A method and apparatus are disclosed for treating fuel to temporarily reduce its combustibility, and thereafter restore its combustibility. As used in an aircraft, the method comprises the following steps:                (a) treating aircraft engine fuel to substantially reduce its combustibility in open air;        (b) carrying the treated fuel in a fuel tank of an aircraft;        (c) increasing the combustibility of a portion of the treated fuel, as needed by the aircraft engine; and        (d) supplying the increased restored combustibility fuel to the aircraft engine.Using this method, the preponderance of the fuel on board the aircraft is maintained at low combustibility for safety.

The present invention relates to a method and apparatus for treating liquid fuel to temporarily reduce its combustibility. In a preferred embodiment, the present invention relates to a system for treating fuel on board an aircraft, to improve the margin of safety in the event of an aircraft accident.
Aircraft accidents are very difficult to survive. Not only does such an accident result in a rapid deceleration at the moment of impact, but, subsequent to impact, loss of life occurs due to smoke inhalation and burning, because of the fire which almost inevitably follows.
Following an aircraft accident, it is imperative that any crew or passengers which remain conscious immediately exit the craft. The time available for such an emergency evacuation varies, but usually only a few minutes, if any, are available before the fuel carried on board the aircraft commences burning and in some cases, explodes.

Method and apparatus for treating fuel to temporarily reduce its combustibility


A system and method for using near-infrared or short-wave infrared (SWIR) light sources for identification of counterfeit drugs may perform spectroscopy using a super-continuum laser to provide detection in a non-contact and non-destructive manner at stand-off or remote distances with minimal sample preparation. Also, near-infrared or SWIR light may penetrate through plastic containers and packaging, permitting on-line inspection and rapid scanning. The near-infrared or SWIR spectroscopy may also be used to detect illicit drugs and their chemical composition. Moreover, the spectroscopic techniques may also be applied to quality assessment and control in pharmaceutical manufacturing, thus permitting the implementation of smart manufacturing with feedback control. Fiber super-continuum lasers may emit light in the near-infrared or SWIR between approximately 1.4-1.8 microns, 2-2.5 microns, 1.4-2.4 microns, 1-1.8 microns. In particular embodiments, the detection system may be a dispersive spectrometer, a Fourier transform infrared spectrometer, or a hyper-spectral imaging detector or camera.

Counterfeiting of pharmaceuticals is a significant issue in the healthcare community as well as for the pharmaceutical industry worldwide. For example, according to the World Health Organization, in 2006 the market for counterfeit drugs worldwide was estimated at around $43 Billion. Moreover, the use of counterfeit medicines may result in treatment failure or even death. For instance, in 1995 dozens of children in Haiti and Nigeria died after taking counterfeit medicinal syrups that contained diethylene glycol, an industrial solvent. As another example, in Asia one report estimated that 90% of Viagra sold in Shanghai, China, was counterfeit. With more pharmaceuticals being purchased through the internet, the problem of counterfeit drugs coming from across the borders into the United States has been growing rapidly.
A rapid, non-destructive, non-contact optical method for screening or identification of counterfeit pharmaceuticals is needed. Spectroscopy using near-infrared or short-wave infrared (SWIR) light may provide such a method, because most pharmaceuticals comprise organic compounds that have overtone or combination absorption bands in this wavelength range (e.g., between approximately 1-2.5 microns). Moreover, most drug packaging materials are at least partially transparent in the near-infrared or SWIR, so that drug compositions may be detected and identified through the packaging non-destructively. Also, using a near-infrared or SWIR light source with a spatially coherent beam permits screening at stand-off or remote distances. Beyond identifying counterfeit drugs, the near-infrared or SWIR spectroscopy may have many other beneficial applications. For example, spectroscopy may be used for rapid screening of illicit drugs or to implement process analytical technology in pharmaceutical manufacturing. There are also a wide array of applications in assessment of quality in the food industry, including screening of fruit, vegetables, grains and meats.
In one embodiment, a near-infrared or SWIR super-continuum (SC) source may be used as the light source for spectroscopy, active remote sensing, or hyper-spectral imaging. One embodiment of the SWIR light source may be an all-fiber integrated SWIR SC source, which leverages the mature technologies from the telecommunications and fiber optics industry. Exemplary fiber-based super-continuum sources may emit light in the near-infrared or SWIR between approximately 1.4-1.8 microns, 2-2.5 microns, 1.4-2.4 microns, 1-1.8 microns, or any number of other bands. In particular embodiments, the detection system may be a dispersive spectrometer, a Fourier transform infrared spectrometer, or a hyper-spectral imaging detector or camera. In addition, reflection or diffuse reflection light spectroscopy may be implemented using the SWIR light source, where the spectral reflectance can be the ratio of reflected energy to incident energy as a function of wavelength.
