A pet waste collector including a shaft including a first end and a second end, a clamp mechanism connected to the second end of the shaft, and an actuator mechanism operably connected to the clamp mechanism, the actuator mechanism be disposed at the first end of the shaft. The clamp mechanism is movable between an open position and a closed position. The clamp mechanism is configured to retain a bag in the open position. The clamp mechanism moves to the closed position in response to actuation of the actuator mechanism to capture pet waste within the bag.

Recent history has seen a proliferation of dogs being adopted as household pets. Pets provide many benefits to our lives; yet, every benefit has an associated duty. Duties associated with pets include caring for them, spending time with them, feeding them, walking them, and, of course, cleaning up after them.
The days of tying up the dog to a post and providing a doghouse in the back yard are over, which is seen, at the very least as socially unacceptable and at most inhumane treatment. Consequently, most pets live in the house with us and must be walked throughout the neighborhood for exercise.
As pets are no longer confined to the back yard, cleaning up after them has taken on a heightened sense of duty. Laws, and the enforcement of them, have become strict regarding cleaning up after pets. This requires having something portable to bring with us during walks that can be used to collect pet waste and transport it back to the home.
Pet waste collectors do exist, but they tend to be heavy and unwieldy. Furthermore, the use of them requires one to clean the fecal matter from the apparatus after use. For this reason pet owners tend to opt for plastic bags as a source of waste collection. The use of bags, however, requires one to kneel down close to the waste, use one's hand as the means to entrain the waste, and carry the entrained waste within the bag back to the home.
Accordingly, there exists a need for a means by which the functionality of a pet waste collector and the ease and convenience of a waste bag can be exploited in one device.


A bed skirt system includes a bed skirt that includes a cloth panel that has a perimeter edge, a top side and bottom side. The perimeter edge includes a front edge, a back edge, a first side edge and a second side edge. A cloth perimeter flap is attached to and extends downwardly from the first side edge, the second side edge and the front edge. A coupler is configured to removably attach the bottom side of the panel to an upper surface of the box spring. The bed skirt is positioned on the box spring and secured thereto with the coupler.

1. Field of the Invention
The present invention relates to bed skirt devices and more particularly pertains to a new bed skirt device for retaining a bed skirt on a box spring so that it does not easily shift when a mattress is placed on the box spring.
2. Description of the Prior Art
The use of bed skirt devices is known in the prior art. U.S. Pat. No. 5,715,553 describes a bed skirt device that is extendable around and attached to bed spring. Another type of bed skirt device is U.S. Pat. No. 3,999,233 again which is extendable around and attachable to a box spring. Still another bed skirt device is found in U.S. Pat. No. 5,621,931 and includes a skirt that is selectively detachable from a panel positioned on top of a box spring.
While these devices fulfill their respective, particular objectives and requirements, the need remains for a device that is easily securable to a box spring and which functions generally as a conventional bed skirt. The device should remain in place when a mattress is positioned on the box spring so that a user need not struggle with repositioning the bed skirt so that it is properly aligned with the box spring.


Novel glucocorticoid and thyroid receptor ligands as provided which have the general formula (I):

