Contaminants from surfaces of temperature sensitive substrates, such as glass substrates are removed by exposing the surfaces to a hydrogen Surface-mixed diffusion flame for a predetermined duration of time. The predetermined duration of time being insufficient to heat up the surfaces substantially thereby causing damage to the temperature sensitive substrates.

Flat panel displays (FPDs) are well known devices commonly used in industrial and consumer devices. The most common FPDs are the Liquid Crystal Displays (LCDs) and the Plasma Display Panels (PDPs). The FPDs have relatively small footprints as compared to Cathode Ray Tube (CRT) displays. They consume less energy. The images produced are not distorted at the edges. FPDs are currently used in almost every field of technology that requires a graphic display. They are fast replacing CRT monitors as the de facto output peripheral for personal computers. FPDs are also displacing the conventional CRT television sets.
One of the important elements of the FPDs is the glass substrates which are used to make the viewable screen of the displays. The quality requirements of such glass substrates are very high. They have to be of high clarity, high degree of flatness, uniform thickness and free from contaminants. These glass substrates are now manufactured in large pieces measuring about 890 mm by 680 mm with a thickness of about 0.7 mm. They are later cut into smaller pieces for their various applications.
FPD manufacturers often rely on service providers to perform the cleaning task and to deliver the ready-to-use glass substrates according to their requirements to reduce their overhead costs. The typical standard of cleanliness that is required of glass substrates of the size 890 mm by 680 mm is approximately 15,000 particles of size 0.3 micron.
In a glass substrate cleaning plant, the manufactured glass substrates are delivered in packages of 10-12, held together by four slotted angles made from urethane foam in order to protect each glass substrate from another. The surface of these glass substrates at this stage is highly contaminated. The contaminants range from small general particulate matter like dust to other organic compounds and protein matter. Some of these organic compounds and protein matter can be attributed to human handling and can include natural oils from the skin or simply put "fingerprints".
The washing or cleaning of glass substrates in the manufacturing of FPDs is crucial. It ensures that the surfaces of the glass substrates are free from contaminants. This is necessary for the proper coating requirements according to the different types of FPDs. The importance of cleaning the glass substrates is basically to ensure the clarity of the images produced when the FPDs are finally assembled. Contaminants present on the surfaces of the glass substrates prevent proper coating and causes distortion.
Some of the possible approaches or methods used in cleaning glass substrates are: high temperature de-ionized water, the Radiance Process®, High Power Ultrasonic cleaning and Plasma cleaning.
The currently most practiced method of cleaning glass substrates is to first wash them with high temperature de-ionized (DI) water, followed by vacuum drying. The glass substrates are then conveyed directly into a clean room environment for packaging. This method though somewhat effective, consumes several million cubic meters of DI water for a typical production process. The use of vacuum drying also increases costs, as power requirements are also very high. Studies have indicated that a plant cleaning 5000 FPD parts a day would require about 1.44 cubic meters of DI water per FPD part. This washing method also becomes less effective when the particulate size approaches 0.3 microns.
The Radiance Process® makes use of a laser and a continuous laminar flow of an inert gas to remove contaminants. The laser breaks the bonds holding the contaminants to the glass substrate and the inert gas carries the contaminants away. Recent demonstrations have shown that the total particulate counts were reduced dramatically. However, the Radiance Process® is highly dependent on maintaining the laminar flow of inert gases over the glass substrate surface. The equipment to provide and carry out this Radiance Process® is presently not available at a low cost.
Another method used is High Power Ultrasonic cleaning. The technology itself is not new. Ultrasonic cleaning has already been used with Printed Circuit Boards. It has been applied here in the cleaning of glass substrates as well. However, the method is far from perfect. During the ultrasonic cleaning process, cavitation of the cleaning fluid results in formation of small bubbles impacting onto the surface of the glass substrates. This sometimes causes micro-fractures on the glass surface and renders the glass substrate unusable.
Plasma Cleaning technology is performed in high vacuum systems by exposing the parts to be cleaned to energized plasmas. Though effective, plasma systems require high sources of energy to energize the plasmas and to provide the high vacuum environments. Invariably, such a system might be too expensive to use merely on account of cleaning the surfaces of a glass substrate.
There is thus a need for a novel, effective and economical method and apparatus for removing of contaminants from surfaces of glass substrates.

Apparatus and method for cleaning glass substrates using a cool hydrogen flame

Agency For Science, Technology and Research


A method is for realizing Multi-Input Multi-Output which includes steps of: sending, by a Central Access Point, a downlink sounding channel, Multi-Input Multi-Output (MIMO) control information, and a feedback resource indicator to a Station (STA); detecting, by the STA, the downlink detection channel to obtain channel information, and feeding back on the feedback resource according to the indication of the MIMO control information; and selecting, by the Central Access Point, a suitable MIMO mode for downlink data transmission according to the feedback of the STA.

With the rapid development of wireless communication technologies, the severe shortage of spectrum resources has increasingly been a "bottleneck" for the development of the wireless communication industry. Currently, one of the hot research subjects in the communication industry is to fully develop and exploit the limited spectrum resources and improve the spectrum utilization. The multi-antenna technology is much preferred due to its ability to improve transmission efficiency and spectrum utilization without increasing the used bandwidth.
With the rapid development of communication technologies, it is more demanding for the method for realizing the MIMO mechanism.

Method and device for realizing multi-input multi-output

BEIJING NUFRONT MOBILE MULTIMEDIA TECHNOLOGY CO., LTD


The invention provides new polymorphs of N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide and salts thereof, pharmaceutical compositions containing them and their use as kallikrein inhibitors in therapy.