In one embodiment, a measurement system includes a light source configured to generate an output optical beam comprising one or more semiconductor sources configured to generate an input beam, one or more optical amplifiers configured to receive at least a portion of the input beam and to deliver an intermediate beam to an output end of the one or more optical amplifiers, and one or more optical fibers configured to receive at least a portion of the intermediate beam and to deliver at least the portion of the intermediate beam to a distal end of the one or more optical fibers to form a first optical beam. A nonlinear element is configured to receive at least a portion of the first optical beam and to broaden a spectrum associated with the at least a portion of the first optical beam to at least 10 nm through a nonlinear effect in the nonlinear element to form the output optical beam with an output beam broadened spectrum, wherein at least a portion of the output beam broadened spectrum comprises a short-wave infrared wavelength between approximately 1400 nanometers and approximately 2500 nanometers, and wherein at least a portion of the one or more fibers is a fused silica fiber with a core diameter less than approximately 400 microns. A measurement apparatus is configured to receive a received portion of the output optical beam and to deliver a delivered portion of the output optical beam to a sample for a non-destructive and non-contact measurement, wherein the delivered portion of the output optical beam is configured to generate a spectroscopy output beam from the sample. A receiver is configured to receive at least a portion of the spectroscopy output beam having a bandwidth of at least 10 nanometers and to process the portion of the spectroscopy output beam to generate an output signal, and wherein at least a part of the delivered portion of the output optical beam is at least partially transmitting through a packaging material covering at least a part of the sample, and wherein the output signal is based on a chemical composition of the sample.
In another embodiment, a measurement system includes a light source configured to generate an output optical beam comprising a plurality of semiconductor sources configured to generate an input optical beam, a multiplexer configured to receive at least a portion of the input optical beam and to form an intermediate optical beam, and one or more fibers configured to receive at least a portion of the intermediate optical beam and to form the output optical beam, wherein the output optical beam comprises one or more optical wavelengths. A measurement apparatus is configured to receive a received portion of the output optical beam and to deliver a delivered portion of the output optical beam to a sample, wherein the delivered portion of the output optical beam is configured to generate a spectroscopy output beam from the sample. A receiver is configured to receive at least a portion of the spectroscopy output beam and to process the portion of the spectroscopy output beam to generate an output signal, wherein the receiver comprises a Fourier transform infrared (FTIR) spectrometer or a dispersive spectrometer, and wherein at least a part of the delivered portion of the output optical beam is at least partially transmitting through a packaging material covering at least a part of the sample.
In yet another embodiment, a method of measuring includes generating an output optical beam comprising generating an input optical beam from a plurality of semiconductor sources, multiplexing at least a portion of the input optical beam and forming an intermediate optical beam, and guiding at least a portion of the intermediate optical beam and forming the output optical beam, wherein the output optical beam comprises one or more optical wavelengths. The method may also include receiving a received portion of the output optical beam and delivering a delivered portion of the output optical beam to a sample, wherein the sample comprises an organic compound with an overtone or combinational absorption band in the wavelength range between approximately 1 micron and approximately 2.5 microns. The method may further include generating a spectroscopy output beam having a bandwidth of at least 10 nanometers from the sample using a Fourier transform infrared (FTIR) spectrometer or a dispersive spectrometer, receiving at least a portion of the spectroscopy output beam, and processing the portion of the spectroscopy output beam and generating an output signal.

Short-wave infrared super-continuum lasers for detecting counterfeit or illicit drugs and pharmaceutical process control


Described herein are microneedle drug delivery systems comprising a pharmaceutical compositions comprising pharmaceutically active agents (e.g., cannabidiol and prodrugs of cannabidiol) and microneedle arrays suitable for local and systemic delivery of the active agent to a mammal. Also described herein are methods of using a microneedle transdermal or topical drug delivery systems comprising pharmaceutical compositions, comprising cannabidiol and prodrugs of cannabidiol, and microneedle arrays in the treatment disease, including pancreatitis and pancreatic cancer.