This invention relates to novel compounds that are liver-selective glucocorticoid receptor antagonists and liver-selective thyroid receptor agonists, to methods of preparing such compounds, and to methods for using such compounds in the regulation of metabolism, especially lowering serum glucose and low density lipoprotein levels.
A major problem with both Type 2 and Type 1 diabetes is that there is excessive and inappropriate production of glucose by the liver. This abnormality is the primary cause of fasting hyperglycemia and occurs in addition to defects in regulation of insulin release and in peripheral sensitivity to insulin. Thus, agents that decrease liver glucose production would be beneficial for treating both Type 2 and also Type 1 diabetes.
Intensive treatment of the hyperglycemia of Type 1 diabetes mellitus has been shown markedly to decrease the development of ocular renal and neuropathic complications, and there is evidence that intensive treatment is also beneficial for Type 2 diabetes. The available data also indicate that most patients are currently not receiving ideal and state-of-the-art treatment for either Type 2 or Type 1 diabetes. This inadequacy exists in spite of the availability of several different types of preparations of insulin for treatment of both Type 2 and Type 1 diabetes, and of a number of additional modalities, including agents that stimulate insulin release (e.g., sulfonylureas), influence liver glucose production (e.g., metformin), affect the sensitivity to insulin (e.g., troglitazone) and glucose absorption (e.g., xcex1-glucosidase inhibitors). In spite of the availability of several different orally-active agents that lower blood glucose levels. many patients with Type 2 diabetes also require insulin for control of their blood sugar levels. Overall, insulin usage in Type 2 diabetes exceeds that for Type 1 diabetes, and there is general agreement that there is a need for additional orally-active agents to treat Type 2 diabetes.
The glucocorticoid secretions of the adrenal gland (dominantly cortisol in humans) were so named because of their ability to regulate glucose metabolism. These steroids stimulate the production of glucose in the liver by promoting gluconeogenesis, which is the biosynthesis of new glucose (i.e. not glucose from glycogen). Thus, in glucocorticoid insufficiency there is a tendency to hypoglycemia, with decreased liver glucose production. Further development of Addison""s disease in the diabetic patient generally leads to lowered glucose levels. Conversely, glucocorticoid excess can provoke frank diabetes in individuals with latent diabetes mellitus, and generally aggravates glycemic control in established diabetic patients. Similar influences have been observed in various animal models.
The increased glucose production in response to glucocorticoids is due to effects on a number of proteins. Important among these are effects on various transaminases that convert amino acids to glucose precursors, and induction of glucose-6 phosphatase and phosphoenolpyruvate carboxy-kinase (PEPCK). Even a modest increase of PEPCK, as obtained in transgenic mice, gives rise to hyperglycemia. In mice with Type 2 diabetes and increased levels of corticosterone (the endogenous glucocorticoid of that species) there is increased expression of PEPCK. This over expression of PEPCK can be repressed by treatment with the known GR antagonist RU486 with a concomitant decrease in the hyperglycemia.
The considerations outlined above indicate that if the action of endogenous glucocorticoids on liver glucose production could be blocked in a specific manner, glycemic control could be improved for the benefit of the diabetic patients. However, to date, all means to block glucocorticoid action have been general. Thus, adrenalectomy leaves the patient with frank adrenal insufficiency and the problems of Addison""s disease. Blockade of adrenal steroid production, for example by metyrapone, or of glucocorticoid action, for example with RU486, is ordinarily of limited duration of effectiveness and when it is effective also results in generalized adrenal insufficiency. Long term compensatory ACTH hypersecretion and increased cortisol release that override the block generally overcome these treatments. By contrast, a liver-specific GR antagonist would not have these problems, should counteract the increased liver glucose production in diabetes mellitus, and should be useful for treatment of Type 2 diabetes.
A liver selective GR antagonist offers a number of advantages. First, it should decrease liver glucose production. This action will have a significant effect on glycemic control. In fact, excessive liver glucose production can be the major defect in Type 2 diabetes. Secondly, such a drug should enhance insulin sensitivity because of the overall improvement in the metabolic milieu and the amelioration of the hyperglycemia-induced defects in insulin action and secretion. The decreased demand on xcex2-cell secretion, as a result of a reduction in glycemia, would retard the progressive xcex2-cell dysfunction characteristic of Type 2 diabetes. Another advantage of GR antagonist treatment compared with sulfonylurea or insulin treatment is that the patient would run a lower risk of hypoglycemia.
Previous efforts to block glucocorticoid action in diabetes have been hampered by the fact that any compounds used would generally block glucocorticoid action in all tissues and would lead to the potential problems of glucocorticoid insufficiency, such as hypotension, shock, and ultimately death if the organism were exposed to sufficiently-strong stress conditions. In contrast, a liver-selective GR-antagonist with minimal effects outside the liver could be used as a front-line therapy for Type 2 diabetes, or could be used in conjunction with other existing therapies.
Thyroid hormones affect the metabolism of virtually every cell of the body. At normal levels. these hormones maintain body weight, the metabolic rate, body temperature, and mood, and influence serum low density lipoprotein (LDL) levels. Thus, in hypothyroidism there is weight gain, high levels of LDL cholesterol, and depression. In excess with hyperthyroidism, these hormones lead to weight loss, hypermetabolism, lowering of serum LDL levels, cardiac arrhythmias, heart failure, muscle weakness, bone loss in postmenopausal women, and anxiety.
Thyroid hormones are currently used primarily as replacement therapy for patients with hypothyroidism. Therapy with L-thyroxine returns metabolic functions to normal and can easily be monitored with routine serum measurements of levels of thyroid-stimulating hormone (TSH), thyroxine (3,5,3xe2x80x2, 5xe2x80x2-tetraiodo-L-thyronine, or T4) and triiodothyronine (3,5,3xe2x80x2-triiodo-L-thyronine, or T3). However, certain of the deleterious effects of thyroid hormones limit the rapidity with which replacement therapy can be given and in some circumstances, particularly in older individuals, even completely exclude replacement therapy.
In addition, some effects of thyroid hormones may be therapeutically useful in non-thyroid disorders if adverse effects can be minimized or eliminated. These potentially-useful influences include weight reduction, lowering of serum LDL levels, amelioration of depression and stimulation of bone formation. Prior attempts to utilize thyroid hormones pharmacologically to treat these disorders have been limited by manifestations of hyperthyroidism, and in particular by cardiovascular toxicity.
Development of liver specific and selective thyroid hormone receptor agonists could lead to specific therapies for lowering of serum LDL levels while avoiding the cardiovascular and other toxicities of native thyroid hormones. Tissue-selective thyroid hormone agonist may be obtained by selective tissue uptake or extrusion, topical or local delivery, targeting to cells through other ligands attached to the agonist.
In accordance with the present invention, compounds are provided which are glucocorticoid and thyroid hormone receptor ligands, and have the general formula I:
in which:
R1 is an aliphatic hydrocarbon, an aromatic hydrocarbon, a carboxylic acid or ester thereof, alkenyl carboxylic acid or ester thereof, hydroxy, halogen, or cyano, or a pharmaceutically salt thereof, and all stereoisomers thereof;
R2 and R3 are the same or different and are hydrogen, halogen, alkyl of 1 to 4 carbons or cycloalkyl of 3 to 6 carbons, at and least one of R2 and R3 being other than hydrogen.
X is carbonyl (Cxe2x95x90O) or methylene (CH2).
R4 is an aliphatic, other than C1 aromatic, heteroaromatic or cycloaliphatic group
R5 is hydrogen, halogen, alkyl of 1 to 4 carbons, cycloalkyl of 3 to 6 carbons or cycloalkyl alkyl of 5 to 8 carbons.
Y is hydroxyl, methoxy, amino, alkyl amino or amide.
Preferably, L is a linear or branched C2 to C6 alkyl more preferably t-butyl.
R2 and R3 are preferably halogen or a halogenated alkyl, more preferably bromine or another hydrophobic group of similar size to bromine. A possible halogenated alkyl is xe2x80x94CF3.
In the (CH2 )n R1 side chain n is preferably 1.
R1 is an acidic or negatively-charged group, and
carboxylic acid or a bioisoster of carboxylic acid is preferred. Bioisosters of carboxylic acids are groups that display the same receptor-binding activity and thus, in general. the same in vivo activity. Examples are tetrazole, acylsulphonamides, phosphonates, and sulphonates.
In addition, in accordance with the present invention, a method for preventing, inhibiting, or treating a disease associated with a metabolic dysfunction or which is dependent upon the expression of a glucocorticoid or thyroid hormone receptor regulated gene is provided, wherein a compound of formula I is administered in a therapeutically effective amount. The compound of formula I is preferably also liver selective. Examples of such diseases associated with metabolic dysfunctions or are dependent upon the expression of a glucocorticoid receptor regulated gene are set out hereinafter and include diabetes and inflammation. Examples of such diseases that are dependent upon expression of thyroid hormone receptor regulated gene include obesity, hypercholoesterolemia, atherosclerosis, cardiac arrhythmias, depression, osteoporosis, hypothyroidism, goitre, thyroid cancer as well as glaucoma and congestive heart failure.
The following definitions apply to the terms as used throughout this specifications. unless otherwise limited in specific instances.
The term xe2x80x9cglucocorticoid receptor ligandxe2x80x9d as used herein is intended to cover any moiety that binds to a glucocorticoid receptor. The term xe2x80x9cthyroid hormone receptor ligandxe2x80x9d as used herein is intended to cover any moiety that binds to a thyroid hormone receptor. The ligand may act as an agonist, an antagonist, a partial agonist, or a partial antagonist.
The term xe2x80x9caliphatic hydrocarbon(s) as used herein refers to acyclic straight or branched chain groups which include alkyl, alkenyl, or alkynyl groups.
The term xe2x80x9caromaticxe2x80x9d hydrocarbons(s) as used herein refers to groups including aryl groups as defined herein.
The term xe2x80x9carylxe2x80x9d as employed herein alone or as part of another group refers to monocylcic and bicyclic aromatic groups containing 6 to 10 carbons in the ring portion (such as phenyl or napthyl including 1-naphthyl and 2-naphthyl) and may be optionally substituted through available carbon atoms with 1, 2, or 3 groups selected from hydrogen, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, trifluoromethyl, thiomethyl, difluoromethyloxy trifluoromethyloxy, thiotrifluoromethyl, alkynyl, hydroxy, nitro, or cyano.
Unless otherwise indicated, the term xe2x80x9clower alkenylxe2x80x9d or xe2x80x9calkenylxe2x80x9d as used herein by itself or as part of another group refers to straight or branched chain radicals of 2 to 12 carbons, preferably 2 to 5 carbons, in the normal chain, which include one to six double bonds in the normal chain, such as vinyl, 2-propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl, 3-nonenyl, 4-decenyl, 3-undecenyl, 4-dodecenyl, and the like.
Unless otherwise indicated, the term xe2x80x9clower alkynylxe2x80x9d or xe2x80x9calkynylxe2x80x9d as used herein by itself or as part of another group refers to straight or branched chain radicals of 2 to 12 carbons, preferably 2 to 8 carbons, in the normal chain, which include one triple bond in the normal chain, such as 2-propynyl, 3-butynyl, 2-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl, 4heptynyl, 3-octynyl, 3-nonynyl, 4-decynyl, 3-undecynyl, 4-dodecynyl and the like.
The term xe2x80x9chalogenxe2x80x9d or xe2x80x9chaloxe2x80x9d as used herein alone or as part of another group refers to chlorine, bromine, fluorine, and iodine as well as CF3, with chlorine or bromine being preferred.
The term xe2x80x9caminoxe2x80x9d as employed herein alone or as part of another group may optionally be independently substituted with one or two substituents, which may be the same or different, such as alkyl, aryl, arylalkyl, hydroxyaryl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl or thioalkyl. These substituents may be further substituted with a carboxylic acid or any of the substituents for alkyl as set out above. In addition, the amino substituents may be taken together with the nitrogen atom to which they are attached to form 1pyrrolidinyl, 1piperidinyl, 1azepinyl, 4morpholinyl, 4thiamorpholinyl, 1piperazinyl, 4alkyl1piperazinyl, 4arylalkyl1piperazinyl, 4diarylalkyl1piperazinyl, 1pyrrolidinyl, 1piperidinyl, or 1azepinyl, optionally substituted with alkyl, alkoxy, alkylthio, halo, trifluoromethyl or hydroxy.
The compounds of formula I can be present as salts, in particular pharmaceutically acceptable salts. If the compounds of formula I have, for example, at least one basic center, they can form acid addition salts. These are formed, for example, with strong inorganic acids, such as mineral acids, for example sulfuric acid, phosphoric acid or a hydrohalic acid, with strong organic carboxylic acids, such as alkanecarboxylic acids of 1 to 4 carbon atoms which are unsubstituted or substituted, for example, by halogen, for example acetic acid, such as saturated or unsaturated dicarboxylic acids, for example oxalic, malonic, succinic, maleic, fumaric, phthalic or terephthalic acid, such as hydroxycarboxylic acids, for example ascorbic, glycolic, lactic, malic, tartaric or citric acid, such as amino acids, (for example aspartic or glutamic acid or lysine or arginine), or benzoic acid, or with organic sulfonic acids, such as (C1-C4)alkyl or arylsulfonic acids which are unsubstituted or substituted, for example by halogen, for example methane- or ptoluene-sulfonic acid. Corresponding acid addition salts can also be formed having, if desired, an additionally present basic center. The compounds of formula I having at least one acid group (for example COOH) can also form salts with bases. Suitable salts with bases are, for example, metal salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium or magnesium salts, or salts with ammonia or an organic amine, such as morpholine, thiomorpholine, piperidine, pyrrolidine, a mono, di or trilower alkylamine, for example ethyl, tertbutyl, diethyl, diisopropyl, triethyl, tributyl or dimethyl-propylamine, or a mono, di or trihydroxy lower alkylamine, for example mono di or triethanolamine. Corresponding internal salts may furthermore be formed. Salts which are unsuitable for pharmaceutical uses but which can be employed, for example, for the isolation or purification of free compounds I or their pharmaceutically acceptable salts, are also included.
Preferred salts of the compounds of formula I which include a basic group include monohydrochloride, hydrogensulfate, methanesulfonate, phosphate or nitrate.
Preferred salts of the compounds of formula I which include an acid group include sodium, potassium and magnesium salts and pharmaceutically acceptable organic amines.
Preferred are compounds of the invention of formula I wherein:
R1 is carboxylic acid (COOH) or esters thereof, OH, CN, or halogen.
R2 and R3 are halogen such as bromo or chloro; or
R2 and R3 are each isopropyl or one is isopropyl and the other is ethyl or tert-butyl.
R4 is aryl.
R5 is isopropyl.
X is a carbonyl (Cxe2x95x90O) or methylene (CH2).
Y is hydroxyl or methoxy.
n is 0-4.
Especially preferred compounds of the invention have the structures
The compounds of formula I may be prepared by the processes exemplified in the following reaction schemes. Examples of reagents and procedures for these reactions appear hereinafter and in the working Examples.
Compounds of formula I of the invention can be prepared using the sequence of steps outlined in Scheme 1 or 2 set out below.
The compounds of the invention are glucocorticoid receptor antagonists or thyroid receptor agonists that are preferably liver selective, and as such are useful in the treatment of diabetes (alone or in combination with agents that stimulate insulin release such as sulfonylureas, influence liver glucose production such as metformin, affect the sensitivity to insulin such as troglitazone, or inhibit glucose absorption such as xcex2-glucosidase inhibitors), obesity, hypercholesterolemia and atherosclerosis by lowering of serum LDL levels (alone or in combination with a cholesterol-lowering drug such as an HMG CoA reductase inhibitor).
The compounds of the invention can be administered orally or parenterally such as subcutaneously or intravenously, as well as by nasal application, rectally or sublingually to various mammalian species known to be subject to such maladies, e.g., humans, cats, dogs and the like in an effective amount within the dosage range of about 0.1 to about 100 mg/kg, preferably about 0.2 to about 50 mg/kg and more preferably about 0.5 to about 25 mg/kg (or from about 1 to about 2500 mg, preferably from about 5 to about 2000 mg) on a regimen in single or 2 to 4 divided daily doses.
The active substance can be utilized in a composition such as tablet, capsule, solution or suspension or in other type carrier materials such as transdermal devices, iontophoretic devices, rectal suppositories, inhalant devices and the like. Pharmaceutical compositions of this invention comprise any of the compounds of the present invention, and pharmaceutically acceptable salts thereof, with any pharmaceutically acceptable carrier, adjuvant or vehicle. Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
The pharmaceutical compositions of this invention may be dministered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The pharmaceutical compositions of this invention may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles. The term parenteral as used herein includes subcutaneous, intracutaneous, intrave-nous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injec-tion or infusion techniques.
The pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension. This suspen-sion may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the ac-ceptable vehicles and solvents that may be employed are mannitol, water, Ringer""s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conven-tionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharma-ceutical-ly-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant such as Ph. Helv or a similar alcohol.
The pharmaceutical compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, and aqueous suspen-sions and solutions. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stea-rate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are administered orally, the active ingredient is combined with emulsify-ing and suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.
As the skilled artisan will appreciate, lower or higher doses than those recited above may be required. Specific dosage and treatment regimens for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combina-tion, the severity and course of the disease, the patient""s disposition to the disease and the judgment of the treating physician. The composition or carrier will contain about 5 to about 500 mg per unit of dosage of a compound of formula I. They may be compounded in conventional matter with a physiologically-acceptable vehicle or carrier, excipient, binder, preservative, stabilizer, flavor, etc., as called for by accepted pharmaceutical practice.