Inhibitors of plasma kallikrein have a number of therapeutic applications, particularly in the treatment of retinal vascular permeability associated with diabetic retinopathy, diabetic macular edema and hereditary angioedema.
Plasma kallikrein is a trypsin-like serine protease that can liberate kinins from kininogens (see K. D. Bhoola et al., "Kallikrein-Kinin Cascade", Encyclopedia of Respiratory Medicine, p 483-493; J. W. Bryant et al., "Human plasma kallikrein-kinin system: physiological and biochemical parameters" Cardiovascular and haematological agents in medicinal chemistry, 7, p 234-250, 2009; K. D. Bhoola et al., Pharmacological Rev., 1992, 44, 1; and D. J. Campbell, "Towards understanding the kallikrein-kinin system: insights from the measurement of kinin peptides", Brazilian Journal of Medical and Biological Research 2000, 33, 665-677). It is an essential member of the intrinsic blood coagulation cascade although its role in this cascade does not involve the release of bradykinin or enzymatic cleavage. Plasma prekallikrein is encoded by a single gene and synthesized in the liver. It is secreted by hepatocytes as an inactive plasma prekallikrein that circulates in plasma as a heterodimer complex bound to high molecular weight kininogen which is activated to give the active plasma kallikrein. Kinins are potent mediators of inflammation that act through G protein-coupled receptors and antagonists of kinins (such as bradykinin antagonists) have previously been investigated as potential therapeutic agents for the treatment of a number of disorders (F. Marceau and D. Regoli, Nature Rev., Drug Discovery, 2004, 3, 845-852).
Plasma kallikrein is thought to play a role in a number of inflammatory disorders. The major inhibitor of plasma kallikrein is the serpin C1 esterase inhibitor. Patients who present with a genetic deficiency in C1 esterase inhibitor suffer from hereditary angioedema (HAE) which results in intermittent swelling of face, hands, throat, gastro-intestinal tract and genitals. Blisters formed during acute episodes contain high levels of plasma kallikrein which cleaves high molecular weight kininogen liberating bradykinin leading to increased vascular permeability. Treatment with a large protein plasma kallikrein inhibitor has been shown to effectively treat HAE by preventing the release of bradykinin which causes increased vascular permeability (A. Lehmann "Ecallantide (DX-88), a plasma kallikrein inhibitor for the treatment of hereditary angioedema and the prevention of blood loss in on-pump cardiothoracic surgery" Expert Opin. Biol. Ther. 8, p 1187-99).
The plasma kallikrein-kinin system is abnormally abundant in patients with advanced diabetic macular edema. It has been recently published that plasma kallikrein contributes to retinal vascular dysfunctions in diabetic rats (A. Clermont et al. "Plasma kallikrein mediates retinal vascular dysfunction and induces retinal thickening in diabetic rats" Diabetes, 2011, 60, p 1590-98). Furthermore, administration of the plasma kallikrein inhibitor ASP-440 ameliorated both retinal vascular permeability and retinal blood flow abnormalities in diabetic rats. Therefore a plasma kallikrein inhibitor should have utility as a treatment to reduce retinal vascular permeability associated with diabetic retinopathy and diabetic macular edema.
Plasma kallikrein also plays a role in blood coagulation. The intrinsic coagulation cascade may be activated by factor XII (FXII). Once FXII is activated (to FXIIa), FXIIa triggers fibrin formation through the activation of factor XI (FXI) thus resulting in blood coagulation. Plasma kallikrein is a key component in the intrinsic coagulation cascade because it activates FXII to FXIIa, thus resulting in the activation of the intrinsic coagulation pathway. Furthermore, FXIIa also activates further plasma prekallikrein resulting in plasma kallikrein. This results in positive feedback amplification of the plasma kallikrein system and the intrinsic coagulation pathway (Tanaka et al. (Thrombosis Research 2004, 113, 333-339); Bird et al. (Thrombosis and Haemostasis, 2012, 107, 1141-50).
Contact of FXII in the blood with negatively charged surfaces (such as the surfaces of external pipes or the membrane of the oxygenator that the blood passes during cardiopulmonary bypass surgery) induces a conformational change in zymogen FXII resulting in a small amount of active FXII (FXIIa). The formation of FXIIa triggers the formation of plasma kallikrein resulting in blood coagulation, as described above. Activation of FXII to FXIIa can also occur in the body by contact with negatively charged surfaces on various sources (e.g. bacteria during sepsis, RNA from degrading cells), thus resulting in disseminated intravascular coagulation (Tanaka et al. (Thrombosis Research 2004, 113, 333-339)).
Therefore, inhibition of plasma kallikrein would inhibit the blood coagulation cascade described above, and so would be useful in the treatment of disseminated intravascular coagulation and blood coagulation during cardiopulmonary bypass surgery where blood coagulation is not desired. For example, Katsuura et al. (Thrombosis Research, 1996, 82, 361-368) showed that administration of a plasma kallikrein inhibitor, PKSI-527, for LPS-induced disseminated intravascular coagulation significantly suppressed the decrease in platelet count and fibrinogen level as well as the increase in FDP level which usually occur in disseminated intravascular coagulation. Bird et al. (Thrombosis and Haemostasis, 2012, 107, 1141-50) showed that clotting time increased, and thrombosis was significantly reduced in plasma kallikrein-deficient mice. Revenko et al. (Blood, 2011, 118, 5302-5311) showed that the reduction of plasma prekallikrein levels in mice using antisense oligonucleotide treatment resulted in antithrombotic effects. Tanaka et al. (Thrombosis Research 2004, 113, 333-339) showed that contacting blood with DX-88 (a plasma kallikrein inhibitor) resulted in an increase in activated clotting time (ACT). Lehmann et al. (Expert Opin. Biol. Ther. 2008, 1187-99) showed that Ecallantide (a plasma kallikrein inhibitor) was found to delay contact activated induced coagulation. Lehmann et al. conclude that Ecallantide "had in vitro anticoagulant effects as it inhibited the intrinsic pathway of coagulation by inhibiting plasma kallikrein".
Plasma kallikrein also plays a role in the inhibition of platelet activation, and therefore the cessation of bleeding. Platelet activation is one of the earliest steps in hemostasis, which leads to platelet plug formation and the rapid cessation of bleeding following damage to blood vessels. At the site of vascular injury, the interaction between the exposed collagen and platelets is critical for the retention and activation of platelets, and the subsequent cessation of bleeding.
Once activated, plasma kallikrein binds to collagen and thereby interferes with collagen-mediated activation of platelets mediated by GPVI receptors (Liu et al. (Nat Med., 2011, 17, 206-210)). As discussed above, plasma kallikrein inhibitors reduce plasma prekallikrein activation by inhibiting plasma kallikrein-mediated activation of factor XII and thereby reducing the positive feedback amplification of the kallikrein system by the contact activation system.
Therefore, inhibition of plasma kallikrein reduces the binding of plasma kallikrein to collagen, thus reducing the interference of plasma kallikrein in the cessation of bleeding. Therefore plasma kallikrein inhibitors would be useful in the treatment of treating cerebral haemorrhage and bleeding from post operative surgery. For example, Liu et al. (Nat Med., 2011, 17, 206-210) demonstrated that systemic administration of a small molecule PK inhibitor, ASP-440, reduced hematoma expansion in rats. Cerebral hematoma may occur following intracerebral haemorrhage and is caused by bleeding from blood vessels into the surrounding brain tissue as a result of vascular injury. Bleeding in the cerebral haemorrhage model reported by Liu et al. was induced by surgical intervention involving an incision in the brain parenchyma that damaged blood vessels. These data demonstrate that plasma kallikrein inhibition reduced bleeding and hematoma volume from post operative surgery. Björkqvist et al. (Thrombosis and Haemostasis, 2013, 110, 399-407) demonstrated that aprotinin (a protein that inhibits serine proteases including plasma kallikrein) may be used to decrease postoperative bleeding.
Other complications of diabetes such as cerebral haemorrhage, nephropathy, cardiomyopathy and neuropathy, all of which have associations with plasma kallikrein may also be considered as targets for a plasma kallikrein inhibitor.
Synthetic and small molecule plasma kallikrein inhibitors have been described previously, for example by Garrett et al. ("Peptide aldehyde . . . ." J. Peptide Res. 52, p 62-71 (1998)), T. Griesbacher et al. ("Involvement of tissue kallikrein but not plasma kallikrein in the development of symptoms mediated by endogenous kinins in acute pancreatitis in rats" British Journal of Pharmacology 137, p 692-700 (2002)), Evans ("Selective dipeptide inhibitors of kallikrein" WO03/076458), Szelke et al. ("Kininogenase inhibitors" WO92/04371), D. M. Evans et al. (Immunolpharmacology, 32, p 115-116 (1996)), Szelke et al. ("Kininogen inhibitors" WO95/07921), Antonsson et al. ("New peptides derivatives" WO94/29335), J. Corte et al. ("Six membered heterocycles useful as serine protease inhibitors" WO2005/123680), J. Stürzbecher et al. (Brazilian J. Med. Biol. Res 27, p 1929-34 (1994)), Kettner et al. (U.S. Pat. No. 5,187,157), N. Teno et al. (Chem. Pharm. Bull. 41, p 1079-1090 (1993)), W. B. Young et al. ("Small molecule inhibitors of plasma kallikrein" Bioorg. Med. Chem. Letts. 16, p 2034-2036 (2006)), Okada et al. ("Development of potent and selective plasmin and plasma kallikrein inhibitors and studies on the structure-activity relationship" Chem. Pharm. Bull. 48, p 1964-72 (2000)), Steinmetzer et al. ("Trypsin-like serine protease inhibitors and their preparation and use" WO08/049595), Zhang et al. ("Discovery of highly potent small molecule kallikrein inhibitors" Medicinal Chemistry 2, p 545-553 (2006)), Sinha et al. ("Inhibitors of plasma kallikrein" WO08/016883), Shigenaga et al. ("Plasma Kallikrein Inhibitors" WO2011/118672), and Kolte et al. ("Biochemical characterization of a novel high-affinity and specific kallikrein inhibitor", British Journal of Pharmacology (2011), 162(7), 1639-1649). Also, Steinmetzer et al. ("Serine protease inhibitors" WO2012/004678) describes cyclized peptide analogs which are inhibitors of human plasmin and plasma kallikrein.
To date, no small molecule synthetic plasma kallikrein inhibitor has been approved for medical use. Many of the molecules described in the known art suffer from limitations such as poor selectivity over related enzymes such as KLK1, thrombin and other serine proteases, and poor oral availability. The large protein plasma kallikrein inhibitors present risks of anaphylactic reactions, as has been reported for Ecallantide. Thus there remains a need for compounds that selectively inhibit plasma kallikrein, that do not induce anaphylaxis and that are orally available. Furthermore, the vast majority of molecules in the known art feature a highly polar and ionisable guanidine or amidine functionality. It is well known that such functionalities may be limiting to gut permeability and therefore to oral availability. For example, it has been reported by Tamie J. Chilcote and Sukanto Sinha ("ASP-634: An Oral Drug Candidate for Diabetic MacularEdema", ARVO 2012 May 6-May 9, 2012, Fort Lauderdale, Fla., Presentation 2240) that ASP-440, a benzamidine, suffers from poor oral availability. It is further reported that absorption may be improved by creating a prodrug such as ASP-634. However, it is well known that prodrugs can suffer from several drawbacks, for example, poor chemical stability and potential toxicity from the inert carrier or from unexpected metabolites. In another report, indole amides are claimed as compounds that might overcome problems associated with drugs possessing poor or inadequate ADME-tox and physicochemical properties although no inhibition against plasma kallikrein is presented or claimed (Griffioen et al, "Indole amide derivatives and related compounds for use in the treatment of neurodegenerative diseases", WO2010/142801).
BioCryst Pharmaceuticals Inc. have reported the discovery of the orally available plasma kallikrein inhibitor BCX4161 ("BCX4161, An Oral Kallikrein Inhibitor: Safety and Pharmacokinetic Results Of a Phase 1 Study In Healthy Volunteers", Journal of Allergy and Clinical Immunology, Volume 133, Issue 2, Supplement, February 2014, page AB39 and "A Simple, Sensitive and Selective Fluorogenic Assay to Monitor Plasma Kallikrein Inhibitory Activity of BCX4161 in Activated Plasma", Journal of Allergy and Clinical Immunology, Volume 133, Issue 2, Supplement February 2014, page AB40). However, human doses are relatively large, currently being tested in proof of concept studies at doses of 400 mg three times daily.
There are only few reports of plasma kallikrein inhibitors that do not feature guanidine or amidine functionalities. One example is Brandl et al. ("N-((6-amino-pyridin-3-yl)methyl)-heteroaryl-carboxamides as inhibitors of plasma kallikrein" WO2012/017020), which describes compounds that feature an aminopyridine functionality. Oral efficacy in a rat model is demonstrated at relatively high doses of 30 mg/kg and 100 mg/kg but the pharmacokinetic profile is not reported. Thus it is not yet known whether such compounds will provide sufficient oral availability or efficacy for progression to the clinic. Other examples are Brandl et al. ("Aminopyridine derivatives as plasma kallikrein inhibitors" WO2013/111107) and Flohr et al. ("5-membered heteroarylcarboxamide derivatives as plasma kallikrein inhibitors" WO2013/111108). However, neither of these documents report any in vivo data and therefore it is not yet known whether such compounds will provide sufficient oral availability or efficacy for progression to the clinic. Another example is Allan et al. "Benzylamine derivatives" WO2014/108679.
In the manufacture of pharmaceutical formulations, it is important that the active compound be in a form in which it can be conveniently handled and processed in order to obtain a commercially viable manufacturing process. Accordingly, the chemical stability and the physical stability of the active compound are important factors. The active compound, and formulations containing it, must be capable of being effectively stored over appreciable periods of time, without exhibiting any significant change in the physico-chemical characteristics (e.g. chemical composition, density, hygroscopicity and solubility) of the active compound.
It is known that manufacturing a particular solid-state form of a pharmaceutical ingredient can affect many aspects of its solid state properties and offer advantages in aspects of solubility, dissolution rate, chemical stability, mechanical properties, technical feasibility, processability, pharmacokinetics and bioavailability. Some of these are described in "Handbook of Pharmaceutical Salts; Properties, Selection and Use", P. Heinrich Stahl, Camille G. Wermuth (Eds.) (Verlag Helvetica Chimica Acta, Zurich). Methods of manufacturing solid-state forms are also described in "Practical Process Research and Development", Neal G. Anderson (Academic Press, San Diego) and "Polymorphism: In the Pharmaceutical Industry", Rolf Hilfiker (Ed) (Wiley VCH). Polymorphism in pharmaceutical crystals is described in Byrn (Byrn, S. R., Pfeiffer, R. R., Stowell, J. G., "Solid-State Chemistry of Drugs", SSCI Inc., West Lafayette, Ind., 1999), Brittain, H. G., "Polymorphism in Pharmaceutical Solids", Marcel Dekker, Inc., New York, Basel, 1999) or Bernstein (Bernstein, J., "Polymorphism in Molecular Crystals", Oxford University Press, 2002).
The applicant has developed a novel series of compounds that are inhibitors of plasma kallikrein, which are disclosed in WO2016/083820 (PCT/GB2015/053615). These compounds demonstrate good selectivity for plasma kallikrein and are potentially useful in the treatment of diabetic retinopathy, macular edema and hereditary angioedema. One such compound is N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide. Initial attempts to prepare N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide were performed by evaporation of the 1% ammonia-methanol/DCM solvent used during chromatography to yield a foam with XRPD data (recorded using Method B) that shows mainly amorphous content consistent with the solid form referred to herein as 'Form A' (FIG. 1a). The applicant has now developed novel crystalline forms of this compound, which are herein referred to as 'Form 1', 'Form 2', 'Form 3' and 'Form 4'. The novel solid forms have advantageous physico-chemical properties that render them suitable for development.
The applicant has also developed novel crystalline salt forms of N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide, specifically novel crystalline hydrochloride, sulfate, phosphate, mesylate, tosylate, edisylate and besylate salts of N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide. The novel solid forms have advantageous physico-chemical properties that render them suitable for development, in particular, they have a low hygroscopicity and their preparation by crystallisation is simple and scalable.