It has now been found that a pharmaceutical composition comprising a cannabinoid, such as cannabidiol, or a cannabinoid prodrug, such as a cannabidiol prodrug, can be transdermally administered to a mammal in conjunction with a microneedle array to treat a medical condition responsive to cannabinoids, such as alcohol use disorders, pain, inflammation and pancreatic diseases, such as pancreatic cancer and pancreatitis, via transdermal or topical drug delivery systems. It has further been found that microneedle transdermal or topical drug delivery systems comprising a pharmaceutical composition, comprising a cannabinoid or cannabinoid prodrug and a penetration enhancer (i.e., co-solvent), and a microneedle array can be used to treat a medical condition responsive to cannabinoids, such as alcohol use disorders, pain, inflammation and pancreatic diseases, such as pancreatic cancer and pancreatitis. It has further been found that microneedle transdermal or topical drug delivery systems comprising a pharmaceutical composition, comprising a cannabinoid or cannabinoid prodrug, a microneedle array and a COX inhibitor, such that the duration in which the microneedle created pore will remain open is increased, can be administered to a mammal. Suitable COX inhibitors include diclofenac and ibuprofen.
The pharmaceutical compositions described herein are suitable for use with a COX inhibitor-containing gel or hydrogel which has been optionally incorporated into a patch. In one embodiment, the COX inhibitor-containing gel or hydrogel which has been optionally incorporated into a patch is distinct from the pharmaceutical composition containing a cannabinoid or a cannabinoid prodrug and is applied to the skin surface either before, during or after the skin has been treated with a microneedle array. In another embodiment, the pharmaceutical compositions comprising the cannabinoid or cannabinoid prodrug further comprises a COX-inhibitor and is administered as a gel or hydrogel which has been optionally incorporated into a patch that is applied to the skin surface either before, during or after the skin had been treated with a microneedle array.
Cannabinoids and Cannabidiol
Cannabinoids, including cannabidiol ("CBD"), have recently been found useful in treating pancreatic illnesses. For example, it has been found that cannabidiol is useful in the treatment of acute and chronic pancreatitis. Pancreatitis is widely known as a very painful disease and can ultimately lead to pancreatic cancer. It has been found that cannabidiol has anti-inflammatory activity that results in a decrease of pain in pancreatitis cases. Pancreatic cancer is the fourth most common fatal cancer in the United States and fifth most prevalent worldwide. Cannabinoids, such as tetrahydrocannabinol and the synthetic cannabinoid WIN 55,212-2, have been found to induce apoptosis of pancreatic tumor cells in vitro and in vivo. Cannabidiol has the same potential to cause the same cascade that results in tumor cell death and diminish proliferation to lateral tumor formation.
In addition, the clinical usefulness of cannabinoids, including cannabidiol, to provide analgesia and neuroprotection, reduce inflammation, help alleviate nausea and emesis, as well as treat epilepsy, anxiety disorders and glaucoma, has been well-recognized. In addition, it is also well-known that cannabidiol lacks the psychoactive effects seen in many of the other cannabinoids, including Δ9-tetrahydrocannabinol, which is currently available in an oral dosage form, sold under the trade name Marinol®.
Pain is the most frequently reported symptom and it is a common clinical problem confronting all clinicians. Millions of people in the United States suffer from severe pain that, according to numerous recent reports, is chronically under-treated or inappropriately managed. Similarly, millions of people also suffer from severe nausea and/or frequent emesis. Moreover, all too frequently, many patients suffering from chronic, under-treated or irretraceable pain also suffer from lack of appetite, nausea and/or frequent emesis. These patients present a greater clinical challenge as they are unable to receive effective doses of oral pain medications, thereby leaving their pain unalleviated. Cannabinoids, including cannabidiol, are effective in alleviating pain. Moreover, cannabinoids, including cannabidiol, can reduce a patient's nausea and vomiting, independent of any pain relief achieved. Thus, cannabinoids are particularly useful in patients experiencing nausea and vomiting secondary to un- or under-treated pain.
A notable percentage of the United States population satisfy the diagnostic criteria for alcohol use disorders ("AUDs"). The consumption of excessive amounts of alcohol results in a complex array of pharmacological effects that directly impact the ability to treat the condition. These effects directly impact the brain and include progressive neurodegeneration, impaired executive function and dependence leading to withdrawal-induced negative effects. It is known that cannabinoids, including cannabidiol, have neuroprotective, anxiolytic and anti-convulsant effects, which may be effective in preventing additional brain damage in persons with AUDs, while simultaneously decreasing the frequency of relapses.