Glucocorticoid and thyroid hormone receptor ligands for the treatment of metabolic disorders

Abstract: in which R1 is an aliphatic hydrocarbon, an aromatic hydrocarbon, carboxylic acid or ester thereof, alkenyl carboxylic acid or ester thereof, hydroxy, halogen, or cyano, or a pharmaceutically acceptable salt thereof. R2 and R3 are the same or different, and are hydrogen, halogen, alkyl of 1 to 4 carbons, or cycloalkyl of 3 to 5 carbons, at least one of R2 and R3 being other than hydrogen. X is carbonyl or methylene. R4 is an aliphatic, aromatic or heteroaromatic. Y is hydroxyl, methoxy, amino, or alkyl amino. n is an integer from 0 to 4. A method for treating diseases associated with metabolism dysfunction or which are dependent on the expression of a glucocorticoid or thyroid receptor gene such as diabetes, hypercholesterolemia, or obesity using these compounds is also disclosed.


The present disclosure provides a method for detecting a position of a movable structure. The movable structure is applicable to an electronic device including a body and a detection component, and configured to move between a first position at which the movable structure is received in the body and a second position at which the movable structure extends out of the body. The detection component includes at least one distance sensor disposed on the movable structure. The at least one distance sensor is configured to be received in the body when the movable structure is at the first position and to protrude beyond the body when the movable structure is at the second position. The method includes: receiving a detection signal value outputted by the at least one distance sensor; and determining a position of the movable structure relative to the body according to the detection signal value.

A phone is a common electronic product in daily life. With higher and higher requirements on experience and feeling of a consumer to the phone, a screen-to-body ratio of the phone is critical for providing a good experience to the consumer, such that a large screen phone or even a full screen phone has been favored by more and more consumers. However, a front camera disposed on a front panel of a conventional phone may influence the screen-to-body ratio of the phone. Thus, how to reasonably dispose and use the front panel on the front panel becomes a technology challenge for improving the screen-to-body ratio of the phone.

Method for detecting position of movable structure, detection component, and electronic device

GUANGDONG OPPO MOBILE TELECOMMUNICATIONS CORP., LTD.


The combination of a portable article and a security system. The security system includes a tether having a length. The tether is attached to the portable article and a support so that the portable article is movable relative to the support and confined in movement relative to the support by the tether within a range dictated by the length of the tether. The security system further includes a security response assembly that is triggered as an incident of the portable article being repositioned with the tether attached to the portable article.

1. Field of the Invention
This invention relates to security systems for portable articles and, more particularly, to a security system that has a response assembly that is triggered through the repositioning of an object that is being monitored.
2. Background Art
The proliferation of portable consumer electronic articles has presented an ongoing challenge to those in the security industry. Myriad products are currently offered and continue to be developed in communications, data management, music playing, etc. The product displays in establishments that offer these products continue to grow in size. In the highly competitive electronics industry, marketing has dictated a "hands on" method of offering the products to end users. Consumers have in recent years become accustomed to going into "mega-" electronics stores and literally having at their finger tips most existing electronic products. The sheer volume of electronic products now displayed in a typical store, by itself, presents a challenge for those responsible for security. In any one store, many hundreds of these products may be simultaneously displayed for handling and operation by consumers. At peak hours, and particularly during high volume buying seasons, the challenge of employees and security personnel to prevent theft becomes daunting.
The electronics industry continues to offer a range of products with different price tags and capabilities to the retail stores for presentation and sale to end users. Individual displays commonly have these products tethered to a support. In the simplest state, the tethers are mechanical cables which have a somewhat limited capability. Electronic systems offer a higher level of security but involve a more significant financial investment on the part of the store owner. With the large volume of items that are displayed, and tethers having a substantial length to allow convenient inspection by a potential purchaser, wire management problems arise.
The assignee herein developed, and has successfully commercially sold, a product that addresses a number of the problems discussed above. More specifically, this product is shown in U.S. Pat. No. Re. 37,590. This product affords an electronic monitoring capability while addressing wire management problems by retracting a tether/conductive cord into a coiled state in a housing. The product being monitored is operatively engaged with the system by using any of a number of different connectors at the end of the conductive element. A reel is normally spring-biased in one rotational direction to retrieve the conductive element into the housing and, in so doing, draw the associated article that is being monitored towards the housing into a display position. By grasping the article and exerting a force thereon, the conductive cord can be withdrawn from the housing against the spring bias force exerted on the reel.
While the above-described product has been highly commercially successful, it has one limitation that is inherent, not to its design, but rather to the high volume of products displayed at point of purchase. Typically, this type of system has an associated alarm that is activated in the event that the conductive cord is severed and/or the connector is separated from the article that is being monitored. This alarm in many system setups is the primary alert to the fact that there has been a breach. Unfortunately, in large operations, even if the system is properly set up and the alarm triggered during a breach, it may still be possible for the individual causing the breach to abscond with the article, particularly in a crowd, without being identified. This problem is aggravated by the fact that often these systems are not properly set up by personnel, as a result of which false alarms may be triggered. This may cause employees and security personnel to either ignore the signals or shut the systems down to avoid annoyance to existing potential consumers.
Thus, to provide greater security, it would be desirable to have some type of backup that complements the above-described security system. For example, video cameras may allow real time monitoring or monitoring at the conclusion of a predetermined time period, such as at the conclusion of the business day. The difficulty with monitoring using cameras is that a person or persons assigned to do the monitoring must keep track of potentially hundreds of these different security systems over a substantial areal region within the establishment. Even in a crowded commercial establishment with hundreds of displayed items, at any one time, there may be only a limited number of the articles that are actually being physically handled by potential consumers. However, in spite of this, security personnel are required to observe all of the articles, even though they are not being handled and in any immediate danger of being taken without authorization. As a result, this conventional backup security monitoring approach may be difficult to use and impractical, particularly when crowds of potential consumers are present.
As the electronics industry evolves, the products become increasingly smaller, yet with more capabilities, and more expensive. At the same time, the level of sophistication of thieves continues to rise. Accordingly, business establishments are facing an ever increasing challenge in terms of implementing security systems and controlling costs. The value of a security system must be evaluated factoring in its initial cost, its maintenance, and cost of personnel involved in setting up and monitoring, as well as its overall effectiveness. The industry continues to seek out more effective ways of monitoring portable consumer articles through systems that are financially feasible when evaluated in terms of their effectiveness.

Security system with triggered response assembly


The present disclosure relates generally to depot formulations of lurasidone and methods of making depot formulations of lurasidone. The depot formulations include a suspending agent and are highly syringeable.

Lurasidone hydrochloride is an atypical antipsychotic drug. It is used for treating schizophrenia and bipolar depression and is available as a tablet formulation for once daily, administration.
Depot formulations are desirable for providing a therapeutic dose of an active agent over an extended period of time, thereby providing convenience and improving patient compliance. There are several long acting injectable atypical antipsychotic products on the market. Long acting injectable product can be administered intramuscular once every week, once every month or once every three months. For depot formulations of anti-psychotic drugs, it is desirable to enable delivery of the depot formulation no more frequently than about once a month.
Depot formulations can be difficult to develop, in part, due to the high concentrations of drug required in order to provide therapeutic levels over an extended period of time. The problem is more difficult with active agents with low solubility such as lurasidone. Particle size is often critical to developing a depot formulation that will release the drug over the desired extended time period. In addition, a desirable depot formulation will be isotonic. Therefore, it is necessary to ensure particles do not agglomerate upon storage in an isotonic medium, thereby changing release characteristics. Hence, it can be challenging to develop a stable depot formulation that contains an optimal particle size and characteristics for consistent, extended drug release, and sufficient drug quantity.
Further, it is desirable for any injectable depot formulation to be administrable with small needle sizes, to minimize patient pain and improve compliance. Syringeability refers to the passability of a formulation through a syringe and can encompass the ease of withdrawing a formulation from a vial, and injectability of the formulation. Syringability is an important consideration in optimizing a depot formulation.

