, for example, etching the optical elements which are, incidentally, very expensive and very crucial parts of the apparatus. Particles present on, or etching surfaces of optical elements may also cause the radiation to be directed in an inaccurate manner, leading to poorly defined features produced on a substrate exposed to the radiation, hence, a need for mitigating debris particles.
The term "mitigating" is meant to encompass any manipulation of the debris particles which may lead to, at least, a reduction of the detrimental effect on the performance of the lithographic apparatus, a reduction of the damage to the lithographic apparatus, or both.
The invention is in particular related to a lithographic apparatus comprising: an illumination system for providing a projection beam of radiation; a support structure for supporting a patterning device, the patterning device serving to impart the projection beam with a pattern in its cross-section; a substrate table for holding a substrate; a projection system for projecting the patterned beam onto a target portion of the substrate; and a debris-mitigation system for mitigating debris particles which are formed during use of at least a part of the lithographic apparatus.
Such a lithographic apparatus is described in WO 99/42904. The debris-mitigation system known from this prior art comprises a filter, in particular a so-called foil trap, which may comprise a plurality of foils or plates which capture the debris particles. The plates or foils are as much as possible oriented parallel to a radiation path so that radiation will pass through the filter.
Although the foil trap is useful, a lithographic apparatus with an additional or alternative debris-mitigation systems is required to, for example, improve the efficiency of the debris-mitigation system, the flexibility in application of a debris-mitigation system and/or allow for more freedom in the design of a lithographic apparatus. It should be understood that charged particles may also be formed from neutrals which are being ionized during mitigation.

Lithographic apparatus having a debris-mitigation system, a source for producing EUV radiation having a debris mitigation system and a method for mitigating debris


A rubber composition including one or more bismaleimides and/or organothiosulfates, while at the same time having a reduced amount of sulfur, provides for excellent final rubber vulcanizate physical properties, including improved adhesion to metal reinforcement. The composition may be used to form several products, for example, coated metal, coated wire, coated cord, tires, hoses, belts, and shoe soles.

Developing rubber compounds containing high sulfur levels has been a serious problem for the rubber industry, and one which has received a great deal of attention. Problems attributable to high levels of sulfur in the rubber include migration of the sulfur to the surface of the rubber stock, commonly referred to as "bloom", which causes decrease of tack at the surface of the rubber stock.
Compounds containing high sulfur levels can exhibit problems with sulfur bloom on the surface of the unvulcanized rubber. This surface layer of sulfur crystallizes, causing a loss of building tack which can cause problems in tire building, such as decreased calendar speed and problems in storage of components.
Numerous modifications of standard rubber processing techniques have been utilized to minimize the sulfur bloom tendencies. These prior methodologies include: the use of insoluble sulfur in the compound; limiting the compound mixing temperatures during the sulfur addition stage; and minimizing the heat history that the compound is exposed to during processing. However, these modifications have led to mixed results.
For example, insoluble sulfur is formed by rapidly quenching molten sulfur that is above 159° C. (preferably 200 to 250° C.), and consists primarily of long chain sulfur molecules and a lesser amount of soluble S8 rings. But there is a tendency for the long chain molecules to revert to the more stable soluble form if exposed to higher temperatures, long storage times, and/or hostile storage environments. To reduce this tendency, commercial insoluble sulfur products contain a stabilizer.
When insoluble sulfur is mixed in a rubber compound, it exists as more or less discreet particles of varying size in the rubber phase. However, above about 118° C., substantial reversion to the soluble sulfur form occurs, thereby resulting in sulfur bloom.
Another approach to the sulfur bloom problem has been to use a low-sulfur rubber compound. Low-sulfur rubber compounds may be obtained by use of suitable sulfur vulcanizing agents, for example, elemental sulfur (free sulfur), optionally in combination with a sulfur donating vulcanizing agent, for example, an amine disulfide, polymeric polysulfide, or sulfur olefin adducts. However, with this approach, adhesion of the rubber compound to reinforcement such as steel wire, steel cord, or the like may be compromised.
Accordingly, there is a need for a rubber composition in which sulfur bloom, and the resulting loss of surface tack, is reduced or avoided over a wider temperature range, without compromising adhesion of the rubber compound to a reinforcement material.

