One aspect of the invention relates to a graft, a surface of which is coated with an amphiphilic block copolymer that includes both hydrophobic and hydrophilic polymer chains. An amphiphilic block copolymer coating according to the invention can serve as a carrier for a very broad range of drugs, possibly including every drug presently used, being considered for use, or likely to be used in the future to inhibit stenosis. The release rates of the drugs can be controlled, for example, through the length of the polymer chains, through their ratio, or through the degree of cross-linking.

Vascular grafts are medical devices used as an artificial conduit for bodily fluids, usually blood. In hemodialysis, the vascular graft serves as a nonstatic reservoir of blood, where blood is readily accessible to a dialysis machine. The vascular graft serves as a life line, an essential interface between the patient and the dialysis machine. In the treatment of peripheral vascular disease and coronary artery disease, vascular grafts provide an artificial conduit bypassing or replacing diseased blood vessels.
Vascular grafts can be natural or artificial. In coronary artery disease, artificial vascular grafts are rarely used due to a high incidence of thrombosis either within the tubular structure or at the anastamosis site. The current graft material of choice is to use a native blood vessel such as the left internal mammary artery or saphenous vein.
In general, thrombosis is problematic with vascular grafts. Thrombosis or cellular growth is the main cause of stenosis within the internal lumen of the vascular graft. Stenosis can occurs as a result of the body's natural healing mechanism. When a vascular graft is implanted, injury occurs to the arterial or venous system to which the vascular graft is sutured and or attached. The vascular graft is also a foreign body. Through a complex process, smooth muscle cells, endothelial cells etc. migrate onto the internal lumen of the graft. As the smooth muscle cells proliferate, they form a neointimal hyperplasia. Over time the neointimal hyperplasia progresses, causing a reduction in the internal diameter of the internal lumen. Stenosis can also be caused by vascular narrowing.
There have been many attempts to inhibit stenosis and thrombosis. Anticoagulants such as heparin have been tried with little success. Antimicrotubule agents such as paclictaxel and docetaxel are known to inhibit mitosis and hence cellular proliferation. Antiproliferative agents such as cyclophosphamide, mithromycin, and actinomycin-D are known to prevent proliferation of smooth muscle cells. Sirolimus, cyclosporine A, dexamethasone and methyl prednisolone are immunosuppressive agents that have been shown to prevent or retard neointimal hyperplasia.
While drugs can significantly inhibit or prevent the occurrence of stenosis and thrombosis, the continued need for the drugs after a graft has been installed can require the patient to remain in a hospital for extended periods of time. It would be advantageous if these drugs could be released from a biocompatible polymer coating within a graft.
At present, there are many biocompatible polymers. For example, poly(ethylene glycol) (PEG) is a water soluble polymer showing excellent biocompatibility and has been frequently used in biomedical applications. Similarly, polysiloxanes are widely used in the biomedical field and have been the subject of intense study both in the academic field as well as in industry.
Amphiphilic polymer networks have also been identified as potentially useful biomaterials. Amphiphilic polymer networks are co-continuous assemblages of hydrophilic and hydrophobic polymer chains that are able to swell in both hydrophilic solvents (e.g., water) and hydrophobic solvents (e.g., a liquid hydrocarbon). Because these materials swell in water, they generally fall into a class of compounds known as "hydrogels".
The first amphiphilic membranes for biomaterials were developed over a decade ago. These were networks of hydrophilic polymers with the hydrophobic crosslinking agent, di-methacryl-telechelic polyisobutylene (MA-PIB-MA). Synthesis was accomplished by living carbocationic polymerization, which involves the free radical copolymerization and can use a variety of inexpensive, commercially available monomers, for example, N-dimethylaminoethyl methacrylate and dimethyl acrylamide.
Kennedy, U.S. Pat. No. 4,486,572 discloses the synthesis of styryl-telechelic polyisobutylene and amphiphilic networks comprising the copolymerization product of the styryl-telechelic polyisobutylene with vinyl acetate or N-vinyl-2-pyrollidone. Kennedy, U.S. Pat. No. 4,942,204 discloses an amphiphilic copolymer network swellable in both water and n-heptane but insoluble in either, comprising the reaction product of an acrylate or methacrylate of a dialkylaminoalkyl with a hydrophobic bifunctional acryloyl or methacryloyl capped polyolefin. The preferred embodiment disclosed is an amphiphilic network having been synthesized by the free-radical copolymerization of a linear hydrophobic acrylate (A-PIB-A) or methacrylate capped polyisobutylene (MA-PIB-MA) with 2-(dimethylamino)ethyl methacrylate (DMAEMA). In a continuation-in-part to U.S. Pat. No. 4,942,204, Ivan et al. U.S. Pat. No. 5,073,381 discloses various amphiphilic copolymer networks that are swellable in water and n-heptane that comprise the reaction product of a hydrophobic linear acryloyl- or methacryloyl-capped polyolefin and a hydrophilic polyacrylate or polymethacrylate, such as N,N-dimethylacrylamide (DMAAm) and 2-hydroxyethylmethyl methacrylate (HEMA).
Hirt, U.S. Pat. No. 5,807,944 discloses a copolymer of controlled morphology comprising at least one oxygen permeable polymer segment and at least one ion permeable polymer segment, wherein the oxygen permeable segments and the ion permeable segments are linked together through a non-hydrolysable bond. The oxygen-permeable polymer segments are selected from polysiloxanes, perfluoroalkyl ethers, polysulfones, and other unsaturated polymers. The ion permeable polymers are selected from cyclic imino ethers, vinyl ethers, cyclic ethers, including epoxides, cyclic unsaturated ethers, N-substituted aziridines, beta-lactones, beta-lactanes, ketene acetates, vinyl acetates and phosphoranes.
U.S. application Ser. No. 09/433,660 discloses an amphiphilic network comprising the reaction product of hydrophobic crosslinking agents and hydrophilic monomers wherein the hydrophobic crosslinking agents are telechelic three-arm polyisobutylenes having acrylate or methacrylate end caps and wherein the hydrophilic monomers are acrylate or methacrylate derivatives.

Vascular grafts with amphiphilic block copolymer coatings


A process and apparatus for the decontamination of oil includes providing a jet compressor having a converging section in which high velocity liquid oil compresses a source of atmospheric pressure gas, a central mixing section that intimately mixes the liquid oil with the gas for providing a large gas and oil surface area for the mass transfer of water from the liquid oil, and a diverging section in which the liquid oil and gas are further mixed during pressure recovery. A tubular member is connected to the diverging section to provide a residence time chamber immediately downstream of the diverging section to increase the efficiency of the rate of transfer of water from the liquid oil to the gas.