Extended release suspension formulation of lurasidone


A crimping assembly roll crimps a cover part over an underlying structure. The crimping assembly includes a base. A first roller extends out from the base and is rotatable with respect thereto. A second roller extends out of the base and is rotatable with respect thereto. In addition, the second roller is movable axially with respect to the first roller. A transmission is operatively connected to the first roller and the second roller such that the first and second rollers roll at the same speed. The crimping assembly also includes a pneumatic motor connected to the transmission to selectively drive the transmission and roll the first and second rollers as the first and second rollers roll over the cover part to force the cover part into engagement with the underlying structure.

1. Field of the Invention
The invention relates to a tool for affixing one element to another. More specifically, the invention relates to a tool for crimping a flange cover over a flange of a motor vehicle.
2. Description of the Related Art
In the complex manufacturing of complex assemblies, it is often required to finish one part by covering it by another. With a motor vehicle, an example of an area where a part is formed over another part is in an opening providing access to a passenger compartment. In the construction of the motor vehicle, a flange extends out around the periphery of the access opening. That flange is covered with a flexible material allowing a door to abut up thereagainst and distort the flexible material slightly to create a seal between the door and the access opening. This is one example of many situations where a part is designed to cover another part.
One problem associated with the design of one part covering another part is the proper securing of the covering part over the underlying structure. Often times, the resulting cover part is crimped over the underlying structure. One example of a tool used to crimp a cover over an underlying structure, such as a flange, is disclosed in U.S. Pat. No. 5,875,670. In this disclosure, a drive means forces one roller into a second roller to crimp a cover over the flange. A biasing means forces the movable roller axially away from the other roller when no pressure from the drive means is being applied against the first roller. The biasing means is a spring which routinely fails over time. This results in a tool that must be consistently serviced. In addition, the spring reduces the effective pressure of the roller because it is always applying a force against the closing pressure. It is a non-removable bias applying constant pressure against the closing pressure.

Lightweight tool for crimping a flange cover


A radio wave detection device including an electric wave receiving/amplifying circuit, a rectifying circuit, a peak-to-peak amplifier, a central processor, a power supply, a reference resistance circuit and a sound/light output unit. The electric wave receiving/amplifying circuit includes an antenna for receiving radio signal in the environment. The radio wave with a specific frequency filters through a wave filter and then is amplified. The rectifying circuit converts the radio signal into analog level voltage which is output to the central processor and peak-to-peak amplifier. In a preset condition, the peak-to-peak amplifier converts the level voltage into a controlling signal which is output to the central processor. The central processor also receives various comparison level voltages generated by the reference resistance circuit and compares the reference level voltage with the level voltage (and the controlling signal). Thereafter, the intensity of the detected radio signal is shown by the sound/light output unit by way of light and sound.

The present invention is related to an improved radio wave detection device, and more particularly to a radio wave detection device which is able to effectively detect the existence of various radio waves and truly show the pattern and intensity of the radio waves to a user.
Wireless telecommunication, wireless network and other wireless signal transmissions are widely used in modern life. All these wireless equipments transmit signals via electric wave. The intensity of the radio wave (carrier wave) will directly affect the quality of the transmission of radio signal.
A conventional radio detection device can be used to detect the environmental radio wave and avoid unauthorized shooting. Such radio detection device has a simple inductor (antenna) for receiving the environmental electricwave and an amplifier (OPAMP) for amplifying the electric wave. Such radio detection device has poor sensitivity and can only find out whether there is electric wave in the environment. However, it is impossible for such radio detection device to truly detect the intensity of the electric wave.
Also, the intensity of the radio signal can be shown on the panel of a mobile phone. The integrated circuit and structure of such mobile phone are quite complicated so that the cost is high. In addition, only the intensity of the carrier wave (radio wave at specific frequency) for transmitting the signal of the mobile phone can be detected. Such mobile phone cannot serve as a general radio detection device.


An apparatus for powering an implant includes first energy interface elements, a removeably attachable holding device and a first energy source, such as a battery. An energy conversion circuit converts first energy into second energy which is transmitted within the body of the patient to the implant. Also, an apparatus for providing information to an implant that includes first energy interface elements and a housing that includes a processor operatively coupled to the first energy interface elements and an energy source operatively coupled to the processor. The processor is structured to generate an information signal and cause the signal to be transmitted within the body of the patient for delivery to the implant. Associated methods are also provided.

In recent years, medical implants have made profound changes in medicine. When implanted within various parts of the human body, these devices perform important in vivo functions including diagnosis, monitoring, and disease treatment. It is clear that the line between biology and technology is blurring, and biological tissues and man-made machines are becoming integrated. This trend will have a broad impact on the future practice of medicine.
Although many technical barriers for designing and utilizing implantable devices have been removed, there still exist two significant problems: (1) they require an electrical energy supply, and (2) they often require a data communication link. Since existing designs, some of which are described below, have many drawbacks, these problems are hampering the development of the next-generation implants.
Currently, most implantable devices within the body, such as cardiac pacemakers and deep brain stimulation devices, use non-rechargeable batteries as power supplies. Because the batteries inside an implantable device cannot be replaced easily without surgery, different approaches have been studied to power implantable devices by delivering electrical energy transcutaneously from outside of the human body. In some cases, wire connections across the skin have been utilized. Clearly, this percutaneous design is highly invasive and prone to infection. Various designs using, for example, magnetic inductive coupling, ultrasound, optical coupling, and volume conduction have been reported. In most of these designs, an energy transmitter is carried or worn by the patient. This transmitter couples with an energy receiver inside the body to transmit electrical energy. Although these designs provide power supplies for implantable devices in principle, the external device with cables carried or worn by the patient is often cumbersome and inconvenient in the daily life of patients. Thus, there is a need for a portable, preferably low-cost, and convenient apparatus that may be used as a platform to supply electrical power to and communicate with implantable devices.

Portable apparatus that delivers power and information to implantable devices

University of Pittsburgh - Of the Commonwealth System of Higher Education


An information-processing apparatus which can easily output an accessory content suitable for a user situation at a point of time in course of an operation to output a main content or before or after the operation is provided. The present invention includes a history-information generation section generates one or more pieces of correlation information each including at least one piece of information on the user utilizing the apparatus at a point of time the apparatus outputs an already used main content and in a time band including the point of time. A user-utilization accessory-content determination section determines an accessory content regarded as a content whose output operation in course of an operation to output a new main content or before or after the operation is considered to be suitable for the user on the basis of one or more pieces of correlation information stored in the correlation-information storage section and characteristics of one or more accessory contents stored in the accessory-content storage section, and outputs the determined accessory content. The present invention can be applied to an information-processing apparatus which can output a piece of music or a picture in course of operations to read and write a mail text.

The present invention relates to an information-processing apparatus, an information-processing method and a program. More particularly, the present invention relates to an information-processing apparatus capable of outputting a second content suitable for a situation faced by the user in course of an operation to output a first content or a situation existing before or after the operation and relates to an information-processing method adopted by the apparatus as well as a program implementing the method.
In recent years, the user is allowed to operate an information-processing apparatus in order to enjoy music or pictures output by the apparatus as BGM (Background Music) or BGV (Background Visual) respectively while the user is utilizing a predetermined content. To put it concretely, the user is allowed to enjoy the BGM or the BGV while, for example, the user is operating the information-processing apparatus to write a text of a mail and send the email to other users or receive a mail from another user and browse the text of the mail. Examples of the information-processing apparatus discussed above include Japanese Patent Laid-open No. 2003-345727; and Japanese Patent Laid-open No. 2003-150507.
However, the conventional information-processing apparatus has a problem that, in order to enjoy the BGM or the BGV by using the conventional apparatus, the user itself generally needs to carry out complicated operations on the apparatus. For example, the user generally needs to operate the information-processing apparatus, specify a desired piece of music and/or a desired picture by specifying their titles and enter a command to start an operation to reproduce the specified music and/or picture.
It is to be noted that, in the case of an operation to write a text of a mail and send the mail to other users, by utilizing the technology disclosed in patent document 1, the user can send the mail with an affection added to the mail. In addition, by utilizing the technology disclosed in patent document 2, a sound for a emoticon included in a mail text can be added to the mail and sent along with the mail.
To a user utilizing an information-processing apparatus receiving such a mail text, however, a sound and/or affection attached to the mail is a sound and/or affection selected by the sender to the bitter end. That is to say, a sound and/or affection attached to the mail is no more than a sound and/or affection selected by the user utilizing an information-processing apparatus transmitting the mail and is not a sound and/or affection selected by the user utilizing an information-processing apparatus receiving the mail. Thus, the conventional information-processing apparatus has a problem that, when a sound attached to the mail is reproduced in another information-processing apparatus, the reproduced sound is not necessarily a sound satisfying the user of the other information-processing apparatus. In other words, it is difficult to output a sound suitable for the situation existing at a time the user browses the mail. In addition, the conventional information-processing apparatus has another problem that it is difficult to express an affection attached to a mail text in terms of music and pictures suitable for the situation on the mail-receiver side.
The example described above raises a problem of using music and/or pictures as a second content while using a first content such as a mail text. It is to be noted, however, that a similar problem is raised with other contents used as the first and second contents.

Information-processing apparatus, information-processing methods and programs


Casting jigs, methods, and kits that may be used in manufacture of anatomical healing caps. A casting jig may include a body having one or more wells within the body, each well being open at a proximal end thereof and having a negative shape corresponding to an anatomical healing cuff body of a given tooth position. Each respective anatomical healing cuff body negative shape includes an asymmetrical cross-section and an irregular surface so that an anatomical healing cuff body having said shape is configured to provide substantially custom filling of at least an emergence portion of a void where a natural tooth once emerged or should have emerged from the void (e.g., in the case of a congenitally missing tooth). The casting jig may further include a socket at a distal end of each well that is configured to receive therein a dental implant or dental implant analog.