Rubber compound containing an organothiosulfate and a bismaleimide


A capacitive component region is formed below a temperature detecting diode or below a protective diode. In addition, the capacitive component region is formed below an anode metal wiring line connecting the temperature detecting diode and an anode electrode pad and below a cathode metal wiring line connecting the temperature detecting diode and a cathode electrode pad. The capacitive component region is an insulating film interposed between polysilicon layers. Specifically, a first insulating film, a polysilicon conductive layer, and a second insulating film are sequentially formed on a first main surface of a semiconductor substrate, and the temperature detecting diode, the protective diode, the anode metal wiring line, or the cathode metal wiring line is formed on the upper surface of the second insulating film. Therefore, it is possible to improve the static electricity resistance of the temperature detecting diode or the protective diode.

In the related art, a semiconductor device has been known which includes a diode as an overheat protection function in order to prevent the thermal breakdown of a MOS (metal-oxide film-semiconductor insulated gate) semiconductor element, such as a metal oxide semiconductor field effect transistor (MOSFET) or an insulated gate bipolar transistor (IGBT). Specifically, in order to protect the MOS semiconductor element from overvoltage, a plurality of diodes or bidirectional diodes are provided between the gate and the source or between the gate and the drain.
As the MOS semiconductor device according to the related art which includes the temperature detecting diode, a device has been proposed in which a capacitor is formed so as to overlap a temperature detecting diode in the thickness direction of a semiconductor substrate and is electrically connected in parallel to the temperature detecting diode, in order to reduce radio frequency noise acting on the temperature detecting diode (for example, see the following Patent Document 1).
Another MOS semiconductor device has been proposed in which a protective capacitor or a diode and a temperature detecting diode are formed on the same substrate and the protective capacitor or the diode is connected in parallel to the temperature detecting diode, in order to improve the static electricity resistance of the temperature detecting diode (for example, see the following Patent Document 2 and Patent Document 3).
Another MOS semiconductor device has been proposed which includes a capacitor for preventing a change in characteristics or damage when a voltage that is higher than the breakdown voltage of a protective diode for a temperature detecting diode is applied to the protective diode in the reverse direction due to, for example, electrostatic discharge (for example, see the following Patent Document 4).
Another MOS semiconductor device has been proposed in which, in order to prevent the arrangement position of a temperature detecting diode from being limited by a diffusion structure in a portion below the temperature detecting diode (a portion which is closer to a semiconductor substrate than the temperature detecting diode), an insulating film is formed on the semiconductor substrate, a conductive layer is formed on the insulating film, the temperature detecting diode is formed on the conductive layer, with an insulating film interposed therebetween, and the temperature detecting diode is electrically insulated from the semiconductor substrate (for example, see the following Patent Document 5).
As another MOS semiconductor device, a device has been proposed in which two polysilicon diodes having an insulating film interposed therebetween are formed on an insulating film formed on the main surface of a semiconductor substrate main surface and the insulating film between the polysilicon diodes is used as a capacitive component region (for example, see the following Patent Document 6). In the following Patent Document 6, the insulating film serving as a capacitor has an opening portion and the polysilicon diode on the insulating film and the polysilicon diode below the insulating film are connected to each other through the opening portion. As such, since the two-layer polysilicon diodes are formed, the area of the polysilicon diode is reduced and the capacitor is electrically insulated from the semiconductor substrate. Therefore, stable capacitance is obtained.
As another MOS semiconductor device, a device has been proposed in which a plurality of stripe-shaped or rectangular zener diodes are formed in a gate pad and are electrically connected in parallel to each other, thereby improving static electricity resistance (for example, see the following Patent Document 7). In addition, as a method for producing a MOS semiconductor device, a production method has been proposed in which, in order to reduce the number of steps when a polysilicon diode, a capacitor, a resistor, and an insulated gate semiconductor element are formed on the same semiconductor substrate, a gate oxide film and an oxide film thicker than the gate oxide film are formed, a polysilicon layer is formed thereon and is then patterned to form a gate electrode, the diode, the capacitor, and the resistor (for example, see the following Patent Document 8).
As another method for producing a MOS semiconductor device, a method has been proposed in which an insulating film between a temperature detecting diode and a semiconductor substrate and a gate oxide film are formed in the same step (for example, see the following Patent Document 9).