Oils in contact with relatively small quantities of a contaminant liquid such as water will dissolve and absorb the liquid up to its saturation limit in the oil. An excess of the contaminant liquid beyond saturation will result in it forming a separate liquid phase within the oil. When the liquid is water, the term free water is used to describe this second liquid phase.
Oil in contact with gases (including water vapour) dissolve these gases generally in accordance with Henry's Law.
Both dissolved liquids and gases can cause problems with oils and with equipment in contact with the oils.
The main contaminant in lubricant and seal oils is water. However, hydrogen sulphide, oxygen, hydrocarbons, and other organic compounds such as alcohols, aldehydes and ketones can be dissolved and absorbed by the oils and can also form separate phases within these oils.
There are several mechanisms by which contaminants adversely effect lubrication oils. For example, when the compounds listed above are absorbed by oil, the oil viscosity is reduced and adversely affected and this affects the ability of the oil to lubricate the moving or bearing surfaces in machinery. The modification to oil viscosity normally leads to a reduction in the thickness of the protective lubricating oil film on the machinery surfaces and metal to metal contact is increased. This leads to high rates of wear and poor machinery performance.
In addition to viscosity effects, water and acid gases such as hydrogen sulphide and hydrogen cyanide cause corrosion to the surfaces they contact. Particles of corrosion products flake off metal surfaces and increase wear via abrasion of the metal surfaces.
Water and volatile gases can also cause erosion of metal surfaces via another mechanism. This erosion is caused on the metal surfaces by the rapid vaporisation that can occur as the lubricating oil containing the volatile gases heats up as it passes through and between the bearings, gears and other highly stressed surfaces causing sudden vaporisation. The resultant rapid increase in oil and gas velocity past the surfaces causes erosion. This is often referred to as cavitation.
Transformer oils are mostly contaminated by water which usually enters in the form of a gas and is absorbed into the oil. The absorbed water reduces the dielectric constant of the oil which leads to inefficiencies within the transformer and in the extreme can lead to an explosion due to arcing and vaporization of the transformer fluids.
Hydraulic oils are mostly contaminated by water which also enters as water vapour normally into the storage compartment. The dissolved water usually causes corrosion within the hydraulic system.
Edible oils, which are normally vegetable oils, contain dissolved water. The water enters the oil during the extraction process from the plant and during oil storage where water vapour condenses from air into the oil. The oil, dissolved water and free water all contain dissolved oxygen. The water in the oil allows the oxygen to act on the oil and cause oxidation and therefore rancidity of the oil, spoiling it as a foodstuff. For this reason, antioxidants are usually added to edible oils. These antioxidants are chemicals which tend to block the oxidation action of oxygen and/or water on oxidizable fractions of the oil. Without these antioxidants, edible oils would rapidly spoil and become unfit for human consumption.
Water is the principal contaminant to be removed from oils to overcome the problems described above. Water can be present in various combinations of the following forms:
Free water which is present as a separate phase from the oil and which separates as such on standing.
Emulsified water which, although present as a separate phase, is so finely dispersed that surface tension forces are not large enough to allow free settling of the water on standing. In general, emulsified water cannot be separated by purely mechanical means.
Dissolved water which is present as a solution within the oil. It is an integral part of the oil phase and cannot be remove by mechanical means (i.e. standing, filtration or centrifuging). Dissolved water exists up to the saturation limit which varies with the type of oil and its temperature. Once the saturation limit is reached, the oil cannot accommodate any more dissolved water and any excess water appears as a separate phase as either free and/or emulsified water.
In addition to water resulting from absorption into the oil from the gaseous phase, oils may be contaminated by liquid water leaking into the oil system, particularly in hydraulic and lubrication oil systems where those systems are normally cooled against cooling water. Water can also enter these systems where it condenses out of the atmosphere above the oil, especially where the oil storage reservoirs are situated in the close proximity of steam turbines or steam vents. These means of gross contamination require extensive water removal if catastrophic failure of the lubrication system and the machinery it is protecting are to be avoided.
Contamination levels of water can vary from a few hundred parts per million through to many thousands of parts per million and some lubrication systems can have periodic gross contamination of up to 10% water in the oil.
The desired level of water in the oil is less than the saturation level for that temperature. For example, most lubrication oils operate in the temperature range 30.degree. C. to 80.degree. C. At 30.degree. C., a typical saturation water level in oil is 100 ppm whereas a typical saturation water level at 80.degree. C. is 500 ppm. However, most lubrication oils give superior performance if water levels of less than 100 parts per million are present in the oil supply to the bearing or gear. A figure of less than 50 ppm in the oil supply would ensure that the oil is in a condition where it has no free water in it and will have the capacitance to absorb any liquid water or any water vapour that comes into contact with the oil. At these low levels, water is not readily available to cause viscosity changes in the oil or to cause corrosion or erosion damage.

Process and apparatus for oil decontamination


A fan shroud structure (10) is constructed and arranged to carry a fan and motor. The fan shroud structure includes a base (12) and an annular rim (24) extending from the base. The rim defines a generally central opening (26) sized to accommodate blades of a fan. Motor mounting structure (28) is coupled with the rim (24) and is disposed generally adjacent to the central opening (26). The motor mounting structure (28) is constructed and arranged to support a motor for driving a fan. The fan shroud structure (10) includes a first pair of opposing sides (14, 16) and a second pair of opposing sides (17, 18) coupled to the base to form a box-like configuration defining a perimeter of the fan shroud structure raised with respect to the base such that the sides are discontinuous with respect to the base (12) to shift resonance of the shroud structure.

Conventional fan shrouds that are of box shape are excitable (by resonance) in the operating range of the fan motor or other periodic signals in the machine the fan is placed in, such as a vehicle. In addition, due to the box-like structure of typical shrouds, there is a need for substantial structural reinforcement to minimize warping and distortion. However, the use of such reinforcement can increase the complexity of manufacturability (e.g. moldability) of the shroud and increase the cost of materials, while adversely affecting airflow properties.
Thus, there is a need to provide a cost-effective, moldable fan shroud structure that reduces or eliminates warping and distortion and reduces resonance.

Fan shroud structure reinforcement to reduce or eliminate warping and distortion


According to one embodiment, an optical filter has a polarization rotator and two instances of an optical bandpass filter (OBPF). The first instance of the OBPF processes a TE-polarized component of an optical input signal to produce a first filtered signal. The polarization rotator then transforms the TE polarization of the first filtered signal into the TM polarization. The polarization rotator also transforms the polarization of a TM-polarized component of the optical input signal into the TE polarization. The second instance of the OBPF processes the resulting TE-polarized signal to produce a second filtered signal. The first and second filtered signals having TM and TE polarizations, respectively, are then combined to produce a filtered output signal.

1. Field of the Invention
The present invention relates to optical communication equipment and, more specifically, to tunable optical bandpass filters.
2. Description of the Related Art
This section introduces aspects that may help facilitate a better understanding of the invention(s). Accordingly, the statements of this section are to be read in this light and are not to be understood as admissions about what is in the prior art and/or what is not in the prior art.
Tunable optical bandpass filters find applications in optical power and performance monitors, broadcast and select networks, add/drop multiplexers, etc. Implementing such filters with standard silicon complementary-metal-oxide-semiconductor (CMOS) technology holds the promise of minimizing production costs, e.g., through monolithic integration of electronic and photonic functions and the use of the massive existing CMOS manufacturing infrastructure. As a result, CMOS-compatible tunable optical bandpass filters are currently being actively developed.

CMOS-compatible polarization-diverse tunable optical bandpass filter


A recombinant DNA molecule adapted for transfection of a host cell comprising a nucleic acid molecule encoding mammalian erythropoietin or tissue plasminogen activator, an expression control sequence operatively linked thereto and at least one SAR element. The invention also relates to expression vectors having the recombinant DNA molecule and to mammalian cells transformed with the expression vector. The mammalian cells lack multiple copies of an amplified amplification gene and are capable of expressing recombinant EPO or tPA in vitro at levels of at least 1,500 u or 500 u/10.sup.6 cells in 24 hours respectively. The invention further relates to a method of expressing recombinant mammalian EPO or tPA using the expression vectors and to a transgenic non-human animal or embryo whose germ cells and somatic cells contain a DNA construct having the recombinant DNA molecule of the invention.