1. The Field of the Invention
This invention relates to casting jigs and associated methods for manufacturing healing caps or cuffs used in any stage of oral surgery where a tooth is extracted or missing. Such an example of oral surgery includes first stage oral surgery, for example, when an implant is initially placed into a tooth void (e.g., whether the tooth is extracted or was congenitally or otherwise missing). The inventive healing caps or cuffs may also be used in any other dental surgery where it is desired to preserve the emergence profile of gingival tissue surrounding one or more teeth (e.g., second stage surgery, immediate or delayed implant placement, etc.).
2. Background and Relevant Art
In modern dentistry, when one or more teeth are removed it is desirable to eventually replace the tooth or teeth with a prosthesis (e.g., a crown, bridge, etc.), although this is typically accomplished weeks later. Once the tooth is removed or missing, a dental implant is placed into the bone tissue of the jaw to provide a secure foundation upon which a prosthesis can be supported. Typically, the site is allowed to heal for a period of time prior to installation of the permanent prosthesis. Currently, a device known as a healing cap, abutment, or cuff is coupled into the dental implant while the site is allowed to heal, to cap or cover the inside of the dental implant and to preserve the ability to re-access the dental implant once the site has sufficiently healed, when it is desired to install a prosthesis. Once the site has healed (e.g., typically 1.5 to 6 months after implant placement), the healing cap, abutment, or cuff is removed, and a custom prosthesis (e.g., a crown) may be installed, supported by the dental implant anchored within the jaw bone.
Existing dental healing caps, abutments, or cuffs, as well as the methods employed in their installation during immediate or subsequent dental placement and oral surgery exhibit several shortcomings. In addition, it would be advantageous to provide for the ability of a practitioner to manufacture his or her own healing caps exhibiting improved characteristics.

This patent is subject to a terminal disclaimer.

Casting jig for chair-side manufacture of customizable sculptable anatomical healing caps


A method to obtain polarization characteristics of an optical transmission medium is disclosed. Sequentially plural different states of polarized light are launched into the optical transmission medium. Intensities of light emerging from the optical transmission medium through combinations of optical elements are measured to obtain Stokes parameters from which Stokes vectors describing the emerging light corresponding to each of the plural sequentially launched states of polarization are obtained; for at least three different launched states of polarization, descriptors are used of these launched states of polarization and the Stokes vectors describing the corresponding emerging light to calculate a Jones matrix which mathematically models the changes that the launched light when described in terms of a Jones vector is subject to when passing through the optical transmission medium; and, the Jones matrix is used to describe the polarization characteristics of the optical transmission medium.