This patent is subject to a terminal disclaimer.

Semiconductor device with temperature-detecting diode


A bumper assembly is provided for a vehicle having a frame. The bumper assembly includes a winch cradle defining a cradle mounting aperture corresponding to a first frame aperture of the frame. A bumper member is configured to at least partially surround the winch cradle and extend laterally from the winch cradle across a portion of the vehicle. The bumper member defines a bumper mounting aperture corresponding to a second frame aperture. The winch cradle is configured to couple to the vehicle frame independent of the bumper member and the bumper member is configured to couple to the vehicle frame independent of the winch cradle.

Certain types of vehicles, such as trucks, SUVs, and UTVs, are often used with a winch. The winch may be mounted to the front bumper or to a frame member adjacent the front bumper.
Certain types of vehicles, such as trucks and SUVs have relatively high ground clearance. When combined with an elevated bed or roof-rack, the height of the truck or SUV can make access to cargo in the bed or roof-rack difficult to access.
The attachment of spot lights, aftermarket mirrors and other accessories trucks and SUVs is a popular hobby and way to increase the utility of such vehicles in specific environments.


An inclinometer is disposed on a wheeled cycle for indicating the inclination of the wheeled cycle and includes a housing, a panel fixed on the housing, a slot longitudinally formed in the panel, a graduation printed beside the slot, a shaft rotatably supported in the housing, a tube rotatably engaged on the shaft, a weight secured to a bottom portion of the tube, and a pointer extended upward from the tube and movable along the slot of the panel. The pointer moves relative to the graduation when the housing rotates relative to the shaft in order to indicate the inclination of the wheeled cycle.

1. Field of the Invention
The present invention relates to an inclinometer, and more particularly to an inclinometer for wheeled cycles.
2. Description of the Prior Art
As far as applicant is aware, no inclinometers were developed for bicycles or motorcycles in order to indicate the inclination of the wheeled cycles.
The present invention has arisen to provide a novel inclinometer for wheeled cycles.


A lamp driving device for driving a lamp. A feedback circuit includes a voltage falling unit and a rectification circuit. The voltage falling unit provides a low voltage signal in response to a first DC power signal, a first AC power signal or a first driving power signal. The rectification circuit rectifies the low voltage signal to generate a feedback signal. The rectification circuit provides the feedback signal. A controller provides a control signal in response to the feedback signal. A first DC-to-AC converter transforms the first DC power signal to the first AC power signal in response to the control signal. A first voltage raising unit raises the voltage of the first AC power signal to generate the first driving power signal. The first raising unit provides the first driving power signal to a first end of the lamp, so that the lamp achieves the desired brightness stably.