Erythropoietin (EPO) is a heavily glycosylated acidic glycoprotein with a molecular weight of approximately 35,000. The protein consists of 166 amino acids and has a leader signal sequence of 27 amino acids which is removed in vivo during secretion from the host cell. The sequence encoding the unprocessed EPO is 579 nucleotides in length (Jacobs et al, 1985, Lin et al, 1985, U.S. Pat. No. 4,703,008 and WO 86/03520).
Erythropoietin is the principal hormone involved in the regulation and maintenance of physiological levels or erythrocytes in mammalian circulation and functions to promote erythroid development, to initiate hemoglobin synthesis and to stimulate proliferation of immature erythroid precursors. The hormone is produced primarily by the adult kidney and foetal liver and is maintained in the circulation at concentrations of about 10-20 milliunits/ml of serum under normal physiological conditions. Elevated levels of EPO, induced by tissue hypoxia, trigger proliferation and differentiation of a population of receptive progenitor stem cells in the bone marrow, stimulating hemoglobin synthesis in maturing erythroid cells and accelerating the release of erythrocytes from the marrow into the circulation.
Recombinant EPO has been used to successfully treat patients, including patients having anemia as a result of chronic renal failure. As EPO is the primary regulator of red blood cell formation, it has applications in both the diagnosis and treatment of disorders of red blood cell production and has potential applications for treating a range of conditions.
The urine of severely anaemic patients was, at one time, almost the sole source for the commercial isolation of EPO. U.S. Pat. No. 3,033,753 describes a method for obtaining a crude EPO preparation from sheep plasma. The preparation of monoclonal antibodies specific for human EPO provided a means for identifying EPO produced from EPO mRNA, for screening libraries and for cloning the EPO gene. Human EPO cDNA has been cloned and expressed in E. coli (Lee-Huang, 1984, Proc. Natl. Acad. Sci. 81:2708). Isolation of the human EPO gene using mixtures of short or long synthetic nucleotides as probes led to the expression of biologically active EPO in mammalian cells (Lin, 1985, Proc. Natl. Acad. Sci. 82:7580; Lin, WO 85/02610; Jacobs, et al., 1985, Nature (Lond.) 313:806; Goto et al., 1988, Biotechnology 6:67). Jacobs, et al, 1985, supra, described the use of plasmids containing EPO DAN which were not integrated into the chromosomes of the COS host cells, but replicated autonomously in the cells to many thousand of copies, thereby killing the cells. Thus the expression of EPO was only a transient phenomenon in these cells.
Lin, in U.S. Pat. No. 4,703,008, reported expression of the human EPO gene in COS-1 and CHO cells. However, attempts to use transfected cells as production vehicles for EPO have been hampered by the low levels of EPO expressed by transfected cells. Given the important applications of recombinant EPO, there is much interest in developing more efficient methods for the expression of EPO.
Lin in U.S. Pat. No. 4,703,008 reported methods to increase the low amounts of EPO produced by transfected CHO cells (e.g. 2.99 u/ml/3 days) by a process of gene amplification. Levels of approximately 1500 units EPO/10.sup.6 cells/48 hours were reported by Lin, following amplification.
Gene amplification involves culturing cells in appropriate media conditions to select cells resistant to a selective agent, such as the drug methotrexate. Selection for cells resistant to methotrexate produces cells containing greater numbers of DHFR genes and passenger genes, such as the EPO gene carried on the expression vector along with the DHFR gene or transfected with the DHFR gene.
However, gene amplification is a very time consuming and labour intensive process. A major disadvantage of amplification is the inherent instability of amplified genes (McDonald, 1990, Crit. Rev. Biotech. 10:155). As it is usually necessary to maintain the amplified cells in the presence of toxic analogs to maintain high copy number, amplification may be inappropriate for large scale production due to the costs and toxicity of the selective agent. The high copy number of the DHFR-target transgene may also sequester transcription factor, leading to a retardation of cell growth.
Genomic clones of human EPO have been used in attempts to develop stably transfected mammalian cell lines that secrete high levels of active erythropoietin (Powell, et al., 1986, Proc. Natl. Acad. Sci. 83:6465; Masatsuga, et al., European Patent Application Publication No. 0 236 059). In PCT Application WO (88/00241 Powell, describes the preparation of mammalian cell lines (COS-7 and BHK) transfected with the Apa I restriction fragment of the human EPO gene and selected for high expression by amplification.
Human EPO cDNA has also been expressed in mammalian cells (Yanagi, et al., 1989, DNA 8:419). Berstein, in PCT application WO 86/03520 describes the expression of EPO cDNA in various host cells, resulting in the secretion of up to 160 ng/ml of EPO into the medium after amplification. European Patent Application publication No. 0 267 678 discloses expression of recombinant EPO and secretion into the culture medium at levels of 600 units/ml.
The coagulation system and the fibrinolytic system are major mechanisms involved in the maintenance of hemostatic equilibrium of the body. In the case of trauma or vascular injury, the coagulation system acts to deposit fibrin matrices at the site of injury to maintain hemostasis and prevent excessive blood loss. Once the normal hemostatic condition is restored, the fibrin clots are removed by the fibrinolytic system through activation of an endogenous fibrinolytic enzyme, plasmin (Collen, D. and Lijnen, H. R., In The Molecular Basis of Blood Diseases, pp. 725-752, 1994).
Activation of plasmin is endogenously effected by plasminogen activators which are categorized into the urokinase-type plasminogen activators (uPA) and the tissue-type plasminogen activators (tPA). Tissue plasminogen activator (tPA or alteplase) is a glycosylated protein with fibrin-enhanced serine proteolytic activity. The protein consists of 527 amino acids with a molecular weight of approximately 68 kD. The N-terminal of the tPA protein is primarily involved in fibrin binding while the catalytic domain responsible for plasmin activation is resided at the C-terminal. When introduced into systemic circulation, tissue plasminogen activator binds to fibrin found in thrombi via lysine residues at its N-terminal "finger domain". The fibrin-bound fibrinogen activator converts the inactive plasminogen to active plasmin by cleavage of a single peptide bond and the plasmin in turn cleaves the fibrin matrices in the blood clot thereby producing thrombolysis.
Similarly, uPA is a serine protease of 411 amino acids which can activate plasminogen to plasmin. Unlike tPA, the catalytic action of uPA is not fibrin-dependent and can therefore readily produce a systemic lytic state and hemorrhagic toxicity.
Therapeutically, tPA is used for the lysis of occlusive coronary artery thrombi associated with evolving transmural myocardial infarction thereby improving ventricular function and reducing the incidence of congestive heart failure. It is also used in the management of acute massive pulmonary embolism, venous thrombosis and acute ischemic stroke. Additionally, tPA may find utility in arterial thrombosis or embolism, arteriovenous cannulae occlusion and intravenous catheter clearance. In contrast to other plasminogen activators such as urokinase and streptokinase, the activity of tPA is comparatively more localized and in theory, it is less likely to produce systemic hemorrhagic disorders.
Both tPA and uPA have been isolated successfully from blood, serum, urine and various tissues and their cell-lines (see U.S. Pat. Nos. 3,555,000; 3,998,947 and 4,245,051; European Patent Publication No. EP 0 023 860). Human omental microvascular endothelial cells and human umbilical vein endothelial cells have been shown to constitutively produce tPA at approximately 8.8 and 2.2 ng per 10.sup.5 cells per day, respectively (Wojta, et al., J. Biol. Chem. 264:2846-2852, 1989). Malignant melanoma LOX cells were also shown to produce and release tPA at approximately 9 ng per 10.sup.6 cells per 3 days (Buo, et al., Anticancer Res. 14(6B):2445-2451, 1994).
With the emergence of recombinant technology, DNA encoding tPA was sequenced and synthesized and recombinant processes for tPA production using prokaryotic and eukaryotic expression hosts have been developed (see U.S. Pat. Nos. 4,766,075; 4,853,330; 5,079,159; 5,185,259 and 5,587,159; see Pennica, et al., Nature 5898: 214-221, 1983; Browne et al., Gene 33: 279-284, 1985; Rajput et al., Science 230: 672-674, 1985; Fisher & Schleuning, Thromb. Haemostasis 54: 4, 1985; Degen et al., J. Biol. Chem. 261: 6972-6985, 1986; Weidle, et al., J. Cell. Biochem. Suppl. 12B: 185, 1988). The product expressed is predominantly single-chain tPA, although a double-chain tPA product was also described to be active. This double-chain product may be prepared by in vitro proteolytic conversation of the single-chain product after expression. Expression levels of tPA in Chinese hamster ovary (CHO) cells without selective amplification was reported to be approximately 0.7 to 1.0 ug tPA per 10.sup.6 cells per day (or approximately 63 to 90 Plough Units per 10.sup.6 cells per day) (90 Plough Units equal 1 ug).
To improve tPA production in mammalian cells, Browne, et al. (Thrombo. Haemost. 54:422-424, 1985) described a method of introducing extra copies of tPA-encoding gene into Bowes melanoma cell line. Production of tPA was increased over the parent cell line by 10-fold to approximately 3 ug per 10.sup.6 cells per day. Wernicke and Will (Anal. Biochem. 203:146-150, 1992) taught a single selection step for dihydrofolate reductase (DHFR)-positive tPA-producing CHO cells using methotrexate to increase tPA yield to 4.6 ug per 10.sup.6 cells per day.
Amplification of the tPA gene using selective amplification to improve tPA expression and yield in CHO cells was disclosed by Levinson et al. in U.S. Pat. Nos. 5,424,198; 5,268,291; 5,011,795 and 5,010,002. Gene amplification involves culturing cells in appropriate media conditions to select cells resistant to a selective agent, such as the drug methotrexate. Selection for cells resistant to methotrexate produces cells containing greater numbers of dihydrofolate reductase (DHFR) genes and passenger genes, such as the tPA gene carried on the expression vector along with the DHFR gene or transfected with the DHFR gene. Levels of approximately 26 to 28 ug tPA per 10.sup.6 cells per day (or approximately 2,340 to 2,520 Plough Units per 10.sup.6 cells per day) were reported by Levinson et al. following amplification with 500 nM methotrexate and 29 to 49 ug tPA per 10.sup.6 cells per day (or approximately 2,610 to 4,410 Plough Units per 10.sup.6 cells per day) following amplication in 10 uM methotrexate.
Kaufman disclosed an improved subcloning strategy for expression of tPA in CHO cells (see U.S. Pat. No. 5,079,159). Without selective amplification, the production rate of tPA was approximately 0.3 ug per 10.sup.6 cells per day (or approximately 30 Units per 10.sup.6 cells per day) (based on the disclosure that 100 Units equal to 1 ug). Following sequential amplification in methotrexate, levels of tPA production increased to approximately 19 ug of tPA per 10.sup.6 cells per day (or approximately 1,900 Units per 10.sup.6 cells per day) at 50 nM methotrexate and approximately 2.0 to 100 ug per 10.sup.6 cells per day (or approximately 200 to 10,000 Units per 10.sup.6 cells per day) at 500 nM methotrexate.
A new gene transmission protocol which can electroporetically introduce up to 800 copies of an expression vector containing the tPA gene into CHO cells was developed (Barsoum, DNA Cell Biol. 9:293-300, 1990). Recombinant host cells transfected using this technique and amplified in 500 nM methotrexate produced approximately 45 ug of the tPA per 10.sup.6 cells per day.
As hereinbefore noted, gene amplification is a very time consuming and labour intensive process and major disadvantages of amplification include the inherent instability of amplified genes, amplification may be inappropriate for large scale production due to the costs and toxicity of the selective agent, and the high copy number of the DHFR-target transgene may attenuate cell growth.
A few scaffold attachment region (SAR) elements have been shown to increase the expression of reporter genes in transfected cells. SAR elements are though to be DNA sequences which mediate attachment of chromatin loops to the nuclear matrix or scaffold. SAR elements are also known as MAR (matrix-associated regions) (reviewed by Phi-Van and Stratling, Prog. Mol. Subcell. Biol. 11:1-11, 1990). These elements will hereinafter be referred to as "SAR elements". SAR elements are usually 300 or more base pairs long, and they require a redundancy of sequence information and contain multiple sites of protein-DNA interaction. SAR elements are found in non-coding regions: in flanking region or introns.
Stief, et al., (Nature 341:343-345, 1989) stably transfected chicken macrophage cells by constructs which contained the CAT gene either fused to the lysozyme promoter, or to the lysozyme promoter and the lysozyme enhancer. When the transcription units contained in both constructs were flanked on both sides by lysozyme 5' SAR elements (A elements), gene expression was increased about 10 times relative to transfectants, which contained the constructs lacking the SAR elements.
Phi-Van, et al., (Mol. Cell. Biol., 10:2302-2307, 1990) determined the influence of the SAR element located 5' to the chicken lysozyme gene (A element) on the CAT gene expression from a heterologous promoter (herpes simplex virus thymidine kinase promoter) in stably transfected heterologous cells (rat fibroblasts). The median CAT activity per copy number in transfectants was 10 times higher for the transcriptional unit flanked on both sides by A elements than for the transcriptional unit lacking SAR elements.
Klehr, et al.,) Biochemistry, 30:1264-1270, 1991) stably transfected mouse L cells by different constructs containing the human interferon .beta. gene. When the construct was flanked by SAR elements, the gene transcription level was enhanced 20-30 fold with respect to the SAR-free construct, containing only the immediate regulatory elements.
However, the above-noted experiments have been limited to a very few examples of SAR elements, expressing mostly reporter genes, such as chloramphenicol acetyl transferase (CAT) or luciferase. SAR elements have not shown consistent results in their effect on the expression of target genes and some target gene sequences have been found to inhibit the effect of SAR elements (Klehr, et al., 1991, Biochemistry 30:1264).