It is well known that the Mueller analysis and the Jones analysis are useful in the study of polarization optics especially relating to the state of polarization of light and polarization properties of an optical transmission medium 18. (reference [18]) Note that a list of the books and literature is referred to in this specification and is shown in Table 3 which is at the end of his specification. The advantage in using the Jones analysis is its simplicity. In spite of the fact that one can study, in principle, only perfectly polarized light in the framework of the Jones analysis, the analysis provides a simple approach compared to the other methods, e.g., Mueller's analysis. The reason for this more simplistic approach comes from the fact instead of using larger 4.times.4 or 3.times.3 matrices as in Mueller's analysis, one uses 2.times.2 matrices for the Jones analysis. The mathematical relation between the Jones' and Mueller's analysis has been studied by Takenaka in 1972 (reference [1]) and is summarized as the difference of the representation of the rotational group. When the polarization dependent loss in of a transmission media is negligible, the elements of the Mueller and Jones matrices are understood as the rotational operator. Concretely, the representations of the rotational group these matrices is known to be a three dimensional orthogonal group: O(3) and the special unitary group: SU(2). These two groups are transformed as a homomorphism mapping. The result of the comparison between the Jones analysis and the Mueller analysis is shown in Table 1. So far, in spite of the advantages explained above, most experimental study of polarization optics is achieved using the Mueller's analysis. Reasons of this dominance of the Mueller's analysis in experimental polarization optics are summarized as follows: (i) in the vector representing the light, a Stokes vector, the parameters represent optical intensities and are directly measurable quantities.(reference [1]) (ii) the Poincare sphere representation of a Stokes vector provides an intuitive way for understanding polarization. However, it is widely known that both the Jones method and Mueller's method have advantages and disadvantages relative to each other. Thus, in some instances, and in practical situations, one can approach the problem in two ways.
TABLE 1 ______________________________________ Jones' Analysis Mueller's Analysis ______________________________________ Description of the state Two dimensional Four or three dimen- of polarization complex spinors: sional real vectors: Jones vector Stokes vector Description of the optical 2 .times. 2 complex 4 .times. 4 or 3 .times. 3 real transmission media in matrices: matrices: case when the polari- Jones matrices Mueller matrices zation dependent loss is negligible Whether the state of Impossible Possible polarization is possible to determine directly or not? Theoretical Analysis Comparatively easy Complicated ______________________________________
Based on the original work by Jones (reference [3],[4]), we will briefly review the conventional matrix measurement method. For the purpose of the matrix determination experimentally, we utilize a 2.times.2 complex Jones matrix as follows: ##EQU1## From which EQU .eta..sub.4 =.beta.. (16.1) EQU .eta..sub.2 =.beta.k.sub.2 (16.2) EQU .eta..sub.3 =.beta.k.sub.4 (16.3) EQU .eta..sub.1 =.beta.k.sub.1 k.sub.4 (16.4)
Then the estimation of .eta..sub.i (i=1, 2, 3, 4) provides the 4 matrix elements. According to Jones, one measures the output electrical fields corresponding the following three incident states of polarization, represented by the Jones vectors as: ##EQU2## The output state of polarization corresponding to the above three vectors are represented as ##EQU3## Then the Jones calculus provides the following relations EQU k.sub.1 =h.sub.1 /h.sub.2 (19.1) EQU k.sub.2 =v.sub.1 /v.sub.2 (192) EQU k.sub.3 =q.sub.1 /q.sub.2 (193) EQU k.sub.4 =(k.sub.3 -k.sub.2)/(k.sub.1 -k.sub.3) (19.4)
The right hand side of these equations are represented as ratios of electric fields, and in principle are measurable quantities from which the matrix elements can be determined experimentally using the relation shown in eqs.(19) and thereafter eqs.(16). For the above discussions, the Jones matrix measurement scheme proposed by R. C. Jones in 1947 has been reviewed This measurement scheme has been utilized until now.
In the field of the optics, accurate determination of the Jones matrix makes it possible to analyze the polarization properties of some transmission media and therefore is important. In the field of the optical communications, and particularly with recent developments in optical amplifier systems, an accurate measurement of the differential group delay (hereafter referred as DGD) of the principal states of polarization (referred as PSP) is required. For this, it is necessary to know the polarization mode dispersion (PMD) characteristics of the single-mode optical fibres being utilized (references [4] and [6])
In general , it is known that the Jones matrices for an arbitrary transmission medium have the following characteristics:
(1) In case where polarization dependent loss of the medium is negligible, the Jones matrix is written in the following form (reference[6]) EQU T=exp(.rho.)U (20) PA0 (3) In case where the polarization dependent losses of the transmission medium are finite and not negligible, the determinant of the matrix U is smaller than the unity.
where P is the medium independent loss or the state of polarization of light, and U (reference[20]) can be written as: ##EQU4## where the asterisk represents the complex conjugate. (2) In the case where the transmission medium is stable, both spatially and over time, it is possible to separate a diagonal matrix which represents the linear birefringence and the effect of the circular birefringence, through a suitable unitary transformation.
From the above discussions, it can be seen that the Jones matrix representation of the medium is useful for the analysis of cases where the degree of polarization (DOP) of the transmitted lightwave is almost unity and the polarization dependent loss(PDL) of the medium are negligible. In this situation, Jones matrix elements can be described as shown in Equations 20 and 21. Based on the unimodular unitary properties of the matrix, Poole and Wagner have derived the concept of the PSP and it is now regarded that the concept plays a fundamental role in polarization mode dispersion analysis (reference[6]). Recently Aso and his colleagues have derived a theoretical formula for polarization mode dispersion measurement using a wavelength scanning method (refercnces[7]). The formula has been confirmed experimentally by using an optical fibre that consists of two polarization maintaining fibres with fmite angular misalignment. In the derivation of the formula the uniitarity characteristics of the Jones matrix have been utilized.
In relation to long haul optical communication systems having optical amplifiers and dispersion shifted fibres, or alternatively conventional single-mode fibres with dispersion compensated fibres, PMD is considered to be an important parameter which limits the transmission capacity of the system. In reference [23] the origins of polarization mode dispersion are summarized. These origins consist of intrinsic and external causes, where the external causes refer to those affects on the optical fibre which originate during cable installation. However, in practice, these causes are randomly distributed along the length of the fibre and the state of the polarization mode coupling changes with time (reference [2]). In such cases local polarization modes are coupled along the fibre and therefore the concept of the eigen states of polarization is not a viable form of analysis. This situation is called random mode coupling. Random mode coupling makes it difficult to analyze the precise nature of the polarization properties of the optical fibre. In such cases, instead of using the eigen states of polarization, the concept of the PSP is a viable form of analysis (reference[8]). Poole and Wagner have proposed a rigorous PMD evaluation method. They have proved the existence of the PSPs (principal states of polarization) both theoretically and experimentally ( reference[22]) and have shown that the DGD time of the PSPs is one of the most important parameters in PMD analysis. Based on their results, B. L. Heffnier has reported a novel measurement technique for estimating the DGD time of the PSPs (reference [4]). This method is referred to as the Jones matrix eigenanalysis (hereafter JME). According to the report from N. Gisin, JE is regarded to as one of the most precise measurement techniques (reference[24]).
In the following discussions, we will briefly review the concept of the PSP and the measurement technique of the DGD time of PSPs. Then we shall consider the problem of the proposed DGD time estimation method. As shown in references [1],[9] and [25] and references therein, the SOP changes along the optical transmission medium and is governed by the equation of the rotational motion in the spinor field (reference[20]). According to the spinorial treatment, under the assumption of perfect polarization and the negligible PDL (polarization dependent loss), the transfer matrix of the medium can be written in the form of the following 2.times.2 unitary matrix(reference[6]) ##EQU5## where the asterisk represents the complex conjugate. In this representation, we assume that the optical losses that are independent of the state of polarization are neglected. However, as shown in reference [6], it is straightforward to extend the following discussions to cases which include the influences of the optical losses and it has been confirmed that the final result of the following discussions coincide. According to the Jones calculus, the relation between the incident state of polarization (SOP) and output SOP is written as EQU .xi..sub.out =exp(i.rho.)U .xi..sub.out (23) EQU .xi..sub.in =exp(-i.rho.)U.sup.+ .xi..sub.in (24)
where + represents the henrite conjugate of the matrix and P is the absolute phase change through transmission of the medium. Taking derivatives of both sides of eq.(23) with respect to the angular frequency of light w and using the relation in eq.(24), provides the following equation ##EQU6## Here the SOP of the incident light are fixed as ##EQU7## As shown in reference [6], principal states of polarization are defined as the SOP that satisfies the following condition ##EQU8## Then the eigenvalue equation is obtained from the relation shown in eq.(25) ##EQU9## The explicit form shown in eq.(22) will lead to the following eigenvalue and corresponding eigen Jones vectors ##EQU10## The eigenvectors corresponding to these eigenvectors eigenvalues are orthogonal (reference[6]) and the vectors are called the incident PSPs (principal states of polarization). Output PSPs are obtained by operating the transfer matrix (22) on the incident PSPs, with the stability of the SOP with respect to frequency changes being first order. In order to satisfy the stability of the PSPS, the following conditions must be met: ##EQU11## where O is the Landau operator and higher than second order quantities are neglected. Principal states of polarization are stable as long as the above conditions are satisfied in practical situations. In this sense, the existence of the PSP is a generalized concept of the eigen state of polaization (reference [1]). According to reference [6], the DGD(differential group delay) time of the PSPs .DELTA.t, are one of the most important parameters describing the PMD. The above expression for the PSP allows us to obtain the following result ##EQU12## The above discussions provide a fundamental framework for PMD analysis based on the PSPs, and are provided as a theoretical background for PMD measurement using the Jones matrix eigenanalysis. One should note that the above DGD time estimation is correct when the conditions (27) are confirmed in the practical situations. In this sense, it is known that the above .DELTA.t estimation is correct to the first order approximation (reference [6]).
For the purpose of this discussion, it is necessary to describe a brief review of another estimation method for the DGD time of PSPs. This method is based on Mueller analysis and sometimes referred as the Stokes parameter method (reference [31]). According to reference [20], measurement of the frequency dependence of the output Stokes vector on the Poincare sphere will allow an estimate the DGD time of PSPs to be made. For this, use will be made of the Stokes space (reference [25]) wherein the normalized Stokes vector defines the SOP space where the geometry of the space is three-dimensional Euclidian. In the following discussions, the normalized Stokes vector is referred to simply as the Stokes vector. The concept of PSP and the DGD time of PSPs represented in the SOP field will be reviewed.
Wavelength dependence of the Stokes vector has been studied by W. Eickhoff and his colleagues (reference [26]). They have proposed the following basic equation as an analogy of the spatial SOP change in the birefringent medium by Uhicb (reference[27]). They also confirmed their own results by experiment. ##EQU13## In this equation, S is the Stokes vector of the output SOP, .omega. is the angular frequency of light. .OMEGA. a vector in the Stokes space whose magnitude coincides with the DGD time of PSPs; the two intersects of the vector with the Poincare sphere represent the PSPs. Therefore the vector is referred as the polarization dispersion vector (reference [29]). In the original paper from Eickhoff et.al.(reference[26]), the transmission media have been considered for cases where the birefingence is homogeneous along the longitudinal direction. Recently, Poole et.al., have shown that the description shown in eq.(32) can be extended straightforwardly to the case where polarization mode coupling exists. Eq.(32) is in the same form as the equation of the rotational motion(e.g., Larmor precession shown in reference[32]). Then the Stokes vector rotates on the Poincare sphere along n if the polarization dispersion vector is independent of the wavelength.
As discussed previously, the original Jones matrix estimation method developed by Jones is very sensitive to the unavoidable experimental errors that violate the symmetry properties of the matrix. Then the unitarity of the estimated matrix is generally violated. Principally the reason of the symmetry breaking could be considered as follows:(a) According to the original method, matrix elements are determined individually; then the unavoidable measurement error directly influences the results, (b)When the PDL(polarization dependent losses) of the medium are not perfectly neglected, the effect of PDL violates the symmetry of the matrix, (e) Degradation of the DOP (degree of polarization) of the output light makes it difficult to maintain consistency between experiments and theory. The matrix symmetry breakdown causes difficulties in obtaining certain important information related to the birefringence of the medium.
As discussed previously, Poole and Wagner have derived the concept of PSP (principal state of polarization ) based on the Jones analysis. According to their results, B. L. Heffner developed the PMD estimation technique (reference[4]). According to Heffhier, he has estimated the Jones matrix using the same approach as the original matrix estimation method (reference[3]). Thus, he could not avoid the matrix symmetry breaking down. However, in order to avoid the difficulties, Heffner has introduced another eigenvalue equation based on a exponential approximation (reference [4]). However since the original PSP theory does not demand his exponential approximation, the following problem has remained: Is the exponential approximation consistent with the first order approximation of the PSP or not? Aso and his colleagues have investigated the difference of the first order approximation region and the exponential approximation region in the wavelength domain. Results of their study using an 80km length dispersion shifted single-mode optical fibre showed that any differences between the sufficient condition of these two approximations could not be found in the frequency domain measurements (reference [10],[11]). However their discussions were never extended straightforwardly to the general case. Thus the importance of maintaining the Jones matrix symmetry is noted in this specification.
As described heretofore, B. L. Heffner has published a design of the PMD measurement system based on the concept of the principal state of polarization (reference [4]). The method is referred as the Jones matrix eigenanalysis. A summary is now provided of the measurement scheme proposed by Hefffier. Firstly, three different SOPs (States of Polarization) with angular frequency .omega..sub.o are launched into a transmission medium under test. Then information of the corresponding output SOP leads us to determine every Jones matrix component of the medium uniquely according to the scheme shown in the previous discussions (reference [3]). According to Heffner, one can construct a characteristic finite differential equation corresponding to the eigenvalue equation (28) from the information of the Jones matrix measured at two frequencies with finite interval .DELTA..omega., say at .omega..sub.o and .omega..sub.o +.DELTA..omega.. The solution of the finite differential equation allows the DGD (differential group delay) time of PSPs to be estimated. Within the framework of the first order approximation criteria, frequency step-size .DELTA..omega. for the measurement is necessary in order to ensure the existence of the PSPs as the base vector in the Stokes space. However, in practice the measurement accuracy demands a large .DELTA..omega.. Nevertheless one can not distinguish the difference of the information between the measurements taken at two frequencies if the stepsize is too small. The above discussion indicates the existence of a suitable frequency stepsize for the PMD measurement from Jones matrix eigenanalysis, wherein a suitable frequency step-size is the largest step-size in which the PSP remains in the first order(reference[30]).
Incorrectly selecting the step-size apparently causes a DGD time mis-estimation. This phenomenon is noted in Hewlett Packard's polarization analyzer user's manual (reference[30]) and is also confirmed in experiments by Aso, etal. (reference[10],[11]). This drawback is considered as the most conspicuous in the Jones matrix eigenanalysis. A technique which has been developed in order to solve the above problem will now be discussed (reference [4],[5],[31]). The first step of this technique is to observe how the trajectory of the output SOP (state of polarization) changes with respect to the angular frequency of light. Based on the equation (32) and (33), the first order frequency change .DELTA..omega. leads us to observe tie trajectory where the Stokes vector traces the arc of a complete circle as shown in FIG. 5. If the choice of the frequency step-size .DELTA..omega. is larger than the "suitable" stepsize, the trajectory runs off the arc of the above reference circle. The suitable stepsize can thus be estimated as the largest frequency step-size where the observed Stokes vector trajectory is on the circle (reference [10]). However, the exact proof that the estimated DGD (differential group delay) time of PSPs (principal states of polarization) using the above .DELTA..omega. by the Jones matrix eigenanalysis seems to have not been given.
According to the Jones matrix eigenanalysis approach reported in reference [4]and[5], the transmission matrix is determined by the original method proposed by R. C. Jones (reference[3]). However, the negligibly small PDL (polarization dependent losses) of the medium and the unavoidable measurement errors may violate the unitarity of the estimated matrix.
Heffner has derived the eigenvalue equation that differs from equation (28); in his equation two eigenvalues coincide with the DGD time of PSPs. His equation is ingenious and the constraint of the matrix symmetry does not explicitly appear. Furthermore he has introduced exponential approximation which did not appear in the original paper (reference[6]). The exponential approximation leads to a convenient analysis. However the scheme seems to have no relation with the first order approximation. Aso and his colleagues have studied the difference of the exponential approximation with first order approximation in the PSP theory. They have measured the difference by using an 80 km dispersion shifted single mode optical fibre (reference [10],[11]). In these experiments, they found no difference between the two approximations. However, their experiments employed a transmission medium and no general proof was provided.
In order to determine a suitable wavelength step-size for PMD (polarization mode dispersion) measurement by Jones matrix eigenanalysis, Aso and his colleagues have proposed the comparison of global and local measurements (reference[11]). However, when one applies the idea to practical measurements, measurements over long durations of time are necessary to determine a suitable .DELTA..omega. and the constraints from the local measurements limit the measurable DGD time of PSPs to less than 5 ps.
What follows is a summary of the causes of the drawbacks of the JME (Jones Matrix Eigenanalysis) method. (a) Measurement apparatus not made precisely according to the original PSP theory obtained by Poole and Wagner (reference [6]).(b) Since the original PSP theory is expressed within the framework of the Jones' calculus, in order to realize the measurements based on the theory, it is necessary to represent the explicit relation between the Jones vector and measurable quantities(e.g., Stokes parameters). Frequency dependence of the output SOP described by the Stokes vector is expressed by the eq.(32). The left hand side of eq.(32): ds/d.omega. corresponds to the derivative of the Jones vector with respect to the angular frequency. However to date the relationship between the eq.(32) and the corresponding equation expressed in the framework of the Jones' calculus seems not to have been analyzed precisely. (c) Also the relationship between the polarization dispersion vector .OMEGA. and the Jones matrix U has not yet been studied.
According to the Jones' calculus, the Jones vector representation of the output principal states is obtained by operating the Jones matrix on the incident Jones vector. The matrix is of 2.times.2 form. On the other hand, according to the Mueller's calculus, the output Stokes vector is obtained in a similar manner as the Jones calculus. However in this case the matrix is 4.times.4 and the number of matrix elements increase. Thus, the Jones calculus makes it easy to realize the calculation and obtain the output SOP. Jones vector measurements techniques which are consistent with the Stokes vector measurements have not yet been demonstrated.