Polymorphs of n-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[2-oxopyridin-1-yl)methyl]phenyl} methyl)pyrazole-4-carboxamide as iallikrein inhibitors


Disclosed are an organic light emitting diode display and a manufacturing method thereof, and more particularly, an organic light emitting diode display capable of minimizing resistance increase of a second electrode and improving light extraction efficiency at the same time by forming a separate reflector, and a manufacturing method thereof.

1. Field
The present disclosure relates to an organic light emitting diode display and a manufacturing method thereof, and more particularly, to an organic light emitting diode display capable of minimizing increase in resistance of a second electrode and improving light extraction efficiency at the same time by forming a separate reflector, and a manufacturing method thereof.
2. Description of the Related Technology
An organic light emitting diode display is a self-emission display device which has an organic light emitting diode which emits light to display an image. Since the organic light emitting diode display does not require a separate light source like a liquid crystal display does, it is possible to relatively reduce thickness and weight thereof. Further, the organic light emitting diode display has high quality characteristics such as low power consumption, high luminance, and high response speed. One application of an organic light emitting diode display is as a display device for portable electronic apparatuses.
An organic light emitting diode is an element using light generated when an electron and a hole are coupled with each other to emit light and the emitted light is dissipated. Generally, the organic light emitting diode includes an electrode for injecting a hole, an electrode for injecting an electron, and an emission layer, and has a structure in which the emission layer is laminated between a positive electrode which is the electrode for injecting a hole and a negative electrode which is the electrode for injecting an electron. When the electron is injected to the negative electrode of the organic light emitting diode and the hole is injected to the positive electrode, charges thereof move in an opposite direction to each other by an external electric field and then are coupled with each other in the emission layer to emit light during emission and dissipation. In the organic light emitting diode, the emission layer is made of a single molecular organic material or a polymer.
The organic light emitting diode display has a multilayer laminated structure, and the light generated from the emission layer is placed in the layer of the organic light emitting diode display and thus a ratio of light which is not discharged outside is considerably high. The phenomenon may be caused by a waveguide phenomenon due to total reflection, and light extraction efficiency in the organic light emitting diode display is considerably low at about 20%. Accordingly, in the organic light emitting diode display, it is very important to increase the light extraction efficiency.

Organic light emitting diode display and manufacturing method thereof


Described herein is a mechanism for automatically correcting perspective of displayed information based on the orientation of the display device. A user can identify a screen orientation where the displayed information does not need perspective correction. The system can monitor changes to the display orientation, and when the orientation changes, the system can measure the distance to a user's eye or calculate the distance based on measured data. Based on the distance, a correction factor can be calculated. An area in the display where corrected information will be displayed is identified. The currently displayed information is corrected based on the correction factor and displayed in the identified display area.

Portability in computing and display systems has provided several benefits and allows users to work wherever they happen to be. However, this creates environments that are less than ergonomic. In such environments, current display screens have perspective failure when a user is unable to adjust the display to be exactly perpendicular to the user's eyes. Such perspective failure can be exacerbated when display devices are mounted to wheelchairs or other similar environments.
It is within this context that the present embodiments arise.

Automatic display adjustment based on viewing angle


This invention relates to a food ingredient, comprising a heat-set protein gel and a polysaccharide hydrocolloid which is present in an amount sufficient to influence the structure and texture of the gel, and a process for the preparation of the food ingredient.

This invention relates to food ingredients, to methods for the preparation of such food ingredients and to food products comprising such ingredients. The invention is particularly, but not exclusively, concerned with food ingredients for use in reduced-fat foods, and with the use of dairy whey protein in the preparation of such reduced-fat foods.
Whey is the co-product from the manufacture of dairy products which utilise the casein proteins of milk. It contains principally lactose, minerals and the whey proteins representing approximately 20% of the total protein of cows"" milk. The whey proteins are represented in majority by the two proteins, xcex1-lactalbumin and xcex2-lactoglobulin. In a previous invention a process was described for the fractionation of these major whey proteins in Australian Patent No. 616,411.
International Patent Application No. WO93/00832 (PCr/AU92/00331) (the full disclosure of which is hereby incorporated herein) describes gelled food products in which microparticulate suspensions are stabilised in heat-set gels for food applications. When restricted protein unfolding occurs as a result of heating certain globular proteins in solution, gelation may occur if specific interactions between protein molecules enable an ordered three-dimensional network to be formed. Such interactions affect intermolecular cross-lining involving hydrogen bonding, ionic and hydrophobic interactions. Adjuncts to such interacting protein systems which affect some or all of such cross-linking mechanisms may serve to modify the overall structure, texture and rheological problems of the gelled product.
Of the milk proteins. only certain of the whey proteins are capable of heat-induced gelation, xcex2-lactoglobulin is considered to be the most important whey protein for gelation since it is capable of forming uniform gels of high strength. Application of the whey protein fractionation technology developed by Pearce, yields a product which is highly enriched in xcex2-lactoglobulin and referred to as xe2x80x9cxcex2-Fractionxe2x80x9d. This product also displays the capability of forming uniform gels of high strength. (see Pearce, R. J. (1991) Applications of cheese whey protein fractions. Food Research Quarterly 51; 74-91.)
Stading and Hermnansson have described the structure and appearance of xcex2-lactoglobulin gels over a range of pH values and have described the clear gels formed below pH 4.0 and above about pH 6.5 as fine-stranded gels and the more turbid gels formed at intermediate pH as aggregate gels. The fine stranded gels formed at low pH were brittle but in the higher pH range were rubber-like. (see Stading, M. and Hermansson. A. M. (1991) Large deformation properties of xcex2-lactoglobulin gel structures. Food Hydrocolloids 5: 339-352.) The ability to form heat-set gels from food proteins is not limited to xcex2-lactoglobulin or to whey proteins. For example, heat set gelation of egg white protein is well known. Variation in the appearance and texture of such egg white gels may be achieved by manipulation of the ionic strength and pH as has been described by Hegg, P. O. (1982) Conditions for the formation of heat-induced gels of some globular food proteins. Journal of Food Science 47, 1241-1244. in a manner similar to that shown for xcex2-lactoglobulin by Stading, M and Hermansson, A-M. (1993) Large deformation properties of xcex2-lactoglobulin gels. Food Hydrocolloids 5, 339-352.
By combining the results, described in International Patent Application No. WO93/00832 with the results of Stading et al., we identified novel gelled food products in which the appearance and texture of the gelled product could be varied from clear to opaque and from elastic to inelastic according to the environmental conditions of the protein during the heat-gelation process. The resulting products demonstrated rheological characteristics of potential value in the formulation of novel foods. However, under textural analysis, these products, whether essentially elastic or inelastic. showed distinct yield points (gel breaking points). This property was considered undesirable for certain food applications.
We have now found that incorporation of a polysaccharide hydrocolloid into a heat-gelled protein results in a gelled material having a modified structure and texture which, rheologically does not display a distinct fracture point (gel breaking point). In this behavior, the gelled product exhibits the textural and Theological properties of a fat (exemplified herein by a texture profile of lard, see FIG. 13) and enables the material to be utilized as a food ingredient, e.g., a texture modifier, in food products, and especially as an ingredient in reduced-fat foods.

Whey protein and carrageenan heat-set gels

Scientific and Industrial Research Organisation


Process for the production of semiconductor devices by using silicon-on-insulator (SOI) techniques. The Si layers of the SOI structure include an interfacial layer of Si and a buffer layer of Si formed thereon, whereby the formation of stacking faults in the Si layers can be effectively prevented. Pretreatment of the underlying insulating material with a molybdate solution and interposition of an additional layer of slowly grown single-crystalline Si between the buffer layer of Si and the overlying active Si layer are also effective to inhibit the stacking faults. Semiconductor devices with high quality can be produced with good yield.