Recombinant DNA molecules and expression vectors for tissue plasminogen activator


A fluid transfer system employing a roller pump for squeezing an elastically deformable tube by a roller to allow fluid to be transferred from a transfer source to a transfer destination, said fluid transfer system being characterized by comprising: a short-cut passageway connecting between an inlet passageway and an outlet passageway of said tube fitted onto said roller pump; and a passageway switching means for selectively bringing fluid into fluid communication with said short-cut passageway.

1. Field of the Invention
This invention relates to a fluid transfer system, and more particularly to a fluid transfer system using a roller pump adapted for squeezing elastically deformable tubes so as to transfer fluid from a transfer source toward a transfer destination.
2. Description of the Related Art
Conventionally, there have been known fluid transfer systems employing a roller pump for the purposes of transferring liquids such as reagents and detergents or gases such as air. If such a system is provided with a plurality of roller pumps, the timing of transfer and the liquid amount thereof for tubes fitted on each pump can be controlled, pump by pump, by driving and stopping the pumps.
In the abovementioned conventional fluid transfer system, if a plurality of fluid transfers are to be individually controlled, there is a necessity of installing a plurality of roller pumps, resulting in increase of cost in addition to large installation spaces.
Furthermore, if an individual fluid transfer is to be controlled by driving and stopping the pump, a certain period of time will be required for establishing stable supply from the starting of a pump-driving motor up to the beginning of fluid supply as well as a period of time for establishing complete termination from the stopping of the motor to the ending of the fluid supply, rendering it difficult to perform constant-amount transfer of liquid with accuracy and precision.
On the other hand, if a plurality of tubes are fitted to one roller, simultaneous fluid transfer to a plurality of sites is possible, but the timing of transfer and the amount of liquid transferred can not be controlled on an individual tube basis.