Method and apparatus for measuring the polarization characteristics of optical transmission medium


An object of the present invention is to provide a methyllactam ring compound that has an SGLT1 inhibitory activity and is useful for a drug, or a pharmaceutically acceptable salt thereof, a pharmaceutical composition comprising it, and pharmaceutical use thereof. A compound of Formula [I]:

SGLT1, i.e., Sodium-Glucose Cotransporter 1, is known to contribute to a great portion of absorption of glucose and galactose in the small intestine. It is reported that human SGLT1-deficient patients cause glucose-galactose malabsorption. Furthermore, it is confirmed that the expression of SGLT1 in the small intestine increases in diabetic patients and it is thought that increased sugar absorption in diabetic patients is caused by the high expression of SGLT1 in the small intestine.
Based on the knowledge, an SGLT1 inhibitor is expected to normalize the blood glucose level by blocking glucose absorption in the small intestine. An SGLT1 inhibitor is, therefore, considered to be effective against diabetes and diabetic complications associated with hyperglycemia. It is also considered to be effective against obesity by inhibiting the inflow of glucose into the body (Non Patent Literatures 1 and 2).
Voglibose, a generic name, is a drug approved for manufacturing and marketing under the Japan Pharmaceutical Affairs Act Article 14 (Approval number: 21600AMZ00368). Voglibose improves excess blood glucose after eating by inhibiting disaccharidase, α-glucosidase, that degrades disaccharides existing in the intestinal mucosa into monosaccharides and inhibiting or delaying the digestion and absorption of carbohydrate in the intestinal tract. Such a pharmacological effect is known to be effective against delayed onset of type 2 diabetes in imparied glucose tolerance.
Based on the knowledge, inhibition of sugar absorption through small intestine with an SGLT1 inhibitor and thereby improvement of excess blood glucose after eating is thought to be effective against delayed onset of type 2 diabetes in imparied glucose tolerance.
The expression of SGLT1 is confirmed in cardiac muscle cells. It is known that GLUT1 (Glucose Transporter Type 1) and GLUT4 (Glucose Transporter Type 4) usually have a role in uptake of glucose into cardiac muscle cells and the contribution of SGLT1 is reduced. The expression of SGLT1 is, however, induced in the cardiac muscle of mice into which is introduced mutated genes of PRKAG2 (gamma 2 subunit of AMPK (AMP-Activated Protein Kinase)) which is a responsible gene of familial hypertrophic cardiomyopathy (glycogen accumulation-type myocardosis), or mice which undergo myocardial ischemia treatment, and SGLT1 is reported to contribute to the uptake of glucose to cardiac muscle cells in these pathologies. Glucose incorporated by SGLT1 is thought to be excessively accumulated or metabolized within cardiac muscle cells and impair the cells. It is reported in the former mouse model that accumulation of glycogen in the cardiac muscle is actually inhibited by the treatment of a non-selective SGLT inhibitor, phlorizin.
Based on the knowledge, an SGLT1 inhibitor is thought to be effective against hypertrophic cardiomyopathy and ischemic heart disease by inhibiting uptake of excess glucose into cardiac muscle cells (Non Patent Literatures 3 and 4).
SGLT1 is stabilized in cancer cells by epidermal growth factor receptors, i.e., surface proteins on many kinds of cancer cells. It is known that transporters of glucose, lactic acid, and amino acid, etc. are involved in nutrition supply to cancer cells, and especially, regarding the transportation of glucose, SGLT1 and GLUT1 continuously supply glucose to cancer cells. When glucose is not supplied over a long period of time, cells are destroyed by autophagy.
Based on the knowledge, an SGLT1 inhibitor is thought to inhibit supply of glucose to cancer cells and show anticancer activity (Non Patent Literatures 5 and 6).
Since carbohydrate is degraded to monosaccharides in the gastrointestinal tract in diet and is absorbed in the upper gastrointestinal tract, many sugars never reach the lower gastrointestinal tract. When, however, drugs that delay or inhibit glucose absorption are administered, or a large amount of resistant polysaccharides are ingested, then undigested sugars are retained in the lower gastrointestinal tract and the undigested sugars retained in the lower gastrointestinal tract cause osmotic diarrhea.
An SGLT1 inhibitor inhibits the glucose absorption and increases the amount of monosaccharides in the lower gastrointestinal tract. The SGLT1 inhibitor is, therefore, believed to be effective against constipation.
Diabetes is caused by elevated blood glucose level due to the deficient insulin action and the persistent elevated blood glucose may cause diabetic complication (e.g., retinopathy, nephropathy, and neuropathy, which are all known as microangiopathy; and cerebrovascular disease, ischemic heart disease, and membrum-inferius arteriosclerosis obliterans, which are all known as macroangiopathy). Other diseases associated with elevated blood glucose level include obesity.
Diabetes is classified as type 1 and type 2 diabetes. Type 1 diabetes is considered to be developed due to the deficient insulin action caused by destruction of pancreatic β cells that secretes insulin, whereas type 2 diabetes is considered to be developed due to environmental factors, such as overeating, insufficient exercise, obesity, and stress, and aging in addition to multiple genetic factors including a decrease in insulin secretion and insulin resistance. Diabetes is diagnosed using three types, such as the normal, borderline, and diabetic type, classified on the basis of the blood glucose level. When any one of the following (1) to (4):
(1) 126 mg/dL or more of blood glucose level in the morning fasting
(2) 200 mg/dL or more of two-hour value in 75 g OGTT (oral glucose tolerance test)
(3) 200 mg/dL or more of casual blood glucose level (4) 6.5% or more of HbA1cg
is identified, then the subject is determined as the diabetic type and diagnosed as diabetes or suspected diabetes (Non Patent Literature 7).
OGTT used in the above (2) is one of the methods for diagnosing diabetes. In general, when a human subject is administered a solution comprising 75 g of glucose after fasting, and a certain period of time after the administration of glucose, the blood glucose level is determined as 200 mg/dL or more, then the subject is diagnosed as diabetes (Non Patent Literature 7). OGTT is, therefore, an index of diabetes diagnosis, and a compound that can reduce blood glucose levels of glucose-loaded subjects in OGTT is considered to be effective against diabetes.

Methyllactam ring compound and pharmaceutical use thereof

Abstract: or a pharmaceutically acceptable salt thereof, a pharmaceutical composition comprising it, and pharmaceutical use thereof is provided.


The invention relates to a human anti-dengue virus antibody (an anti-DENV antibody) that binds to a DENV envelope protein and is cross-reactive with DENV serotype 1, DENV serotype 2, DENV serotype 3, and DENV serotype 4. The disclosure provides an anti-DENV antibody that cross-reacts with and neutralizes all four DENV serotypes. Also provided is a nucleic acid molecule that encodes such an anti-DENV antibody. Also provided is a method to produce and use such an antibody or nucleic acid molecule encoding such an antibody.