1. Field of the Invention
The invention relates in general to a lamp driving circuit, and more particularly to a lamp driving circuit applied in a backlight module.
2. Description of the Related Art
Refer to FIG. 1A and FIG. 1B. FIG. 1A is a diagram of a conventional backlight module lamp driving circuit; FIG. 1B is a circuit diagram of a conventional feedback circuit. Liquid crystal display uses a fluorescent lamp 102 in a backlight module lamp driving circuit 100 as the backlight source to provide the light source during display. A conventional backlight module lamp driving circuit comprises a feedback circuit 104, a DC-to-AC converter 106, a voltage raising unit 108 and a controller 110. The feedback circuit 104 provides a feedback signal FSi in response to driving power signal PS required to drive the fluorescent lamp 102, so that the backlight module lamp driving circuit 100 adjusts the driving power signal PS for the fluorescent lamp 102 to achieve the desired brightness and maintain stability in response to the feedback signal FSi. The conventional feedback circuit 104, which is an ordinary rectification circuit, comprises diodes D1 and D2, a resistor R and a capacitor C, rectifies and filters the AC driving power signal PS, then provides the feedback signal FSi. When the rectification circuit corresponds to a small-sized liquid crystal display, the position of disposition, as illustrated in FIG. 1, can only be coupled to the fluorescent lamp 102 and the grounding end, or between the high voltage side coil of the voltage raising unit and the grounding end. Since the single end of the fluorescent lamp 102 is connected to the ground voltage, the feedback circuit 104 is serially connected to a low-voltage node.
As the size of liquid crystal display becomes larger and larger, the length of the fluorescent lamp 102 becomes longer and longer, and so too the striking and operating voltage of the fluorescent lamp 102 become higher. When the length of the fluorescent lamp 102 is over 900 mm, the required voltage of the fluorescent lamp 102 will be over 1.5 KV. So the lamp driving circuit 100 in the backlight module of a large-sized liquid crystal display has evolved from original single side drive mode to dual side drive mode, so that the two ends of the fluorescent lamp 102 will not have a low-voltage node. However, if a conventional feedback circuit 104 is used to convert the high voltage driving power signal PS into a feedback signal Fsi, the voltage of the feedback signal Fsi will be too high thus cannot be used by the controller 110 directly. Moreover, the elements of conventional feedback circuit 104 is too weak in terms of voltage resistance, so is unable to receive the high voltage driving power signal PS. Therefore, conventional feedback circuit 104 cannot be applied in the floating system backlight module 100.


A method comprising: providing a substrate comprising one or more electronic structures; providing a layer of perovskite overlaying the one or more electronic structures; coating a layer of photoresist material overlaying the layer of perovskite; aligning a mask with the one or more electronic structures and patterning the photoresist material; and using the same etchant to remove sections of the patterned photoresist material and the perovskite underneath the sections of the photoresist material.

Perovskite materials such as hybrid organic-inorganic perovskites can be used as optoelectronically active layers in electronic devices such as photodetectors, photo-emitters or any other suitable apparatus. However it is difficult to structure perovskite into a predefined pattern which makes it difficult to fabricate electronic devices using perovskite.
It is useful to provide improved methods of forming an apparatus comprising perovskite.

Method of forming an apparatus comprising perovskite


A method for diagnosing vascular endothelial injury, which comprises measuring the serotonin level in a plasma sample.