Fluid transfer system and blood cell counter including the same system


A housing for a bevel gear includes a pinion bearing seat configured to support a pinion bearing for a driveshaft having a drive pinion. The housing also includes an attachment structure configured to attach a support bearing seat to the housing such that the position of the support bearing seat with respect to the pinion bearing seat is variable in the radial direction.

Bevel gears are used in different applications for redirecting driving forces. An example of a bevel gear is a differential. In many vehicles, differentials, e.g., are used as bevel gears. Large forces often act on differentials, which can be the case especially with differentials for heavy vehicles (e.g. trucks). These large forces can occur in particular in a pinion bearing for supporting the driveshaft. The driveshaft drives a drive pinion which drives a ring gear of the differential. Using the ring gear, output shafts can be driven via further transmission elements. In many conventional differentials a support bearing is used on one axial shaft end in order to support the large forces in the pinion bearing. Thus in some differentials the problem arises that the supporting of the driveshaft is overdetermined. The pinion bearing often comprises an assembly of two main bearings which mutually support each other. The pinion bearing itself is statically determinate. For example, the pinion bearing can comprise two tapered bearings in an O-arrangement. It can also be that the two main bearings of the pinion shaft or driveshaft determine the axis of rotation of the driveshaft. The support bearing can be installed in the housing such that it is not aligned with this axis of rotation, for example, due to manufacturing errors. As a result, forces can arise in the support bearing and in the pinion bearing.
Therefore in some conventional differentials an increased bearing clearance is provided for the support bearing. In some applications this bearing clearance can largely eliminate the alignment problem and the occurrence of constraining forces. However, in some circumstances, the providing of an increased bearing clearance in the support bearing can also lead to a loading of only some rolling elements. But, in some cases this situation of an unequal load distribution can easily lead to an overloading of the support bearing. For example, a premature wear of the rolling elements or of the raceways can occur. This effect is undesirable and may lead to increased maintenance costs of the transmission. In other conventional bevel gear bearings, similar forces can arise in the pinion bearing.

Bevel gear housing, bevel gear and method of assembling the same


One embodiment of a substrate laminator comprises a housing that includes a cartridge receiver, a substrate transport, a cartridge and a cartridge position adjustment mechanism. The substrate transport mechanism is configured to feed substrates along the processing path in a lengthwise direction. The cartridge is received in the cartridge receiver and includes a ribbon supply. The cartridge position adjustment mechanism is configured to adjust the position of the cartridge in a widthwise direction relative to the substrate processing path.

Credential production devices process credential substrates to form credentials, such as, for example, identification cards, driver's licenses, passports, and other valuable documents. The credential substrates that are used to form such credentials include, for example, paper substrates, plastic substrates, semi-rigid or rigid plastic cards, and other materials. Exemplary processes performed on the credential substrates by credential production devices to produce the credential include printing an image on the substrate, writing data to the substrate, applying an overlaminate material to the substrate and other processes.
Credential laminators are generally configured to apply an overlaminate material to one or more surfaces of credential substrates to protect the surfaces from abrasion and environmental conditions. The lamination operation performed by credential laminators utilizes a laminating roller to apply heat and pressure to the overlaminate material that overlays the surface of the substrate and bonds the overlaminate material to the surface.
One type of overlaminate material is in the form of an overlaminate patch that includes a layer of adhesive on a protective material, such as polyester. The adhesive layer of the patch is used to adhere the patch to a surface of the substrate during the lamination process.
It is desirable to have the overlaminate patch precisely conform to the surface of the credential substrate in order to provide full edge-to-edge protection to the surface. Unfortunately, due to inaccuracies in the laminating process, variances in the overlaminate ribbon and other factors, the overlaminate patch must be made slightly smaller than the surface of the substrate to ensure that the patch can be aligned with the substrate without overhanging the substrate's edges. There is a continuous effort to minimize the size difference between the patch and the substrate in order to get closer to the desired full edge-to-edge surface protection.

Credential substrate laminator having a cartridge position adjustment mechanism


The device and method for placement of an instrument, specifically electrodes, in the GI tract allows for placement of electrodes for gastric electrical stimulation into the gastric wall using endoscopic techniques. The device has one or more electrodes disposed on an elongated body having a pointed first end and a bolster disposed on a second end. When placed within the GI tract, the first end of the device extends through the gastric and abdominal walls, extending outside of the patient's body with the bolster in contact against the inner lining of the gastric wall to retain the device. Exposed electrodes contact the gastric smooth muscle. Insulated wires in electrical connection with-the electrodes run the length of the device body. Once the device is placed, the first end of the device body is removed to expose the wires, allowing electrical connection to an external electrical signal generator to provide electrical stimulus.

1. Field of the Invention
The present invention relates to electrical stimulation of neuromuscular activity in the gastrointestinal (GI) tract by artificial gastric pacemakers. More specifically, the invention is a device and method for the placement of electrodes in the GI tract.
2. Description of the Related Art
Electrical impulses can be used to stimulate contractions in the gastrointestinal (GI) tract, much as an artificial pacemaker can stimulate contractions in the heart. Gastric electrical stimulation (GES) can be used in the treatment of gastroparesis, a disorder in which food moves through the stomach more slowly than normal, among other GI disorders. Electrical impulses can also be used to decrease appetite. The precise effect of GES appears dependent on the location of electrodes used to provide electrical stimulus, as well as the amplitude and frequency of the applied electrical impulse.
U.S. Pat. No. 3,411,507, issued on Nov. 19, 1965 to R. Wingrove, discloses a method of gastrointestinal stimulation with electrical pulses, for the management of the condition often referred to as paralytic ileus. The method involves nasogastrically placing a first electrode into a patient's stomach in proximity to or past the pyloric valve. A second electrode is applied to the patient's body at a convenient location such as the abdominal wall, and electrical impulses are applied between the electrodes. The result of the impulses is the inducement of peristaltic waves, and the restoration of peristaltic activity.
U.S. Pat. No. 5,292,344, issued on Mar. 8, 1994 to D. Douglas, discloses a percutaneously placed electrical gastrointestinal pacemaker stimulatory system including, as part of the system, a tubular device having one or more electrodes protruding from an end bolster. The device extends through the skin with the end bolster held in position against the inner lining of the gastrointestinal tract. Electrodes extending from the end bolster are pre-bent and partially insulated "tentacles" intended to contact the gastrointestinal mucosa. A plurality of electrodes is provided to ensure that, once the device is placed, at least one electrode is in contact with the mucosa.
U.S. Pat. No. 5,690,691, issued on November 25 to J. Chen et al., discloses a gastrointestinal pacemaker having phased multi-point stimulation. A portable or implantable gastric pacemaker includes multiple electrodes that are positionable on the inner or outer surface of an organ in the gastrointestinal tract, the multiple electrodes being positioned at multiple sites.
U.S. Pat. No. 6,542,776, issued on Apr. 1, 2003 to P. Gordon et al., discloses a gastric stimulator apparatus and a method for installing the apparatus. The apparatus comprises an implantable pulse generator, a lead system, and an electrode assembly or implant device. The apparatus is installed, preferably, through a trocar inserted through the patients skin. A series of trocars may be installed to allow for access of surgical instruments, as well as for a laparoscope to allow viewing of the attachment process.
U.S. Pat. No. 6,535,764, issued on Mar. 18, 2003 to M. Imran et al., discloses a gastric treatment device and method that includes an electronic stimulation device, which is attached to the interior of the stomach by an anchor device. The anchor device may have an electrode that contacts the stomach wall when the device is implanted through the stomach wall. A contact on the anchor device connects the electrode electrically to an electronic circuit within the stimulation device once the stimulation device is placed onto the anchor.
To the best of the inventor's knowledge, currently gastric electrodes are implanted by either laparascopic or open surgical techniques. There is a need for a device and method for placement of electrodes in the gastrointestinal tract by endoscopic techniques. This is because it is desirable, in any form of GES therapy, to minimize the surgically invasive nature of procedures used to implant electrodes, and to minimize risks associated with general anesthesia and surgical techniques including bleeding, infection, pain, and others.
None of the above inventions and patents, taken either singly or in combination, is seen to describe the instant invention as claimed. Thus, the device and method for placement of electrodes in the GI tract of the present invention solving the aforementioned problems is desired.