Field of the Invention
This invention relates to a process for the production of semiconductor devices. In particular, this invention relates to a process for the production of semiconductor devices which comprise a single-crystalline layer of silicon, as an active layer, on a single-crystalline layer of insulating materials such as magnesia spinel (MgO.multidot.Al.sub.2 O.sub.3) and sapphire (.alpha.-Al.sub.2 O.sub.3). Such an active silicon layer on an insulator or insulating layer is generally referred to in the art as an SOI (silicon-on-insulator), and is used for fabrication of bipolar transistors, metal-oxide semiconductor (MOS) devices, high-voltage bipolar integrated circuits (IC's), or similar circuits and devices.
Description of the Related Art
Many types of SOI's have been proposed and used in the production of semiconductor devices due to the advantages offered by the same. First, they do not necessitate isolation in the devices or, even if isolation is necessary, it is easy to form an isolation area. Further, semiconductor devices having SOI structures show no or little parasitic capacitance. These remarkable advantages ensure the production of semiconductor devices having a high quality and integrity.
A typical example of the prior art SOI structure can be found in FIGS. 1a and 1b. As illustrated in FIG. 1a, the SOI material comprises a (100) Si substrate 1 having deposited thereon an SiO.sub.2 layer 2 and an amorphous Si layer 3. The amorphous Si layer 3 is generally formed by using vapor phase epitaxy (VPE) or other techniques.
In order to convert amorphous Si in the layer 3 to single-crystalline Si, the material is annealed at a temperature of about 600.degree. C. to 1100.degree. C. Crystallization of the amorphous Si is started at an exposed portion of the Si substrate 1, as is shown in FIG 1b. Namely, the exposed portion of the substrate 1 acts as a seed for crystallization. The single-crystalline Si area 4 gradually extends over the layer 3. Finally, all of the amorphous Si in the layer 3 is converted to a single-crystalline form of silicon.
The result is shown in FIG. 2, which is a schematic plan view of the resulting SOI structure. Unexpectedly, the single-crystalline Si layer 4 has partially formed (110) and (111) crystal structures in addition to the (100) crystal structure. This means that the layer 4 is not a single-crystalline form, but polycrystalline form. Such an undesirable result can be frequently encountered in the formation of the illustrated SOI structure.
Heteroepitaxy is also well-known and widely used in the formation of SOI structures. As we have already reported in, for example, M. Ihara et al., "Vapor phase epitaxial growth of MgO.multidot.Al.sub.2 O.sub.3 ", J. Electrochem. Soc., Vol. 129, No. 11, pp. 2569-2573, Nov. 1982, and M. Ihara, "Epitaxial spinel growth for integrated circuits", Microelectronic Engineering, Vol. 1, pp. 161-177, 1983, SOI structures produced by using heteroepitaxy or the heteroepitaxial growth technique have many advantages. For example, the resulting active Si layers on sapphire or spinel show high quality and mobility. High voltage isolation can be achieved. The large-sized Si wafers can be used as the substrate, therefore low-price devices can be produced.
However, this technique suffers from a drawback that the active Si layers have unavoidable stacking faults due to their heterojunction with the underlying sapphire or spinel layer. This defect will become clearer with reference to FIG. 3, which illustrates a typical Si-on-spinel (MgO.multidot.Al.sub.2 O.sub.3)-on-Si double heterostructure.
In FIG. 3, the illustrated SOI structure comprises a (100) single-crystalline Si substrate 1 having deposited thereon a (100)--oriented spinel epitaxial layer 5 and (100)-oriented single-crystalline Si layer 6. The Si layer 6 is generally deposited by VPE. During the VPE process, stacking faults (111) are induced in the growing Si layer 6. We found that the formation of the stacking faults is started at limited portions of the Si/spinel interface, each of which acts as a core of the fault formation during crystal growth. Such core portions are considered to be due to the about 0.8% lattice mismatch between Si and spinel.
The stacking faults result in conspicuous straight defects on a surface of the active Si layer after they have passed through the layer. This means lowering of the yield of the SOI structure and, accordingly, the finally produced devices. It is, therefore, desirable to provide improved methods for forming SOI structures which have thin or thick layers of single-crystalline Si with high quality and without stacking faults, on an insulating layer of spinel, sapphire, or other single crystals.

Process for the production of semiconductor devices utilizing multi-step deposition and recrystallization of amorphous silicon


The invention relates to a method of fabricating a compound semiconductor device by forming a first and a second compound semiconductor devices having a plurality of different epitaxial layers on a common semiconductor substrate. The method comprises the steps of sequentially forming a plurality of first epitaxial layers for manufacturing the first compound semiconductor device on the semiconductor substrate; forming a first insulating film pattern for defining an active region of the first compound semiconductor device; etching the plurality of first epitaxial layers using the first insulating film pattern as a mask; forming a second insulating film on the resultant structure; forming a sidewall insulating spacer on the sidewall of the active region of the first compound semiconductor device by dry etching the second insulating film; sequentially forming a plurality of second epitaxial layers for manufacturing the second compound semiconductor device on the portion from which the plurality of first epitaxial layers is etched back; forming each electrode of the first and second compound semiconductor devices; and forming an interconnection electrode interconnecting each electrode of the first and second compound semiconductor devices.

1. Field of the Invention
The present invention relates to a method of fabricating a compound semiconductor device, and more particularly, to a method of fabricating a compound semiconductor device which can prevent the deterioration of the characteristics of the isolation between devices and a large step difference between two devices, when more than one semiconductor device type such as an optical device and an electron device are fabricated on a common semiconductor substrate.
2. Background of the Invention
Conventional method for fabricating more than one device type such as optical device and field effect transistor, for example, high electron mobility transistor(HEMT) on a common semiconductor substrate, comprises the steps of defining an active region of the device by wet etching an epitaxial substrate for field effect device using a single nitride film, and growing epitaxial layers for optical device by a molecular beam epitaxy(MBE) method under the condition that the sidewall of the active region formed by etching is exposed.
FIGS. 1A to 1F show a conventional method for fabricating optical device and field effect device on a semiconductor devices.
Specifically, FIG. 1A shows epitaxial layers for manufacturing the field effect device(HEMT) including a semi-insulating gallium arsenide(GaAs) substrate 1, a buffer layer 2, a sub-channel 3, a channel layer 4, a spacer layer 5, a Schottky layer 6 and an n-type GaAs ohmic layer 7.
Referring to FIG. 1B, epitaxial layers for manufacturing the optical device include an AlGaAs etch-stop layer 8, a buffer layer 9, an InGaAs absorption layer 10, an AlGaAs Schottky layer 11 and a GaAs Schottky layer 12 formed in order.
As shown in FIG. 1C, an insulating film pattern 13 is formed to define an active region of the optical device, and then the epitaxial substrate for optical device is etched to form a mesa by etching the GaAs Schottky layer 12, the AlGaAs Schottky layer 11, the InGaAs absorption layer 10, the buffer layer 9 and the etch-stop layer 8 in order, so as to form the active region of the optical device, and simultaneously the epitaxial layer in which HEMT will be located is exposed.
Referring to FIG. 1D, the epitaxial layers for HEMT device is etched in the order of the ohmic layer 7, the Schottky layer 6, the spacer layer 5, the channel layer 4, the sub-channel 3 and the buffer layer 2 to form a mesa, and then the insulating film pattern 13 is removed.
Referring to FIG. IE, an ohmic electrode 14 is formed and the ohmic layer 7 is etched to form a recessed portion. And, a gate electrode 15 of HEMT is formed. FIG. 1E is a cross-sectional view taken in the direction of the gate electrode 15. Then, Schottky electrode 16 of the optical device (MSM photo diode) is formed, and an interconnection electrode 17 connecting the above two devices is formed. Thus, the optical device and the field effect device are formed on a common substrate as shown in FIG. 1F.
In the conventional method, as can be seen from FIG. 1F, the length of the interconnection electrode 17 connecting the optical device to the field effect device is so long that there are too many parasitic components, which leads the decrease of the reliability of the device. And, the mesa etching method for forming an isolation region brings about a loss of the active region. Thus, the integration of the devices is decreased. And, the large step difference between the two devices may lead cutting of the interconnection electrode 17. And, since the gate electrode 15 of the HEMT device is in contact with the channel layer 4 of the HEMT active layers, a passage of the leakage current is generated between a gate and a source or a drain, which results the problems including the deterioration of the electric characteristics.

Method of fabricating a compound semiconductor device

Electronics And Telecommunications Research Institute


A lighted arrow nock capable of easily turning on or off a light, and being easily connected to an arrow shaft includes a light emitting unit including a light and a battery and turning on or off the light by moving the light toward the battery or away from the battery; an arrow adaptor which includes a cylindrical structure so that an outer surface is inserted into a rear end of an arrow, in which the battery is inserted into an inner space of the arrow adaptor; and a light operator which is inserted in an upper portion of the arrow adaptor, while a lower portion of the light operator receives the light, and is moved up and down to turn on or off the light in a state in which the light operator is inserted in the arrow adaptor.

Field of the Invention
The present invention relates to an arrow nock, and, more specifically, to a lighted arrow nock capable of easily turning on or off a light, and being easily connected to an arrow shaft.
Background of the Related Art
In general, an arrow 1 used for archery includes, as illustrated in FIG. 1, an arrow shaft 10 of a cylindrical cross section made of duralumin, glass fiber, carbon fiber, or the like to form a body, an arrowhead 20 fitted to a front end of the arrow shaft 10, feathers 30 designed to stabilize flight of the arrow 1 and to keep the arrow pointed in the direction of travel, and a nock 40 which is a notch in the rearmost end of the arrow and serves the arrow in place on the string as a bow is being drawn.
There has been recently developed a technology of providing the arrow with a lighting function in order to enable a user to effectively enjoy the archery even at night or on a cloudy day. In this instance, a light and a battery are provided to the rear end of the arrow, that is, the nock 40, and the light is turned on or off, so that the lighted arrow can be used.


A circuit pattern of a power line and a circuit pattern of a signal line are disposed in a first layer of a laminated circuit board device, a circuit pattern of the signal line to be protected is disposed in a second layer, and a circuit pattern of a power line is disposed in a third layer. The shapes of the first circuit pattern of the power line of the first layer and the second circuit pattern of the power line of the third layer are substantially matched with each other with respect to a portion of the second layer facing the circuit pattern of the signal line. The direction of the current of the first circuit pattern coincides with the direction of the current of the second circuit pattern.