The present invention relates to a method for diagnosing vascular endothelial injury or arteriosclerotic pathology, i.e., to a method for measuring serotonin which exactly reflects the state of endothelial injury or arteriosclerosis.
Coronary artery disease has killed so many people that it is important to detect and treat it in early stages. Coronary artery disease almost always involves arteriosclerotic vascular lesions, and markers for diagnosis of arteriosclerotic pathology and its changes have been sought after. Markers which make it possible to diagnose arteriosclerosis are vital to diagnosis of arteriosclerotic diseases.
Hypercholesterolemia is a risk factor for arteriosclerosis, and cholesterol is considered as an etiogenic agent in the development of arteriosclerotic lesions. The research group organized in 1983 for studies on primary hyperlipidemia by the Ministry of Health and Welfare under a research project against specific diseases reported that the prevalence of coronary artery disease increases about five times from 2.3% to 12.9% with increase in serum cholesterol from 199 mg/dl or below to 400 mg/dl or above. In recent years, LDL cholesterol, oxidized LDL and other etiogenic agents for arteriosclerosis have been studied as diagnostic markers for diagnosis of arteriosclerotic pathology.
Another risk factor for arteriosclerotic disease under study is an inflammation marker, CRP (C-reactive protein) (Paul M. Ridker et al., The New England J. Medicine, 23, p.836, 2000) because inflammation of the arteriosclerotically injured vascular endothelium is accompanied by increase of CRP, which serves as an inflammation marker. However, because the CRP level (concentration) increases not only after vascular endothelial injury the but also after destruction of organ tissues and bacterial infection, CRP has a problem with specificity and is improper for exact diagnosis of arteriosclerotic pathology and vascular endothelial injury.
As discussed above, diagnostic markers for endothelial injury are essential important not only for diagnosis of vascular endothelial injury but also for diagnosis of arteriosclerotic pathology. The object of the present invention is to provide a substance which serves as a novel diagnostic marker for endothelial injury and arteriosclerotic pathology.
A search for a novel marker to attain the above-mentioned object hit on serotonin, the level of which in plasma increases upon development of a gastrointestinal tumor (Ming-shih Lee, et al., Clinical Chemistry, 46, p.422 (2000)) or a carcinoid tumor from secretory cells in the gastrointestinal tract (Kiyoshi Saijo, Nihon Rinsho, 53, p.527 (1995)). It is known that plasma serotonin transiently increases at the sites of stenosis in the coronary artery during coronary angioplasty (Paolo Golino et al, The New England J. Medicine, 330, P.523 (1994), and Dario Leosco et al., The American J. Cardiology, 84, p.1317 (1999)). However, it is also reported that there was no change in the plasma serotonin level in abdominal aortic blood during coronary angioplasty (Paolo Golino et al., The New England J. Medicine, 330, p.523 (1994)).
The results of measurements of serotonin in platelet-rich plasma obtained by centrifuging blood from patients with coronary artery disease for 5 minutes at 450xc3x97g revealed that the serotonin level is significantly higher in patients younger than 60 years old than in normal subjects without coronary artery disease (Kjell Vikenes et al., Circulation, 100, p.483, 1999). However, there has been no report that suggests ectoglobular free serotonin outside of the platelets in blood, or serotonin in platelet-free plasma, as a marker for diagnosis of vascular endothelial injury and arteriosclerotic pathology.
The plasma serotonin levels in carcinoid patients are higher than those in healthy people. Comparison between a group of carcinoid patients with coronary heart disease and a noncardiac group of carcinoid patients demonstrated that the plasma serotonin level in the cardiac group was significantly higher (Paul A. et al., Circulation, 92, p.790-795 (1995)). However, the results were obtained with a particular group of patients having carcinoids with high plasma serotonin levels and do not suggest association of plasma serotonin with vascular endothelial injury or arteiosclerotic disease in non-carcinoid individuals.
Therefore, in order to attain the above-mentioned object, according to the first aspect of the present invention, the present invention provides a method for diagnosing vascular endothelial injury, which comprises measuring the serotonin level in a plasma sample. In order to attain the above-mentioned object, according to the second aspect of the present invention, the present invention provides a method for diagnosing vascular endothelial injury, which comprises measuring the ratio of the serotonin level in a plasma sample to the serotonin level in a blood sample, a serum sample or a platelet sample. In order to attain the above-mentioned object, according to the third aspect of the present invention, the present invention provides a method for diagnosing arteriosclerotic pathology, which comprises measuring the serotonin level in a plasma sample. In order to attain the above-mentioned object, according to the fourth aspect of the present invention, the present invention provides a method for diagnosing arteriosclerotic pathology, which comprises measuring the ratio of the serotonin level in a plasma sample to the serotonin level in a blood sample, a serum sample or a platelet sample. Now, the present invention is described in detail.

Diagnostic marker for vascular endothelial injury