Device and method for placement of electrodes in the GI tract


A temperature measuring device includes a heat plate exposed to the ambient, one or more sensor chips, and one or more device electronics that include a power transmitter, a wireless communication receiving block, and a processor. Each sensor chip includes a wireless communication transmitting block, a temperature sensor, a signal processing block, and an energy harvesting circuit. The heat plate and the sensor chips are positioned within an indent formed in an exposed surface of a device cover, such as a glass cover. The energy harvesting circuit harvests energy from an electromagnetic signal transmitted by the power transmitter. Temperature data sensed by each temperature sensor is wirelessly transmitted by the wireless communication transmitting block to the wireless communication receiving block. The processor determines an ambient temperature corrected for heat influences on the temperature sensors by internal device electronics. The temperature measuring device is implemented within a mobile electronics device.

Temperature sensors are commonly used to measure the ambient temperature. However, implementing a temperature sensor within an electronic device for the purpose of measuring ambient temperature poses challenges. Electronic devices generate heat which affects the measurements made by the temperature sensor. If the objective is to measure the ambient temperature, such as the room temperature, and not the temperature of the electronic device within which the temperature sensor is mounted, then the temperature sensor either must be isolated from the heat generating portion of the electronic device, or the sensed temperature must be adjusted to account for that portion attributable to the heat generation of the electronic device. Adjusting the sensed temperature measurements to compensate for the internal heat generation is difficult as the amount of heat generated within the electronic device varies based on current power being consumed, such as the amount of processing power being used, and other operational aspects of the device. Orientation of the device, such as standing up or laying down, and the relative position of the temperature sensor may also influence the temperature readings since heat rises.
The location of the temperature sensor on or within the electronic device influences the measured temperature results. If the temperature sensor is positioned within the housing of the electronic device, then the temperature sensor is exposed to the heat generating components of the electronic device, thereby influencing the sensed temperature measurements. Further, there is little airflow into the housing for measuring of the ambient air temperature outside the housing. As such, positioning the temperature sensor within the electronic device housing for the purpose of measuring ambient temperature is not effective.
The temperature sensor can alternatively be positioned on an outer surface of the electronic device. However, typical housings are made of heat conducting material, such as metal, and therefore conduct heat generated from within the electronic device, again influencing the sensed temperature measurements. Also, many users of handheld electronic devices, such as cellular telephones, use protective cases over the device to protect from damage. Such cases block a temperature sensor positioned on the external housing. Some electronics devices have a surface made of a non-conductive material, such as a display surface of a cellular telephone having an exposed glass layer. When the temperature sensor is placed on the external side of the non-conducting glass layer, the glass layer insulates the temperature sensor from the heat generating components internal to the device. This insulation reduces the affects of the heat generating components on the sensed temperature measurements.
Positioning the temperature sensor on the external side of the glass layer provides insulation from the heat generating components within the electronic device. However, simply placing the temperature sensor on the exposed surface of the glass layer is not amenable for protecting the sensor as the sensor protrudes from the surface, exposing the sensor to potentially damaging contact. Additionally, temperature sensors are typically wired to electronic components to receive power and to transmit the measured sensed temperatures. The temperature sensor is wired to the electronic components used to operate the electronic device, which are also the heat generating components. The wired connection is heat conducting, and as such heat is conducted from the heat generating components to the temperature sensor via the wired connection. Providing a wired connection through the glass cover also poses manufacturing difficulties.
Accordingly, how can the temperature sensor distinguish between the heat generated by the electronic device and the ambient temperature? Further, in order to measure the ambient temperature, the temperature sensor needs to be exposed to the ambient air. How can the temperature sensor be assembled into the electronic device such that the temperature sensor is sufficiently exposed to the ambient air? Still further, the temperature sensor must be insensitive to errors due to device orientation, humidity, pressure, and other environmental and device related factors that may impact the temperature sensor measurement.


A tool damage/abnormality detecting device capable of easily appropriately setting an allowable range for a value of comparison between a present value and a near past average for indexes indicative of loads on a tool. A machining cycle counter index i is adjusted to i=0, machining is performed as the loads are detected in a given period, and indexes H(i) (area S of load values, absolute value (G−) of a maximum inclination between two points obtained during a decrease of loads, etc.) are acquired for n number of cycles. Thereafter, the indexes and values of comparison between the index value for a present cycle and the indexes for the n number of cycles are acquired. A first comparison value can be used for initial value setting for threshold values. If any of the comparison values is deviated from the allowable range, the threshold values are updated so that the allowable range extends, and an update history is saved. If damage/abnormality is observed visually or in any other manner, a threshold value update discontinue command is inputted, machining is stopped after completion of the cycle concerned, and update values for the latest threshold value are collected to be used as set threshold values.