Chronic abusers of cannabis can develop dependence and experience withdrawal symptoms when they attempt to discontinue use of the drug. Collectively, cannabis dependence and withdrawal are referred to herein as cannabis use disorders. It is known to those of skill in the art that cannabinoids, including cannabidiol, are useful in treating cannabis use disorders.
Dystonia is a neurological movement disorder, with many known causes, and characterized by involuntary, continual muscular contractions causing twisting and repetitive movements or abnormal postures. Cannabinoids have been shown to reduce the muscular contractions characteristic of this disorder.
The etiological pathology of many diseases relates to the inflammatory processes that are regulated by an individual's immune system. Inflammation may result from (1) an otherwise appropriate immunoresponse to an outside trauma, such as brain swelling secondary to a closed head injury; (2) an overactive immunoresponse, such as an allergic reaction or dermatitis; or (3) an inappropriate auto-immunoresponse, such as certain forms of multiple sclerosis, inflammatory bowel disorders and arthritis. Regardless of the underlying cause of the inflammation, it is therapeutically desirable under these circumstances to regulate the immune system and lessen the inflammatory response. Cannabinoids have been shown to regulate various steps in the immune response and could show some therapeutic benefit in the treatment of certain inflammatory diseases such as psoriatic arthritis.
Rheumatoid arthritis affects approximately 0.5-1% of the United States population, and autoimmune diseases in general affect more than 20 million Americans. The pain associated with rheumatoid arthritis can often be disabling. Cannabinoids have been found to be useful as an adjunct treatment for rheumatoid arthritis and joint pain secondary to other autoimmune diseases, such as inflammatory bowel disease, multiple sclerosis and systemic lupus erythematosus.
In addition, transdermally administered cannabinoids have been found to be useful to alleviate pain and other conditions associated with deeper tissues, such as peripheral nerves, muscles and synovial tissues. Examples of conditions associated with deeper tissues responsive to cannabinoids include: peripheral neuropathic pain, including but not limited to, the peripheral neuropathic pain associated with diabetic neuropathy, ankylosing spondylitis, Reiter's syndrome, gout, chondrocalcinosis, joint pain secondary to dysmenorrhea, fibromyalgia, musculoskeletal pain, neuropathic-postoperative complications, polymyositis, acute nonspecific tenosynovitis, bursitis, epicondylitis, post-traumatic osteoarthritis, osteoarthritis, rheumatoid osteoarthritis, synovitis and juvenile rheumatoid arthritis. When cannabinoids are administered transdermally to treat pain and other conditions associated with deeper tissues, including peripheral neuropathic pain, it may be useful to have significant local tissue and systemic levels of cannabinoids.
In addition to the above-discussed therapeutics benefits, cannabinoids, such as cannabidiol and cannabidiol prodrugs, present a variety of pharmacological benefits, including, but not limited to, anti-inflammatory, anti-convulsant, anti-psychotic, antioxidant, neuroprotective, anti-cancer, such as melanoma, and immunomodulatory effects.
Given these systemic therapeutic benefits, it would be advantageous to develop a composition in which a cannabinoid, such as cannabidiol or a prodrug of cannabidiol, is delivered systemically to achieve therapeutically effective plasma concentrations in a patient. However, cannabinoid oral dosage forms, including those comprising cannabidiol, must overcome several obstacles in order to achieve a therapeutically-effective systemic concentration. First, cannabinoids are generally highly lipophilic. Their limited water solubility thereby restricts the amount of cannabinoid available for absorption in the gastrointestinal tract. Second, cannabidiol, as with the other cannabinoids, undergoes substantial first-pass metabolism when absorbed from the human gastrointestinal tract. Finally, the oral bioavailability of any product is further diminished when a patient suffers from nausea or emesis, as either the patient avoids taking his oral medications or the oral dosage form does not remain in the gastrointestinal tract for a sufficient period of time to release the entire dose and achieve a therapeutic concentration.
Therefore, in view of the foregoing, it would be desirable to systemically deliver therapeutically effective amounts of a cannabinoid, such as cannabidiol or cannabidiol prodrug, to a mammal in need thereof for the treatment of one or more medical conditions responsive to cannabinoids, including pancreatic cancer, pancreatitis, pain, nausea or appetite stimulation, by a route of administration that does not depend upon absorption from the gastrointestinal tract of the mammal. One non-oral route of administration for the systemic delivery of cannabidiol is transdermal administration.