Dengue virus (DENV) causes the most prevalent mosquito-borne viral disease: over 2.5 billion people are at risk for infection in over 100 countries. Each year, dengue virus infects and exhibits symptoms in about 100 million people worldwide. Of those infected, about 250,000-500,000 develop severe illness, and up to 50,000 die from dengue hemorrhagic fever (DHF) each year (see, e.g., Dengue and dengue hemorrhagic fever, World Health Organization Media center, Fact Sheet No. 117, March 2009; Deen J L et al., 2006, Lancet 368, 170-173; Kyle J L et al., 2008, Annu Rev Microbiol 62, 71-92). In 2010, dengue virus re-entered the US via the Florida Keys, after an absence of sixty-five years (see, e.g., Homeland Security News Wire, 2 Jun. 2010).
There are four closely related, but antigenically distinct, dengue virus serotypes, namely DENV serotype 1 (DENV-1), DENV serotype 2 (DENV-2), DENV serotype 3(DENV-3), and DENV serotype 4 (DENV-4). Each serotype comprises several genotypes that exhibit differences in their infection characteristics in both the mosquito vector and the human host. Recovery from infection by one serotype provides lifelong immunity against that serotype, but confers only partial and transient protection against subsequent infection by other serotypes. One of the confounding problems that has faced vaccine development for decades has been this inability of one serotype to protect against infection by another. Rather, the induced humoral immune response to one DENV serotype as a result of infection can enhance the infection and disease processes brought about by a subsequent infection with another DENV serotype. Such subsequent infection is thought to increase the risk of developing dengue hemorrhagic fever (DHV), a potentially lethal condition. (see, e.g., WHO Fact Sheet No. 117, ibid.; Halstead S B et al., 2007, Lancet 370, 1644-1652; Dejnirattisai W, et al., 2010, Science 328, 745-748.)
Dengue virus is a single positive-stranded RNA virus of the Flaviviridae, genus Flavivirus. The viral genome of about 10.7 kilobases is translated as a single polypeptide that is cleaved into three structural proteins (namely a capsid protein (C), a membrane protein (M, prM/M), and an envelope protein (E)), and seven non-structural proteins (namely NS1, NS2a, NS2b, NS3, NS4a, NS4b, and NS5).
The initial step of dengue virus infection is entry of the virus into cells; such entry is mediated by DENV envelope E, a glycoprotein (see, e.g., Dimitrov D S, 2004, Nat. Rev. Microbiol. 2, 109-122). DENV E is a type II fusion protein and consists of three domains (see, e.g., Dimitrov D S, ibid.; Kuhn R J et al., 2002, Cell 108, 717-725). The domains are named ED1, ED2, and ED3, respectively; other names for the envelope domains are domain I (DI), domain II (DII), and domain III (DIII, or Env-DIII), respectively. ED3 has been proposed to contain a receptor binding domain (Huerta V et al., 2008, Virus Res 137, 225-234; Crill W D et al., 2001, J Virol 75, 7769-7773).
Antibodies are important for protective and pathogenic immune responses to dengue virus (see, e.g., Halstead et al., ibid.). Their major target is the DENV E protein (see, e.g., Marasco W A et al., 2007, Nat Biotechnol 25, 1421-1434; Modis Y et al., 2005, J Virol 79, 1223-1231; Roehrig J T et al., 1998, Virology 246, 317-328; Bedouelle H et al., 2006, FEBS J 273, 34-46; Thullier P et al., 2001, J Gen Virol 82, 1885-1892). The amino acid sequences of E proteins for DENV-1, DENV-2, DENV-3, and DENV-4 differ by 25% to 40%; the amino acid sequences of E proteins for genotypes within a DENV serotype vary by up to 3% (see, e.g., Holmes E C et al., 2003, Infect Genet Evol 3, 19-28). Antibodies against ED3 are both serotype specific and cross-reactive; such antibodies are effective DENV neutralizers, typically better than antibodies against ED1 or ED2 (see, e.g., de Alwis R, et al., 2011, PLoS Negl Trop Dis 5, e1188; Balsitis S J, et al., 2010, PLoS Pathog 6, e1000790; Beltramello M et al., 2010, Cell Host Microbe 8, 271-283; Sukupolvi-Petty S et al., 2010, J Virol 84, 9227-9239; Shrestha B et al., 2010, PLoS Pathog 6, e1000823; Rajamanonmani R et al., 2009, J Gen Virol 90, 799-809; Sukupolvi-Petty S et al., 2007, J Virol 81, 12816-12826; Gromowski G D et al., 2010, Virology 407, 237-246; Matsui K et al., 2010, J Gen Virol 91, 2249-2253; Matsui K et al., 2009, Virology 384, 16-20; Gromowski G D et al., 2008, J Virol 82, 8828-8837; Gromowski G D et al., 2007, Virology 366, 349-360; Hiramatsu K et al., 1996, Virology 224, 437-445; Lok S M et al., 2008, Nat Struct Mol Biol 15, 312-317). The cross-reactive antibodies are generally weaker neutralizers than the serotype-specific antibodies (see, e.g., Sukupolvi-Petty S et al, 2007, ibid.; Gromowski G D et al., 2008, ibid.). Anti-ED3 serotype-specific and cross-reactive antibodies are elicited using ED3 as a vaccine immunogen (see, e.g., Guzman M G et al., 2010, Vaccines 9, 137-147; Bernardo L et al., 2011, Vaccine 29, 4256-4263; Bernardo L et al., 2009, Clin Vaccine Immunol 16, 1829-1831; Izquierdo A et al., 2008, Virus Res 138, 135-138; Simmons M et al., 1998, Am J Trop Med Hyg 58, 655-662; Simmons M et al., 2001, Am J Trop Med Hyg 65, 159-161; Srivastava A K et al., 1995, Vaccine 13, 1251-1258) and in infected humans (see, e.g., de Alwis R et al., ibid.; Midgley C M, 2011, J. Virol. 85, 410-421; Rothman A L, 2004, J. Clin. Invest. 113, 946-951; Wahala, W M et al., 2009, Virology 392, 103-113). Recently, several human monoclonal antibodies were selected from immortalized B cells obtained from DENV-infected people, a few of which also exhibited some cross-reactive neutralizing activity against all four serotypes; a cocktail of three of antibodies targeting distinct epitopes and engineered to prevent FcγR binding was successful in a mouse model of disease when administered one day after challenge (Beltramello M et al, 2010, ibid.).
There remains a need for an effective therapeutic, an effective prophylactic, or an effective therapeutic and prophylactic against dengue virus infection, not only to protect an individual from an initial infection, but also to protect that individual from subsequent infection not only by the same DENV serotype but also by any and all other DENV serotypes. As such, there is a need for an anti-DENV antibody that cross-reacts with and neutralizes DENV-1, DENV-2, DENV-3, and DENV-4 dengue virus serotypes. There is also a need for a vaccine that comprises an epitope recognized by such a cross-reactive anti-DENV antibody to protect an individual from dengue virus infection.

Cross-reactive antibodies against dengue virus and uses thereof


Genetic testing allows an individual to determine whether or not he or she has a predisposition to a certain disease. The degree of expressivity of a certain disease will be determined in part by an individual's environment and lifestyle. The present invention interprets a patient's gene sequence and his or her environment and lifestyle to come up with a personalized prognosis. This procedure can be repeated many times over the course of a disease state to monitor a patient's condition. In addition, disease-causing pathogens can also have their genes sequenced. Using these sequences in combination with information about a patient's environment and lifestyle, it is possible to come up with a personalized treatment plan, ideally to eliminate the pathogen. It is also possible to use the procedure described above to monitor the course of the disease-state produced by a pathogen. Finally, a genotype-to-phenotype map or database can be constructed for developing better treatments and for research purposes.

Most major chronic conditions are related to patient environment and lifestyle factors that act on preexisting genetic dispositions to diseases. This is true of many cancers, hypertension, heart disease, diabetes, and mental illnesses. Ways to prevent or reduce the severity of such diseases include changing a patient's environment and/or lifestyle (e.g. diet, exercise, stress, substance abuse, pollution) or by following therapeutic regimes that lessen the impact of environment or lifestyle (e.g. taking cholesterol lowering drugs).
One of the difficulties in changing patient behavior is that a prognosis based on lifestyle factors is very imprecise and it is easy for a patient to rationalize why such a prognosis does not apply to him or her, or at least not yet. Everyone knows an example of someone who smoked and drank and lived to a ripe old age. Everyone also knows of someone who was health-conscious and jogged every day, yet died of a heart attack. Because a prognosis is vague and difficult to individualize to a patient, many patients do not change their behavior until it is too late.
A major advance in preventative medicine is the ability to test for a genetic predisposition for certain diseases. Unfortunately, the human genome is incredibly complex and based on a gene sequence alone, there are still too many degrees of freedom to make an accurate and personalized prognosis for an individual patient. This is especially true for genetic diseases that are heavily influenced by environmental and lifestyle factors.
In order to use genotypes for disease prevention, it is necessary to. develop better methods for profiling a patient's phenotype in order to reduce the degrees of freedom and provide a more accurate prognosis. It may also be necessary to continue to profile the patient over time in order to monitor behavior and adjust the prognosis. In addition, it is hoped a patient will be more motivated to adhere to a prescribed treatment or regimen if he or she can easily see the effects of changes in behavior.
Diseases that are not caused by genetic factors are often caused by pathogens. Many virus-induced diseases such as hepatitis, AIDS, and herpes are incurable in part because of the high mutation rate of the pathogens. Vaccines created to combat such pathogens are quickly rendered ineffective.
With the recent advances in biotechnology, it is now possible to sequence genes to create a genetic profile of an organism. Thus it is possible to determine the specific genetic makeup of a pathogen in a patient, and to use that information to create a patient-specific treatment or vaccine.
Unfortunately, because genomes are so complex and because the patient phenotype upon which the pathogen acts is so variable, there are too many degrees of freedom to tailor a precise treatment to a patient's need. In order to use pathogen genotypes in treatment of disease, it is necessary to develop better methods of profiling a patient's phenotype in order to reduce the degrees of freedom and provide a more accurate prognosis. It may also be necessary to monitor the patient over time in order to determine the effectiveness of the treatment and to adjust the treatment to the patient's response.
All of these approaches are very cost-intensive since they are predicated on collecting patient-specific genotype and phenotype data. Using traditional data collection methods, in view of the rapidly growing genotype knowledge, is therefore inadequate.

System and method for preventing, diagnosing, and treating genetic and pathogen-caused disease