In various electronic circuits such as an in-vehicle device, a malfunction may occur or the performance of the device may decrease due to an influence of noise generated from other devices, wiring, or the like existing at an adjacent position. Therefore, various kinds of noise countermeasures have been taken at the time of designing the device and the time of disposing the device.
For example, Patent Literature JP-A-11-220056 discloses a technique for reducing an inductance of a wiring or a wiring lead in a semiconductor package disposed on a general wiring board and reducing an inductive crosstalk. Specifically, a predetermined wiring is disposed on an insulating board, and an electromagnetic wave shielding film (metal foil) is disposed at a position close to the wiring. In addition, an electromagnetic wave shielding film is disposed on a surface of a semiconductor chip on which an integrated circuit is formed with an insulating film interposed therebetween, a lead is disposed on the electromagnetic wave shielding film with an insulating film interposed therebetween, and the lead and an external terminal of the semiconductor chip are electrically connected to each other, and sealed with a sealing material to form a semiconductor device.
In addition, Patent Literature JP-A-2016-92864 discloses a technique for reducing noise of an electric power conversion device. Specifically, the electric power conversion device includes a multilayer board in an output wiring portion that outputs the converted electric power. A multilayer board, a ground layer, and output wiring layers (U, V, W) are provided, and vias are provided between the output wiring layers. The output wiring layer is a flat plate, and the output wiring layers are arranged side by side with a wide area facing the ground layer. A plurality of vias are formed between the output wiring layers and penetrate from the ground layer to the surface of the multilayer board. A conductive sheet is provided on an end portion of a via (ground potential) exposed on the surface of the multilayer board.
Incidentally, for example, in the case of electronic devices such as DC/DC converters mounted on vehicles or switching devices for switching electric power paths, a power system line (power line) that handles a large current and a signal system line (signal line) through which only various signals having a very small amount of current pass are disposed in a mixed state on the same printed board. That is, the power line and the various signal line are disposed at positions adjacent to each other.
In addition, since the wiring pattern on the printed board is generally formed of a very thin foil-like conductor, it is important to reduce the power loss due to the resistance of the wiring pattern of the power line on the board when a large current flows. Therefore, in a normal design, the resistance is reduced by sufficiently increasing the line width and the area of the wiring pattern with respect to the power line and the ground line (earth).
In addition, when a multilayer board can be used, a wiring pattern of a power line may be formed on each of a plurality of layers on the same board. For example, when the wiring patterns of the two layers are connected in parallel, the resistance value per unit area of the wiring pattern can be reduced to half, it becomes easy to suppress the increase in the area of the wiring pattern of the power line and reduce the area occupied by the board of the electronic device.
However, in a case where a power line and a signal line exist in a plurality of layers adjacent to each other in the thickness direction of the same board, there is a concern that the influence of noise appears on the signal line since the distance between the wiring patterns of the power line and the signal line facing each other becomes very small. Specifically, the noise waveform is superimposed on the wiring pattern of the adjacent signal line due to the counter electromotive force of the induction magnetic field generated when the current on the power line changes.
In particular, in the case of an electronic device such as a DC/DC converter, since switching of a large current is periodically performed at high speed, there is a concern that large noise may be induced in a signal line adjacent to a power line through which the current flows in synchronization with a timing of a current change in switching.
As a countermeasure against such noise, it is assumed that a wiring pattern of a ground line is disposed between a noise generation source and a signal line, and an electromagnetic shield is provided as a general design method.
For example, as in the configuration example illustrated in FIG. 7, in the case of using a multilayer board in which a conductive pattern is formed in each of a first layer, a second layer, and a third layer, a power line is disposed in the first layer, a signal line to be protected is disposed in the third layer, and a wiring pattern of the ground line is allocated to the second layer between the first layer and the third layer. Accordingly, since a ground line having a constant potential exists in the second layer between the power line of the first layer, which is the noise source, and the third layer in which the signal line exists, it is possible to block the induction magnetic field and suppress the induction of noise in the signal line of the third layer.
However, in the case of the configuration as described above, the second layer in the middle of the three layers is occupied only by the ground line of the noise countermeasure, and the power line can be disposed only on the first layer. That is, since the power line, which is the source of noise, cannot be disposed in the third layer, the power line cannot be distributed in a plurality of layers and disposed in each layer. Therefore, the resistance cannot be reduced as long as the wiring pattern area of the power line is not increased.


Disclosed are diagnostic techniques for the detection of human prostate, bladder and breast cancer. Genetic probes and methods useful in monitoring the progression and diagnosis of prostate, bladder and breast cancer are described. The invention relates particularly to probes and methods for evaluating the presence of RNA species that are differentially expressed in prostate, bladder and breast cancer compared to normal human prostate, benign prostatic hyperplasia, or normal bladder or breast tissue.