1. Field of the Invention
The present invention relates to a tool damage/abnormality detecting device for detecting damage/abnormality, such as breakage of a tool used in machining, in machining workpieces of the same material into one and the same shape or continuously machining a large number of workpieces, such as components of the same specifications, by using a machine tool, and more specifically, to a technique to enable the detecting device to appropriately easily set an allowable range for indexes used for tool damage/abnormality detection. Typical tools to be subjected to damage/abnormality detection include a drill of a machining center, a tapping tool for tapping work, etc.
2. Description of the Related Art
In general, a tool used in a machine tool has its edge worn so that its cutting resistance gradually increases with the passage of machining time. With the passage of additional time, moreover, breakage of the tool, as well as its abrasion, results in damage or other similar abnormality, so that necessary machining accuracy for workpieces cannot be maintained. In such a case, it is naturally inappropriate to continue the same machining, and the tool must be replaced with a new one. The aforesaid damage or other similar abnormality will hereinafter be referred to as damage/abnormality.
Already proposed on this background are techniques for automatically detecting a situation equivalent to tool damage/abnormality in the currently prevailing unattended machining or long-time automatic machining. Many of the conventionally proposed techniques are based on a system described in JP 3446518B and JP2003-326438A and JP2004-130407A. In this system, indexes indicative of loads that act on a tool for machining a workpiece (torque of a motor for driving the tool and thrust load applied to the tool) are detected in a plurality of machining cycles. For each machining cycle, the index for the present machining cycle and an average of the indexes for the machining cycles preceding the present machining cycle are compared. If the result of the comparison is deviated from an allowable range of preset indexes, it is concluded that the tool is subject to damage/abnormality.
In setting the allowable range for an index, threshold values (normally, upper and lower limit values) for the index are preset, so that it is important how to determine the preset threshold values. If the preset threshold values are inappropriate, detection of damage/abnormality may be delayed to cause machining failure (because the allowable range is upwardly or downwardly too wide). If the detection of damage/abnormality is premature (or if the allowable range is upwardly or downwardly too narrow), on the other hand, tools with sufficient life expectancy may be wasted.
Actually, so far, no satisfactory technology development has been made to provide a method for appropriately setting threshold values for indexes indicative of loads that act on tools.
There is a method, for example, in which threshold values for an index (load average) are determined by multiplying, for example, a load average obtained by a cutting test or a load average obtained immediately before machining by a given coefficient. However, there is no designation of a specific method for setting the given coefficient. According to JP 3446518B in which "abnormality detecting method for rotary tool and apparatus therefor" is described, by way of example, threshold values are set in accordance with the changing rate of a load value. By doing this, abnormality can be detected accurately and appropriately on a real-time basis. More specifically, the threshold values are set by multiplying a damage load level Lmax fixed according to the size of a drill or the like by a constant k within the range of 0 to 1 that is settled depending on a changing rate ΔFn of the load value.
However, there is no definite indication of specific methods for determining the aforesaid values Lmax and k. In general, data on damage loads vary depending on the machine, tool, work material, machining conditions, etc., so that it is very desirable to collect the data on the site of work. In the case of a drill or tap, although its abnormality can be detected during a machining cycle, it can be dealt with only after the termination of the machining cycle. Thus, real-time detection is not essential.

Tool damage/abnormality detecting device


A voltage controlled oscillator comprises a plurality of differential amplification stages each arranged to introduce a phase shift between its differential input signal and its differential output signal. The frequency at which the desired phase shift occurs can be controlled by adjusting the control signal Vc. The stages are arranged such that the output of one amplifier becomes the input to the next amplifier, making the phase shift additive. Further, a phase shift of 180.degree. may be introduced by inverting the output from one stage before inputting it to the next stage. The total phase shift introduced by the stages is 360.degree.. In this way, an oscillating signal of varying phase shift is produced at the output of each stage. Each stage comprises a standard differential amplifier, well known in the art, having a matched pair of p-channel transistors and a matched pair of n-channel transistors. The differential input is applied to each gate of the n-channel transistor pair, and the differential output is generated at the drains of the n-channel transistor pair.

A common application of a voltage controlled oscillator is in a phase locked loop. A phase locked loop comprises a phase comparator which compares the phase between a periodic incoming signal and a feedback signal. The phase comparator generates an error signal dependent on the phase difference. The error signal is passed through a filter to form a control signal for a voltage controlled oscillator which generates an output signal oscillating at a frequency dependent on the voltage of the control signal supplied from the filter to the voltage controlled oscillator.
Such loops are well known and have many applications, one of which is to increase on a chip the frequency of an external clock signal supplied to the chip. In such a case the output signal from the voltage controlled oscillator is fed back through a divide-by-n circuit to form the feedback signal for the phase comparator. The external clock signal is used as the incoming signal and the output signal from the voltage controlled oscillator (before it is fed back through the divide-by-n circuit) thus forms a periodic signal which oscillates at a selected multiple of the frequency of the incoming signal and at a fixed phase relative thereto.
Phase locked loops have been used to perform this function for some years now. However, problems have arisen when these loops are implemented on a chip with other circuitry. On chip circuitry, particularly logic circuitry, generates noise which can have a significant effect on the power supply which is required for operation of the phase locked loop. It is desirable that the phase locked loop be immune to such noise. Moreover, the stability of the loop is a function of its open loop gain which varies considerably with process and temperature conditions. It is difficult therefore to design a phase locked loop to have a particular open loop gain which will remain constant under different conditions.
An important component of a phase locked loop is the voltage controlled oscillator, and with existing designs this is also the most sensitive to noise affecting its power supply. A commonly used voltage controlled oscillator is based on a principle of operation in which a current source within the voltage controlled oscillator is controlled by the control signal for the voltage controlled oscillator to generate a current in dependence on the voltage of the control signal. The value of this current affects the rate at which a capacitor of the voltage controlled oscillator charges or discharges. On a graph of voltage against time, a ramp of a gradient depending on the current is thus generated. At the point at which this crosses a predetermined threshold, a voltage transition is generated which forms an edge of the output signal. The frequency of the output signal is related to the gradient of the ramp. If the output signal of the voltage controlled oscillator is to produce edges at fixed intervals it is important that the voltage ramp always crosses the threshold with a fixed delay from initiation of the ramp. Noise from the power supply can affect the shape of the ramp by introducing spikes or glitches so that there is no longer certainty over the time at which the ramp will cross the threshold. In these circumstances, the output signal is said to suffer from "jitter". A clock signal with jitter is unacceptable for many timing applications.
To overcome this, with some voltage controlled oscillators, a resistor is placed in one of the power supply lines to form, with capacitance between the positive and ground supply lines, a filter for filtering noise from the power supply. In this way, the voltage controlled oscillator is decoupled from the power supply. This has a disadvantage in that voltage is dropped across the resistor which reduces the supply available to the phase locked loop. As the speed requirement for the phase locked loop increases, so more current will be consumed and with this the voltage drop across the resistor will be increased, perhaps to such an extent that there will be insufficient supply to operate the phase locked loop.
It is an object of the present invention to provide a voltage controlled oscillator which is less sensitive to power supply noise. This means that the resistor included in the supply line of the power supply can be reduced in value or removed altogether. This would have the desirable result that less or no voltage would be dropped across the resistor, thus allowing the voltage controlled oscillator to consume more current and hence function at higher frequencies.

Voltage controlled ring oscillator having differential amplifier stages


The apparatus of the present invention provides the user with a receptacle for a hot tub cover that can be moved away from the hot tub thereby preventing blocking of the view. The apparatus of the present invention is dimensioned such that it will accept both foldable and non-foldable type covers and can be used with both round and rectangular tubs. Further, the vertical support member of the apparatus is angled such that when the cover is stored it is prevented from blowing out.

Hot tubs, or spas as they are sometimes denominated, have been in use for many years. Modernly, both fixed and portable hot tubs are in wide use. These hot tubs come in a variety of geometries, but are generally round or rectangular. Common to most hot tubs is a cover that is used to keep the water from cooling off when the hot tub is not in use. These covers are constructed of a thick insulation and have a fabric skin to protect the underlying insulation.
While not true for virtually all hot tub covers, far and away the majority are dimensioned approximately the same. The covers have a foam insulating section that is four to six inches thick and a vinyl or canvas covering skin to protect the foam from harmful solar rays and weather. Many of the contemporary covers fold in half in order to allow the user to remove the cover for use. Common to these covers are two elements: they are awkward and bulky, and they are heavy after the insulation has become saturated with water. This saturation occurs due to water vapor condensation from the underlying body of water.
Contemporary hot tub covers appear in two main design camps. The first is the free standing type cover. In this design the user must remove the cover and wrestle it to a temporary storage place during hot tub use. Due to the large sail area involved, any breeze will make the cover very difficult to handle and can cause injury to the user. However, this type of design does have the advantage of removing the cover completely from the view of the hot tub user.
The second design type is the hinged cover. In this design a frame is attached to the hot tub and the cover then attached to the frame by some mechanical means. When the user desires to enter the hot tub, the cover is folded or lifted and then folded, with the bulk of the force being taken up by the hinge mechanism. This neatly solves the problem of the stand alone covers, but introduces a highly undesirable problem; the user's view is blocked by the cover on the end of the tub to which the hinge mechanism is attached.
What would be desirable would be a hot tub cover storage apparatus that would eliminate both the problem with the difficulty in handling associated with stand alone covers and at the same time the view blockage problem associated with the hinged type covers.