In addition, the epidermis and dermis of many mammals, such as humans and guinea pigs, contains enzymes which are capable of metabolizing active pharmaceutical agents which pass through the stratum corneum. The metabolic process occurring in the skin of mammals, such as humans, can be utilized to deliver pharmaceutically effective quantities of a cannabinoid, such as cannabidiol, to the systemic circulation of a mammal in need thereof. Described herein are prodrugs of cannabinoids, such as cannabidiol prodrugs, and compositions comprising prodrugs of cannabinoids that can be transdermally administered to a mammal, such as a human, so that the metabolic product resulting from metabolism in the skin is the cannabinoid which is systemically available for the treatment of a medical condition responsive to cannabinoid, for example pancreatic diseases, such as pancreatitis and pancreatic cancer.
Unfortunately, due to its highly lipophilic nature, cannabidiol is poorly absorbed through membranes such as the skin of mammals, including humans. Therefore, the success of transdermally administering therapeutically effective quantities of cannabidiol to a mammal in need thereof within a reasonable time frame and over a suitable surface area has been substantially limited.
Microneedles and COX Inhibitors
Enhancing the transdermal delivery of an active pharmaceutical agent by use of microneedle treatment has become an important area of research in the field of transdermal drug delivery. In addition, shorter microneedles may alternatively be used to topically administer an active pharmaceutical agent for local delivery to treat dermal conditions. It has further been found that a pharmaceutical composition comprising a cannabinoid or cannabinoid prodrug and a penetration enhancer can be administered to a mammal in conjunction with a microneedle array to treat a medical condition responsive to cannabinoids, including alcohol use disorders and pancreatic diseases, such as pancreatic cancer and pancreatitis. To enhance the transdermal or topical delivery of cannabinoids when administered in conjunction with microneedles, cannabinoid prodrugs (e.g., cannabidiol prodrugs) have been designed which typically have a greater water solubility than the parent cannabinoid molecule in order to take advantage of the aqueous pores created by microneedle use.
Microneedles are generally considered to be structures that are between about 20 μm and about 1000 μm in length capable of puncturing the outermost layer of the epidermis (stratum corneum) to create large-scale openings (relative to the size of the active pharmaceutical agent to be delivered there through) or pores through which one or more active pharmaceutical ingredients can be delivered. The depth of microneedle penetration is sufficient to enhance transdermal drug delivery but not sufficient to stimulate nerve endings. Therefore, the use of microneedles is pain-free. This aspect, as well as their economical and easy use, makes a system incorporating microneedle technology an attractive alternative for transdermal drug delivery.
The active pharmaceutical agents to be delivered in conjunction with microneedle technology range from large oligonucleotides to insulin, and highly water-soluble compounds. Compared to other methods of physically altering the cutaneous structure to aid in improving transdermal transport, microneedle delivery is a relatively simple technique. Microneedles are typically micromachined to increase permeability and decrease skin sensation and come in various forms, such as biodegradable polymers, silicon and stainless steel. Various researchers have studied the effects of microneedle-treated skin on increased permeation of mostly water soluble compounds through microneedle-created aqueous pores. It has been shown that the use of microneedles can enhance the permeation of many compounds including non-viral gene therapy vectors, desmopressin, insulin and naltrexone. Further, the application of microneedles has been shown to be pain free in comparison to a 26-gauge hypodermic needle.
The effectiveness of microneedles is dependent on the duration of time that the microneedle-created pores in the stratum corneum remain sufficiently open and "un-healed." It is during this time that the enhanced delivery of the active pharmaceutical agent can continue. Recently there have been many determinations in pore lifetime and viability via a number of experiments involving transepidermal water loss, microscopic visualization and pharmacokinetic analysis. Transepidermal water loss ("TEWL") measures the rate at which water escapes from the skin. TEWL values are commonly measured in damaged skin to determine water loss over time as a function of skin repair. By using an evaporimeter, an instrument that measures water loss, damage or changes in skin morphology can be determined by an increase in rate of water loss compared to "normal" skin. It has now been shown that TEWL readings are a valid measurement to observe the status of the permeability barrier.