A. Field of the Invention
The present invention relates generally to nucleic acid sequences useful as probes for the diagnosis of cancer and methods relating thereto. More particularly, the present invention concerns probes and methods useful in diagnosing, identifying and monitoring the progression of prostate cancer, benign prostatic hyperplasia, bladder cancer or breast cancer through measurements of gene products.
B. Description of the Related Art
Genetic detection of human disease states is a rapidly developing field (Taparowsky et al., 1982; Slamon et al., 1989; Sidransky et al., 1992; Miki et al., 1994; Dong et al., 1995; Morahan et al., 1996; Lifton, 1996; Barinaga, 1996). However, some problems exist with this approach. A number of known genetic lesions merely predispose to development of specific disease states. Individuals carrying the genetic lesion may not develop the disease state, while other individuals may develop the disease state without possessing a particular genetic lesion. In human cancers, genetic defects may potentially occur in a large number of known tumor suppresser genes and proto-oncogenes.
The genetic detection of cancer has a long history. One of the earliest genetic lesions shown to predispose to cancer was transforming point mutations in the ras oncogenes (Taparowsky et al., 1982). Transforming ras point mutations may be detected in the stool of individuals with benign and malignant colorectal tumors (Sidransky et al, 1992). However, only 50% of such tumors contained a ras mutation (Sidransky et al., 1992). Similar results have been obtained with amplification of HER-2/neu in breast and ovarian cancer (Slamon et al., 1989), deletion and mutation of p53 in bladder cancer (Sidransky et al., 1991), deletion of DCC in colorectal cancer (Fearon et al., 1990) and mutation of BRCA1 in breast and ovarian cancer (Miki et al., 1994).
None of these genetic lesions are capable of predicting a majority of individuals with cancer and most require direct sampling of a suspected tumor, making screening difficult.
Further, none of the markers described above are capable of distinguishing between metastatic and non-metastatic forms of cancer. In effective management of cancer patients, identification of those individuals whose tumors have already metastasized or are likely to metastasize is critical. Because metastatic cancer kills 560,000 people in the US each year (ACS home page), identification of markers for metastatic cancer, such as metastatic prostate and breast cancer, would be an important advance.
A particular problem in cancer detection and diagnosis occurs with prostate cancer. Carcinoma of the prostate (PCA) is the most frequently diagnosed cancer among men in the United States (Veltri et al., 1996). Prostate cancer was diagnosed in approximately 210,000 men in 1997 and about 39,000 men succumbed to the malignancy (Parker et al., 1996; Wingo et al., 1997). The American Cancer Society expects that more than 340,000 new cases of prostate cancer will be diagnosed in 1998 (Orozco et al., 1998). Although relatively few prostate tumors progress to clinical significance during the lifetime of the patient, those which are progressive in nature are likely to have metastasized by the time of detection. Survival rates for individuals with metastatic prostate cancer are quite low. Between these extremes are patients with prostate tumors that will metastasize but have not yet done so, for whom surgical prostate removal is curative. Determination of which group a patient falls within is critical in determining optimal treatment and patient survival.
The FDA approval of the serum prostate specific antigen (PSA) test in 1984 has subsequently changed the way prostate disease was managed (Allhoff et al., 1989; Cooner et al., 1990; Jacobson et al., 1995; Orozco et al., 1998). PSA is widely used as a serum biomarker to detect and monitor therapeutic response in prostate cancer patients (Badalament et al., 1996; O'Dowd et al, 1997). Several modifications in PSA assays (Partin and Oesterling, 1994; Babian et al., 1996; Zlotta et al., 1997) have resulted in earlier diagnoses and improved treatment.
While an effective indicator of prostate cancer when serum levels are relatively high, PSA serum levels are more ambiguous indicators of prostate cancer when only modestly elevated, for example when levels are between 2-10 ng/ml. At these modest elevations, serum PSA may have originated from non-cancerous disease states such as BPH (benign prostatic hyperplasia), prostatitis or physical trauma (McCormack et al., 1995). Although application of the lower 2.0 ng/ml cancer detection cutoff concentration of serum PSA has increased the diagnosis of prostate cancer, especially in younger men with non-palpable early stage tumors (Stage Tlc) (Soh et al., 1997; Carter et al., 1997; Harris et al., 1997; Orozco et al., 1998), the specificity of the PSA assay for prostate cancer detection at low serum PSA levels remains a problem.
In current clinical practice, the serum PSA assay and digital rectal exam (DRE) is used to indicate which patients should have a prostate biopsy (Lithrup et al., 1994; Orozco et al., 1998). Histological examination of the biopsied tissue is used to make the diagnosis of prostate cancer. Based upon the American Cancer Society estimate of 340,000 cases of diagnosed prostate cancer in 1998 and a known cancer detection rate of about 35% (Parker et al., 1996), it is estimated that in 1998 over one million prostate biopsies will be performed in the United States (Orozco et al., 1998). Clearly, there would be much benefit derived from a serological test that was sensitive enough to detect small and early stage prostate tumors that also had sufficient specificity to exclude a greater portion of patients with noncancerous or clinically insignificant conditions.
Several investigators have sought to improve upon the specificity of serologic detection of prostate cancer by examining a variety of other biomarkers besides serum PSA concentration (Ralph and Veltri, 1997). One of the most heavily investigated of these other biomarkers is the ratio of free versus total PSA (f/t PSA) in a patient's blood. Most PSA in serum is in a molecular form that is bound to other proteins such as .alpha.1-antichymotrypsin (ACT) or .alpha.2-macroglobulin (Christensson et al., 1993; Stenman et al., 1991; Lilja et al., 1991). Free PSA is not bound to other proteins. The ratio of free to total PSA (f/tPSA) is usually significantly higher in patients with BPH compared to those with organ confined prostate cancer (Marley et al., 1996; Oesterling et al., 1995; Pettersson et al., 1995). When an appropriate cutoff is determined for the f/tPSA assay, the f/tPSA assay can help distinguish patients with BPH from those with prostate cancer in cases in which serum PSA levels are only modestly elevated (Marley et al., 1996; Partin and Oesterling, 1996). Unfortunately, while f/tPSA may improve on the detection of prostate cancer, information in the f/tPSA ratio is insufficient to improve the sensitivity and specificity of serologic detection of prostate cancer to desirable levels.
Genetic changes reported to be associated with prostate cancer include: allelic loss (Bova, et al., 1993; Macoska et al., 1994; Carter et al., 1990); DNA hypermethylation (Isaacs et al., 1994); point mutations or deletions of the retinoblastoma (Rb) and p53 genes (Bookstein et al., 1990a; Bookstein et al., 1990b; Isaacs et al., 1991); and aneuploidy and aneusomy of chromosomes detected by fluorescence in situ hybridization (FISH) (Macoska et al., 1994; Visakorpi et al., 1994; Takahashi et al., 1994; Alcaraz et al., 1994).
A recent development in this field was the identification of a prostate metastasis suppresser gene, KAI1 (Dong et al., 1995). Insertion of wild-type KAI1 gene into a rat prostate cancer line caused a significant decrease in metastatic tumor formation (Dong et al., 1995). However, detection of KAI1 mutations is dependent upon direct sampling of mutant prostate cells. Thus, either a primary prostate tumor must be sampled or else sufficient transformed cells must be present in blood, lymph nodes or other tissues to detect the missing or abnormal gene. Further, the presence of a deleted gene may frequently be masked by large numbers of untransformed cells that may be present in a given tissue sample.
The most commonly utilized current tests for prostate cancer are digital rectal examination (DRE) and analysis of serum prostate specific antigen (PSA). Although PSA has been widely used as a clinical marker of prostate cancer since 1988 (Partin & Oesterling, 1994), screening programs utilizing PSA alone or in combination with digital rectal examination have not been successful in improving the survival rate for men with prostate cancer (Partin & Oesterling, 1994). While PSA is specific to prostate tissue, it is produced by normal and benign as well as malignant prostatic epithelium, resulting in a high false-positive rate for prostate cancer detection (Partin & Oesterling, 1994).
Other markers that have been used for prostate cancer detection include prostatic acid phosphatase (PAP) and prostate secreted protein (PSP). PAP is secreted by prostate cells under hormonal control (Brawn et al., 1996). It has less specificity and sensitivity than does PSA. As a result, it is used much less now, although PAP may still have some applications for monitoring metastatic patients that have failed primary treatments. In general, PSP is a more sensitive biomarker than PAP, but is not as sensitive as PSA (Huang et al., 1993). Like PSA, PSP levels are frequently elevated in patients with BPH as well as those with prostate cancer.
Another serum marker associated with prostate disease is prostate specific membrane antigen (PSMA) (Horoszewicz et al., 1987; Carter et al., 1996; Murphy et al., 1996). PSMA is a Type II cell membrane protein and has been identified as Folic Acid Hydrolase (FAH) (Carter et al., 1996). Antibodies against PSMA react with both normal prostate tissue and prostate cancer tissue (Horoszewicz et al., 1987). Murphy et al. (1995) used ELISA to detect serum PSMA in advanced prostate cancer. As a serum test, PSMA levels are a relatively poor indicator of prostate cancer. However, PSMA may have utility in certain circumstances. PSMA is expressed in metastatic prostate tumor capillary beds (Silver et al., 1997) and is reported to be more abundant in the blood of metastatic cancer patients (Murphy et al., 1996). PSMA messenger RNA (mRNA) is down-regulated 8-10 fold in the LNCaP prostate cancer cell line after exposure to 5-.alpha.-dihydroxytestosterone (DHT) (Israeli et al., 1994).
A relatively new potential biomarker for prostate cancer is human kallekrein 2 (HK2) (Piironen et al., 1996). HK2 is a member of the kallekrein family that is secreted by the prostate gland. In theory, serum concentrations of HK2 may be of utility in prostate cancer detection or diagnosis, but the usefulness of this marker is still being evaluated.
As prostate cancer is one of the most prevalent forms of cancer in men, breast cancer is one of the most prevalent forms of cancer in women. Breast cancer is the leading cause of death for women between 30-50 years of age in the United States. Pathological breast cancer staging (tumor size, nodal status) is still the most reliable method for predicting outcome. In contrast to other forms of cancer, only a few tumor markers have been identified for breast cancer (e.g., estrogen receptor, progesterone receptor, S-phase, P53, Erb-2, cathepsin D) (see, e.g. Slamon el al, 1987).
Mutational analysis of important tumor suppressor genes such as p53 (Elledge, 1994) and BRCA1 (Miki et al., 1994) has recently been introduced as a diagnostic and prognostic test for breast cancer. However, many of those markers are not reliable enough to be used for routine purposes in the clinic. Two tumor suppressor genes that are mutated in a number of other cancers (Rb and p53) show a frequency of mutation of only about 30% in breast cancer (Cox et al., 1994). Mutations in the recently identified breast cancer susceptibility genes BRCA1 (chromosome 17q21) and BRCA2 (chromosome 13q13) are associated with familial breast cancer, accounting for about 5% of total breast cancer cases, but have not been found in sporadic breast cancer (Stratton and Wooster, 1996). There has yet to be found a single genetic change that accounts for the majority of sporadic breast cancers. Therefore, there is an urgent need for better prognostic markers in breast cancer diagnosis.
It is known that the processes of transformation and tumor progression are associated with changes in the levels of messenger RNA species (Slamon et al., 1984; Sager et al., 1993; Mok et al., 1994; Watson et al., 1994). Recently, a variation on PCR analysis known as RNA fingerprinting has been used to identify messages differentially expressed in ovarian or breast carcinomas (Liang et al., 1992; Sager et al., 1993; Mok et al., 1994; Watson et al., 1994). By using arbitrary primers to generate "fingerprints" from total cell RNA, followed by separation of the amplified fragments by high resolution gel electrophoresis, it is possible to identify RNA species that are either up-regulated or down-regulated in cancer cells. Results of these studies indicated the presence of several markers of potential utility for diagnosis of breast or ovarian cancer, including a6-integrin (Sager et al., 1993), DEST001 and DEST002 (Watson et al., 1994), and LF4.0 (Mok et al., 1994).
There remain, however, deficiencies in the prior art with respect to the identification of the genes linked with the progression of prostate, bladder or breast cancer and the development of diagnostic methods to monitor disease progression. Likewise, the identification of genes which are differentially expressed in prostate, bladder, breast and other forms of cancer would be of considerable importance in the development of a rapid, inexpensive method to diagnose cancer.

Biomarkers and targets for diagnosis, prognosis and management of prostate, breast and bladder cancer


A temporary clamping structure for electronics includes a bracket fastened to a ceiling surface of the interior of a room, an electronic device body connected to the ceiling surface by screwing down to the bracket, fitting holes formed on the bracket side, and a fitting pawl provided on the electronic device body and fittable into the fitting holes. The temporary clamping structure for electronics is arranged such that the fitting pawl is unfixed from the fitting hole by bending the tip end of second protrusion of the electronic device body in the direction in which the second protrusion goes away from the first protrusion.

1. Field of the Invention
The present invention relates to a temporary clamping structure for electronics, installed in the interior of a room of movable bodies such as a motor vehicle, an electric train, and a ship, for instance, for installing a display (electronics) on one side in the interior of the room, such as a liquid crystal television monitor (hereinafter referred to as a TV monitor).
2. Description of the Related Art
Conventionally, as electronics of this type, there has been generally known an on-vehicle display monitor fastened in an openable and closable manner to the ceiling of the passenger room of a motor vehicle.
FIG. 17 is an exploded perspective view showing the configuration of a conventional on-vehicle display monitor. FIG. 18 is an enlarged front view showing the clamping structure of the on-vehicle monitor shown in FIG. 17.
Referring to FIG. 17 and FIG. 18, reference numeral 1 denotes an on-vehicle display monitor, which is generally composed of a vehicle-side sheet metal bracket (hereinafter referred to as a bracket) 2 and an electronic device body 3. The bracket 2 is generally composed of a virtually U-shaped frame 2a, a virtually rectangular monitor mounting part 2b provided within this frame 2a, a virtually rectangular first supporting part 2c extending to the center of the frame 2a along the ceiling surface of the vehicle (not shown) after once bends to the ceiling surface of the vehicle (not shown) side from one lengthwise side of this monitor mounting part 2b, and a virtually rectangular second supporting part 2d extending along the ceiling surface of the vehicle (not shown) after once bends to the ceiling surface of the vehicle (not shown) side from the other lengthwise side of the monitor mounting part 2b. A space is formed between the monitor mounting part 2b and the ceiling surface of the vehicle (not shown). Moreover, openings 2e and 2f are formed between the frame 2a, the monitor mounting part 2b, and the first supporting part 2c. Tapped holes 4a, 4b, 4c, and 4d are formed in the four corners of the monitor mounting part 2b, and grommet insertion holes 5a, 5b opened in rectangular cross-section form between the tapped holes 4a, 4b, and between the tapped holes 4c, 4d, respectively.
The electronic device body 3 is generally composed of a monitor casing 6 directly screwed down to the monitor mounting part 2b of the bracket 2 and a TV monitor 7 rotatably supported relative to the monitor casing 6. The monitor casing 6 is generally composed of a tabular clamping part 8 to clamp the bracket 2 and an operating part 9 provided on the clamping part 8 and having a mechanism to mechanically or electrically operate the TV monitor 7. In the clamping part 8, there are formed four tapped holes 8a, 8b (two remaining tapped holes are not shown) each corresponding to the four tapped holes 4a, 4b, 4c and 4d located on the bracket 2 side. In an about half area of the undersurface of the clamping part 8, there is provided a housing surrounding wall 10 to house therein the TV monitor 7, and a central partition wall 10a thereof is adjacent to the operating part 9. Furthermore, on the undersurface of the clamping part 8, a rotating shaft 11 to rotatably support the TV monitor 7 is provided in the farthest location from the central partition wall 10a. In addition, in the operating part 9, there is provided an engaging mechanism 12 to engage the TV monitor 7 housed within the housing surrounding wall 10 (closed state). This engaging mechanism 12 is generally composed of an engaging pawl (not shown) that engages with a concavity 14 formed on a front end face 7a of the TV monitor 7, through an opening 13 formed in the central partition wall 10a and a push button 15 to release the engagement of the engaging pawl with the concavity 14.
Rectangular cross-section grommets 16 are screwed between the four tapped holes 8a in the clamping part 8 of the electronic device body 3 by screws 17. Each of the grommets 16 has a pair of fitting pawls 16a as shown in FIG. 18.
The method of mounting the conventional on-vehicle display monitor 1 will now be described below.
First of all, after the bracket 2 is fastened to the main base sheet metal (not shown) of the ceiling surface of the vehicle (not shown), the grommets 16 of the electronic device body 3 are inserted into the grommet insertion holes 5a, 5b on the bracket 2 side. The fitting pawls 16a of the grommets 16 are closed when the pawls pass through the grommet insertion holes 5a and 5b, and they are opened after having passed therethrough to fit the grommets 16 into the grommet insertion holes 5a, 5b. This fitting temporarily clamps the electronic device body 3 to the bracket 2.
Subsequently, in the above-mentioned temporarily clamped state, the tapped holes 8a, etc. on the electronic device body 3 side and the tapped holes 4a, etc. on the bracket 2 side are screwed down by screws (not shown). By going through the above procedures, the mounting work is completed.
However, the conventional mounting of the on-vehicle display monitor thus carried out as above enables a relatively easy mounting of the electronic device body 3 on the bracket 2, but a detachment work thereof is not necessarily easy in contradiction thereto. That is, when detaching the electronic device body 3 for repair or exchange, for instance, complicated works entail, involving unscrew of the screws (not shown) screwed down into the tapped holes 4a, etc. on the bracket side and the tapped holes 8a, etc on the electronic device body side, and removal of the grommets 16 from the main base sheet metal (not shown) after the screws 17 have unscrewed.