The invention relates to the use of para-coumaric acid or para-hydroxycinnamic acid derivatives in cosmetic or dermatological compositions, specifically to the use of at least one compound derived from para-coumaric acid having a general formula (I) below:

To combat solar radiation, the skin has differentiated cells that are particularly suited to this function: the melanocytes. In the course of a complex process, melanogenesis, these cells manufacture melanin, a dark pigment which has the effect of protecting the skin structures and of increasing the time required to contract a solar erythema. However, not all melanins are protective. In particular, there exists one form of melanin, known as phaeomelanin, that is extremely phototoxic. Like all melanins, it is capable of reacting with certain forms of free radicals, but it can also cause the formation of free radicals that are even more toxic, and which are liable to cause irreversible damage to the genetic material of keratinocytes. Moreover, certain disorders associated with dysfunction of the melanization unit are liable to cause hyperpigmentation, which is occasionally particularly unsightly.
Thus, the use of melanin synthesis inhibitors is particularly advantageous in cosmetology, not only for applications in which true depigmentation is desired, as in the case of the bleaching of highly pigmented skin or the inhibition of hyperpigmentation in certain unaesthetic aspects, for example, but also for applications for lightening the complexion and for giving luminosity to the skin and radiance to the surface tissues. This inhibition of melanin synthesis may also be particularly advantageous in the context of therapeutic treatment for treating a true pathology.
para-Coumaric or para-hydroxycinnamic acids have been described as inhibitors of melanin production in numerous studies. However, these substances do not make it possible to obtain significant inhibitory effects on melanin synthesis. This excessively weak activity does not make it possible to obtain strong enough effects and these substances are thus little used in cosmetic or pharmaceutical topical applications for effectively combating unsightly pigmentations.
The prior art mentions in particular the use of vitamin C (or derivatives thereof) or kojic acid (or derivatives thereof) for inhibiting tyrosinase, but these molecules are either cytotoxic at the concentration used, or of little efficacy. It is known practice in particular to use ferulic acid or caffeic acid as depigmenting agent in cosmetic compositions. However, these compositions are not entirely satisfactory as regards the efficacy of the depigmenting action.
Thus, an aim of the present invention is essentially to solve the technical problem that consists in providing a depigmenting agent that is more active than those currently used, such as caffeic acid or ferulic acid.
Another aim of the present invention is also to provide compositions using these depigmenting agents, cosmetic care methods and/or pharmaceutical treatment methods using these depigmenting agents, and also the use of these depigmenting agents to exert antiradical and/or antiinflammatory activity.
A further aim of the present invention is also to provide compositions whose active compounds are extracted from plants.
Yet a further aim of the present invention is also to provide compositions that can be applied topically.
An additional aim of the present invention is also to provide depigmenting agents for combating skin hyperpigmentation, especially for aesthetic purposes, mainly when the skin has at least one hyperpigmented localized area.
A further aim of the present invention is to solve the technical problems mentioned above in a safe and reliable way and especially while avoiding undesirable side effects, particularly in human beings, for example by reducing the cytotoxicity of the active agents used.

This patent is subject to a terminal disclaimer.

Para-coumaric acid or para-hydroxycinnamic acid derivatives and their use in cosmetic or dermatological compositions

Abstract: in which, especially, Z represents an oxygen or an —NH— group; X and Y are identical and each represent a CH or CH2 group, as an active principle with depigmenting, free-radical-scavenging and/or antiinflammatory activity. The invention also relates to the use of the above compounds for cosmetic care or for the preparation of a pharmaceutical composition, especially for depigmenting an area of skin, having antiradical and/or antiinflammatory activity.

BASF Beauty Care Solutions France S.A.S.


There is provided a lens module including: a first lens having positive refractive power; a second lens having positive refractive power; a third lens having a shape in which an object-side surface thereof is concave; a fourth lens having refractive power; a fifth lens having negative refractive power; and a sixth lens having negative refractive power, having a shape in which an image-side surface thereof is concave, and having at least one point of inflection formed on the image-side surface thereof.

The present disclosure relates to a lens module having an optical imaging system including six lenses.
Generally, a camera for a portable terminal includes a lens module and an imaging device.
Here, the lens module includes a plurality of lenses and includes an optical system configured using the plurality of lenses and projecting an image of a subject onto an imaging device. Here, the imaging device may be a device such as charge coupled device (CCD), or the like, and generally has a pixel size of 1.4 μm or more.
However, in accordance with a gradual decrease in portable terminal and camera module sizes, a pixel size of the imaging device has been decreased to 1.12 μm or less. Therefore, development of a lens module having a low F No. of 2.3 or less in which a high resolution may be implemented even under the above-mentioned conditions has been demanded.
For reference, as the related art associated with the present disclosure, there are provided Patent Documents 1 and 2. Patent Documents 1 and 2 disclose a lens module having an optical system including six lenses.


A converter module for use as a phase in a multiphase DC-DC converter having a data bus for transferring current-sharing information is provided. The converter module includes a power stage and a controller. The power stage comprises an input for receiving an input voltage and an output for providing an output voltage and an output current. The controller is coupled to the power stage to receive a feedback signal from the power stage. The controller further comprises a data bus port configured to receive the current-sharing information from the data bus and provide updated current-sharing information to the data bus.

a. Field of the Invention
The instant invention relates to active current sharing in a multiphase DC-DC converter.
b. Background
Power supplies for high performance microprocessors often must deliver low supply voltages with high currents while maintaining tight output voltage regulation in the presence of large load transients. Interleaved multiphase converters have been used in such systems due to advantages, such as lower switching frequencies for each phase, total current division among the phases, fast transient response, and use of smaller active and passive components. Multiphase converters, however, generally require additional circuitry to ensure appropriate current sharing and phase shifting between the phases.
Many analog approaches have been used to achieve current sharing. "Master-slave" schemes, for example, include a converter that operates as a master converter to regulate the current of that converter and other slave converters via a reference signal. "Democratic" or "autonomous" schemes have also been used in which multiple converters are connected to an analog sharing line to produce a current reference and the individual converters are controlled to match their output currents to the current reference. "Central-limit" schemes utilize a central controller to provide a current error of each phase relative to the average load current. In each of these approaches, however, the master must receive information from each phase. This results in a delay in the controller while information is transferred and requires dedicated traces to each phase (resulting in a relatively large board area) and a communication protocol so that information can be through the phases or across a shared bus (e.g., a CAN bus, a daisy-chain, etc.).
Digital control approaches have also been proposed for multiphase converters in order to provide for increased design flexibility and programmability, immunity to analog component variations, ease of integration with other digital systems, and the ability to implement more advanced control schemes. Previously proposed digital control approaches, however, have been based on a master digital controller in which one of the digital controllers (or another dedicated digital controller that is not part of a phase) operates as a master controller to regulate the current of that converter and other slave via a reference signal. In each of these cases, however, a relatively large area of a PC board and number of hard wired communications configurations between the phases and/or the dedicated master and the phases.

Active current sharing multiphase DC-DC converter

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