Temporary clamping structure for electronics


A film comprising a matrix of transparent polymeric resin, and polymeric particles is disclosed. The particles are characterized in that their refractive index is different from that of the polymeric resin and in that their average particle size is 1 and 100 μm. One surface of the film is structured its 60° gloss value is greater than 0.5 and smaller than 20%, and its roughness is greater than 3 and lower than 25 μm. The other surface has a 60° gloss value greater than 50%. The film is suitable for use in flat screens.

Light-scattering translucent products of transparent plastics with various light-scattering additives and mouldings produced therefrom are known.
US 2004/0066645 A1 describes in general light-scattering materials which comprise 0.2 to 5% of light-scattering particles and which have a light transmission of greater than 70% and a haze of at least 10%.
The scattering additive has an average diameter of from 3 to 10 μm.
JP 07-090167 describes a light-scattering plastics which comprises 1 to 10% of particles which have a refractive index of less than 1.5 and a particle size of from 1 to 50 μm and 90 to 99% of an aromatic polycarbonate, the particles substantially being insoluble in the aromatic polycarbonate. Acrylate, polystyrene, glass, titanium dioxide or calcium carbonate particles are employed as scattering additives. LCD are mentioned as a use.
EP 0 269 324 B 1 describes a scattering additive composition and light-scattering thermoplastics polymer compositions comprising 0.1 to 10% of scattering additive.
In EP 0634 445 B1, Paraloid EXL 5137 is employed as a scattering additive in combination with inorganic particles in polycarbonate. 0.001 to 0.3% of these particles (e.g. titanium dioxide) contributing towards an improved resistance to ageing and therefore colour stability. This is particularly advantageous if compounds having high scattering agents contents (>2%) are exposed to elevated use temperatures (e.g. 140° C.) over a relatively long period of time (>500 hours).
WO 2004/090587 describes diffuser sheets having a thickness of 2 mm for use in LCD, which comprise 0.2 to 10% of scattering additive and have a gloss of 20 to 70% (measured in accordance with JIS K 7105) at least on one side. Coextruded sheets in which the coextruded layer is 20 to 200 μm thick are furthermore described. The base and coextruded layer comprise scattering additives. Crosslinked silicones, acrylates or talc are compounded in as scattering additives which have a particle diameter of from 5 to 30 μm.
The diffuser films known from the prior art have an unsatisfactory brightness, in particular in conjunction with the set of films conventionally used in a so-called backlight unit. To evaluate the suitability of the light-scattering sheets for so-called backlight units for LCD flat screens, the brightness of the total system must be considered.
In principle, a backlight unit (direct light system) has the structure described in the following. As a rule, it comprises a housing in which a varying number, depending on the size of the backlight unit, of fluorescent tubes, so-called CCFL (cold cathode fluorescent lamp), are arranged. The inside of the housing is equipped with a light-reflecting surface. The diffuser sheet, which has a thickness of from 1 to 3 mm, preferably a thickness of 2 mm, is positioned on this illumination system. On the diffuser sheet is a set of films which may have the following functions: light-scattering (diffuser films), circular polarizers, focusing of the light in the forwards direction by so-called BEF (brightness enhancing film) and linear polarizers. In this context, the linearly polarizing film is positioned directly under the LCD display on top.
Light-scattering plastics compositions in optical uses conventionally comprise inorganic or organic particles having a diameter of from 1 to 50 micrometers, and in some cases even up to 120 μm, i.e. they contain scattering centres which are responsible both for the diffusive and for the focusing properties.
In principle all acrylates, in particular core-shell acrylates, which are thermally stable up to at least 300° C., in order not to be destroyed at the processing temperatures of the transparent plastics, preferably polycarbonate, may be employed as transparent scattering pigments. Furthermore, the pigments should have no functionalities which lead to a degradation of the polymer chain of the polycarbonate. Thus e.g. Paraloid® from Röhm & Haas and Techpolymer® from Sekisui are particularly suitable for use for pigmenting transparent plastics. A large number of various types are available from these product lines. Core-shell acrylates from the Paraloid series are preferably employed.
The object of the present invention was to provide films which have improved properties compared with currently used films, in particular improved brightness with simultaneously high light-scattering, so that they are particularly suitable for use for backlight units.

Light-scattering films and the use thereof in flat screens


Methods for treatment of sexual dysfunction in men and women using combinations of phosphodiesterase (PDE) type 5 inhibitors and l-deprenyl or propargylamine compounds are described. Methods of reducing the dosage and preventing the side effects of PDE type 5 inhibitors are also described. The methods comprise administering a therapeutically effective amount of l-deprenyl or propargylamine compounds (also called monoamine oxidase [MAO] inhibitors) in combination with PDE inhibitors. Stimulation of nitric oxide production and vasodilation by l-deprenyl and propargylamine compounds augments the actions of PDE inhibitors or other drugs and methods used in the treatment of sexual dysfunction. The composition described here enhances the actions of PDE inhibitors primarily by increasing the generation of cyclic GMP by stimulating the nitric oxide pathway and secondarily by providing several additional benefits such as enhanced dopamine activity. Methods of enhancing the efficacy of various PDE inhibitors in the treatment of a number of disorders other than sexual dysfunction are also disclosed.

Normal sexual function involves a complex interaction of emotional, neuronal, vascular and hormonal factors. In addition sexuality incorporates personal, family, social and religious beliefs and is altered with aging, health status, and personal experience (Tomlinson, 2004).
A disruption in any of these areas may lead to sexual dysfunction. Sexuality in females may particularly involve many brain-mediated responses. About 43 percent (40 million) women in the US experience some form of sexual dysfunction. Sexual dysfunction in a female may include hypoactive sexual desire disorders, arousal disorders, orgasmic, or sexual pain disorders. Physical and emotional stimulation lead to breast and genital vasodilation and clitoral engorgement. In the female, dilation and engorgement of the blood vessels in the labia and tissue surrounding the vagina produce an orgasmic response.
Male sexual dysfunction may include erectile dysfunction and impotence. Erectile dysfunction (ED) in the male is defined as the inability to maintain an erect penis with sufficient rigidity to allow sexual intercourse. Erectile dysfunction is a common problem affecting about 30 million men in the US (NIH, 1993). It is estimated that the world-wide incidence of ED will increase from 152 million in 1995 to 322 million men by the year 2025 (Ayta et al; 1999).
It is an age-related condition with about 39% of men over 40 and 67% of men over 70 years suffering from erectile dysfunction (Seftel, 2003). Many conditions such as atherosclerosis can reduce blood flow to the penis, causing ED. Other conditions such as diabetes, hypertension, hyperlipidemia, and cigarette smoking also will lead to ED. Normal erection is mediated through the central nervous system which transmits psychogenic and sensory stimuli to the sympathetic nervous system which controls penile blood flow (Steif, 2003). The arterial blood vessels dilate and deliver blood to the penis, which enables the corpora cavernosa sinus system to become engorged with blood. Vasodilation of the cavernosal arteries and closure of the venous drainage in the penis produce an erection. The hypothalimic-pituitary-testicular axis also has a role as testosterone is required for normal libido (Rhoden, 2002).
Any psychological, neurologic, vascular, urogenital and endocrine abnormality may cause erectile dysfunction. Diabetes is one of the most common causes of ED (DeAngelis, 2001; Utkan, 2001). Other factors leading to ED are smoking, vascular disease, atherosclerosis, hypertension (Burchardt, 2000), hypercholesterolemia, renal failure, injury, surgery, hypogonadism and drugs. A variety of drugs can initiate and accelerate erectile dysfunction (Galle, 2003). These drugs include antihypertensives like beta adrenoreceptor blockers, diuretics, digoxin, antidepressants and antipsychotics, histamine-2 receptor antagonists, alcohol, opiates, amphetamines, and cocaine.
About 80% of patients with ED develop the condition because of a drug or some organic illness. The remaining 20% have a primary psychogenic cause (Rosen, 2001). Psychogenic ED may be treated with behavioral therapy (DeBeradis, 2003), which is successful in half of the patients. If ED is due to organic illness, or if it is psychogenic, but cannot be corrected by behavioral therapy, drug therapy is used (Galle, 2003; Carson 2000).
Current Methods for Treatment of ED
    1. Vacuum constriction devices suitable for patients with venous disorders (Dutta 1999).    2. Prosthetic devices which are directly implanted into paired corporal bodies. These devices may be rigid, malleable, hinged, or inflatable.    3. Vascular reconstructive surgery is used for patients with disorders of the arterial system.    4. Testosterone (injection or skin patches) can be used for men with documented androgen deficiency. Men with prostatic cancer or elevated PSA should not be given testosterone.    5. Direct injection of prostaglandin E1 (alprostadil) into the penis. Common side effects are dizziness, local pain, fibrosis, and infection (Chiang, 2000).    6. Drugs like apomorphine, dopamine receptor agonists, phentolamine, yohimbine, papaverine, vasoactive intestinal peptide, melanocortin receptor agonists, and combinations of these drugs (Carson 2000; Goldstein 2000).    7. Phosphodiesterase (especially type 5) inhibitors (McMahon, 2000).Phosphodiesterase Inhibitors
Phosphodiesterase (PDE) inhibitors are a class of intracelleular enzymes which mediate the catabolism of second messengers like cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). These enzymes have been classified into at least eleven groups (types I-XI) and various subclasses based on their amino acid sequence and substrate specificity (Polson, 1996; Trophy, 2000). The various PDE differ in their tissue, cellular distribution, and their specificity towards cAMP or cGMP. (table 1). So phosphodiesterase inhibitors have applications in a number of disorders including vascular, neuronal and inflammatory disorders (Zang 2002, Martin 2002, Grootendorst 2002, Burnouf, 2002). PDE inhibitors are drug candidates for the treatment of a number of disorders including heart failure, depression, asthma, inflammation, sexual dysfunction, and erectile dysfunction. Phoshodiesterase 4D has been shown to have a role in ischemic stroke (Gretarsdottir, 2003).
TABLE 1Human Phosphodiesterases (PDE)PDESpecificitytypeTissue localizationDisorderInhibitorscAMP3Heart, corpusEnoximone,cavernosum,piroximoneplatelets, smootholprinone,muscle (vascular,motapizone,visceral, bronchial),milrinone,vagus nerve, liver,amrinone,kidney endothelium,cilostamide,lymphocyte, mastcilostazolcell4Kidney, lung, heart,InflammatoryRolipram,skeletal muscle,disorderspiclamilastsmooth muscledepressiontibenelast,(vascular, visceral,allergy, asthmabenafentrineairway),strokezardaverine,endothelium,tolafentrineinflammatory cells,platelets, vagusnerve7Skeletal muscle,Dipyridamoleheart, kidney,airways,lymphocytes,monocyte eosinophil8Testis, ovary, ileum,Dipyridamolecolon, heart, brain,kidney, pancreas,airways, monocyte,thyroidcGMP5Corpora cavernosa,ErectileSildenafil,platelets, skeletaldysfunctionTadalafilmuscle, smoothfemale sexualVardenafilmuscle (vascular,dysfunction,zaprinast,visceral, airway),pulmonarydipyridamolekidney, vagus nervehypertesionpapavenneImpotence6Retina (rods andPDE 5cones)inhibitors9Spleen, smallZaprinastintestine, braincAMP &Heartt, brain,MIMX,cGMPkidney, liver,vinpocetineskeletal muscle,phenothiazinessmooth muscle(vascular, visceral,airway), vagusnerve2Adrenal cortex,EHNA (erytro-brain, heart, liver,9-[2-hydroxyl]corpus cavernosum,adenine)platelet, airwaysmooth muscle10Brain (putamen,IBMXcaudate nucleus)11Skeletal muscle,zaprinastprostate, kidney,dipyridamoleliver, pituitary,salivary glands,testisNitric Oxide and Erectile Dysfunction
Nitric oxide (NO) formed from L-arginine by the enzyme nitric oxide synthase (NOS) is the prime mediator of endothelium-dependent smooth muscle relaxation and penile erection (Burnett, 1992). NO regulates vascular tone and promotes blood vessel relaxation and also has other roles in immune system, nervous system, and inflammation. NO is synthesized and released by neuronal (nNOS) and endothelial (eNOS). Both eNOS and nNOS are constitutively expressed in the endothelium and penile nerve endings (Hedlund, 2000; Bloch, 1998). Upon sexual stimulation NO is released from nerve endings, or from endothelial cells stimulated by acetylcholine from cholinergic nerve endings (Lue, 2000). It is likely that penile erection is mediated by both nNOS and eNOS. Reduced androgen levels, found in elderly men cause impaired expression of penile NO synthesis. NO synthesis is also impaired by hypertension, high levels of oxidized LDL, TNF alpha, and cAMP. NO activates a soluble guanyl cyclase that forms cyclic guanosine mononphosphate (cGMP). Cyclic GMP is the primary second messenger that mediates penile erection. Phosphodiesterase 5 inhibitors like sildenafil prevents the degradation of cGMP and enhances erectile function. NO activates prostaglandin synthesis. The prostacyclin thus formed along with NO released by eNOS and nNOS stimulation causes relaxation of smooth muscle cells. Impaired NOS function, rather than NOS expression is considered to be the cause of insufficient NO production and the inability to stimulate the penile corpora cavernosa to elicit a normal erectile response Gonzalez-Cadavid, 2000; Maas, 2003). Prostaglandin E1 and its derivative alprostadil, which induce relaxation mainly through cAMP also enhance erection (Porst, 1996).
Inflammatory processes cause a shift from vasodilatory to vasoconstrictor eicosanoids. Under such conditions NO generated from eNOS and nNOS is not sufficient to cause smooth muscle relaxation.
Oxidative stress contributes to the development of atherosclerosis, endothelial dysfunction, and ED. By reacting with NO itself, or by interfering with NO-mediated pathways, reactive oxygen species (ROS) could contribute to erectile dysfunction. Thus antioxidants will enhance erectile function by scavenging ROS and enhancing bioavailability of NO.
Examples of type V (5) phosphodiesterase inhibitors include, but not limited to, sildenafil, tadalafil, vardenafil, avanafil, Zaprinast®, papaverine and dipyridamole. Other type 5 PDE inhibitors are disclosed in PCT Publication Nos. WO 94/28902, WO 96/16644, U.S. Pat. No. 6,338,862 and U.S. Pat. No. 6,476,037.
Other Potential Applications of PDE5 Inhibitors
                1. Enhance sexual function in men following prostate surgery.        2. Enhance sexual function in hypogonadal men by combining testosterone and PDE inhibitor.        3. Treatment of premature or rapid ejaculation.        4. Enhance sexual function in women        5. Enhance endothelial function in patients with primary pulmonary hypertension.        6. Treatment of urinary tract symptoms due to benign prostatic hyperplasia.        7. Treatment of urinary incontinence.        8. Treatment of sickle cell anemia by combination therapy with hydroxyurea        9. Enhance sexual function in men and women by combination therapy with antioxidants, vitamin E, arginine, apomorphine , dopamine agonists, alpha adrenergic blocker etc.        10. Prevention and treatment of stroke.        11. Treatment of coronary and cerebral vascular diseases.        12. Treatment of thrombosis        13. Treatment of ocular hypertension        14. Treatment of pregnancy-induced hypertension.        15. Treatment of anal sphincter disorders (Jones, 2002).        16. Treatment of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyloid diseases, Prion diseases.        17. Treatment of other diseases where cGMP is implicated to have beneficial effects.
Side Effects and Complications of PDE5 Inhibitors
The side effects of PDE inhibitors include hypotension, flushing, headache, nasal congestion and heartburn and these effects are dose dependent (Moreira, 2000). The incidence of cardiovascular events and deaths have been reported with the use of PDE 5 inhibitors (Lim, 2002). This may be due to the fact that PDE5 inhibitors dilate the coronary arteries which makes the patient feel better. This may lead to vigorous physical activity (exercise or intercourse). Such activity may lead to ischemia and heart attack. Also interaction with other drugs including nitroglycerine poses substantial risks. The visual side effects of PDE 5 inhibitors are due to the inhibition of PDE 6 found in the retina. Currently available therapies for ED are palliative, have significant failure rates and side effects, and require treatment prior to each sexual encounter. So novel methods of treatment for patients unresponsive to current treatments are required. In ED, the activity of penile NOS is reduced, or the NO synthesis is not sufficient to produce a normal erectile response. Therefore, stimulation of penile NO synthesis seems to be the ideal treatment for ED. Use of synthetic NO donor compounds have not proved successful due to poor stability and delivery problems of these compounds. Enhancing NO synthesis by administration of the substrate L-arginine is another approach. But the availability of L-arginine is not a rate-limiting step for NOS. Administration of massive doses of L-arginine for long-term is necessary to produce any detectable increase in NO production. This invention describes a practical and efficient method for stimulation of nitric oxide production and enhancing the efficacy of PDE 5 inhibitors in the treatment of ED and other disorders.
Brain mechanisms, particularly activation of dopamine receptors play a major role in normal sexual function (Giuliano, 2001). PDE 5 inhibitors have no effect on brain dopamine activity. Apomorphine and other agents that enhance dopamine also enhance erectile function (Stief, 2003). But these dopaminergic drugs do not enhance penile blood flow. Deprenyl and other MAO inhibitors elevate dopamine levels in the brain and thus can augment sexual function (Knoll, 1989).
Deprenyl and other propargylamine compounds will enhance the efficacy of PDE 5 inhibitors by several mechanisms including stimulation of nitric oxide production and enhanced dopamine activity.

Methods and compositions to enhance the efficacy of phosphodiesterase inhibitors