Occlusive coverings, such as patches or hydrogels (which can be optionally incorporated into a patch), can be used to maintain microneedle-created pores. When a microneedle array was placed on the skin and removed without having been treated with an occlusive patch, the skin healed rapidly and TEWL readings returned to baseline levels within 30 minutes. In contrast, it has been demonstrated that under an occlusive environment, microneedle-created pores remained open for at least 48-72 hours. Likewise, microscopic visualization after staining has revealed that pores were present up to 72 hours. In hairless guinea pigs treated with 6-β-naltrexol hydrochloride, significant enhancement in microneedle pore viability was observed for 48 hours after microneedle exposure and occlusion, compared to untreated skin. It has also been shown that therapeutic levels of naltrexone (2.5±1.1 ng/mL) were achieved when a 16% naltrexone hydrochloride gel was administered to 6 healthy human volunteers after microneedle pretreatment. Further, it has been observed that when used in conjunction with microneedles, steady state naltrexone concentrations were achieved within two hours and remained for 48 hours. These results indicate that microneedle application to skin provides an alternative delivery route to oral, injectables and traditional passive transdermal delivery.
Even with the use of occlusive techniques (e.g., a patch which may optionally have a hydrogel incorporated therein) in conjunction with the microneedle-generated pores, it is, nevertheless, desirable to further extend the lifetime of microneedle-created pores. Such an increase in the duration of the pore opening can correspond to an increase in the interval between which doses are administered. Said differently, by increasing the duration of the pore opening, it is possible to reduce the frequency with which an active must be administered. Reductions in the dosage frequency have a positive impact on patient acceptance and compliance. Thus, it would be desirable to further enhance the viability of the microneedle-created pores in order to increase the rate, duration and extent of transdermal delivery of an active pharmaceutical agent.
It has been found that the rate and extent of cannabinoid transdermal absorption can be improved by administering a cannabinoid (e.g. cannabidiol) or a cannabinoid prodrug (e.g., a prodrug of cannabidiol) and optionally a penetration enhancer or co-solvent and/or a COX inhibitor, in pharmaceutical compositions in conjunction with microneedle arrays. It has further been discovered that by optimizing the composition excipients, the cannabinoid or cannabinoid prodrug can be administered, in conjunction with a microneedle array, on a schedule that encourages patient compliance, by reducing frequency of dosing to once or twice daily or even once or twice weekly.
Accordingly, a significant advancement in the art would occur with the development of a transdermal drug delivery system comprising pharmaceutical compositions, comprising a cannabinoid (e.g. cannabidiol) or a cannabinoid prodrug (e.g., a prodrug of cannabidiol), and a microneedle array in treatment of conditions responsive to cannabinoids. A further advancement would be the development of a transdermal drug delivery system comprising a pharmaceutical composition, comprising a cannabinoid (e.g. cannabidiol) or a cannabinoid prodrug (e.g., a prodrug of cannabidiol) and a microneedle array in treatment of (i) acute pancreatitis; (ii) chronic pancreatitis; (iii) pancreatic cancer; (iv) pain; (v) inflammation or (vi) alcohol use disorders.
Topical Delivery
In addition to the benefits of systemically administered cannabinoid discussed above, cannabinoids, including cannabidiol and prodrugs of cannabidiol, have been found to have localized benefits from topical administration. For example, topically administered cannabinoids have been found to be useful to alleviate pain and other conditions originating at or near the surface of the skin, including but not limited to, pain associated with post-herpetic neuralgia, shingles, burns, actinic keratosis, oral cavity sores and ulcers, post-episiotomy pain, psoriasis, pruritis, contact dermatitis, eczema, bullous dermatitis herpetiformis, exfoliative dermatitis, mycosis fungoides, pemphigus, severe erythema multiforme (e.g., Stevens-Johnson syndrome), seborrheic dermatitis, melanoma and psoriatic arthritis. Also, it has been found that the topical administration of cannabinoids, including cannabidiol, can inhibit the growth of hair.
In order to achieve these local benefits, it may be advantageous for the cannabinoid, (e.g., cannabidiol) or a cannabinoid prodrug (e.g., a cannabidiol prodrug) to penetrate the stratum corneum but not be absorbed systemically. In such a case, the cannabinoid (e.g., cannabidiol) or cannabinoid prodrug (e.g., a prodrug of cannabidiol) would concentrate in the skin and/or pilosebaceous unit, thus maximizing its local effect. Not only does the localized effect increase the potential therapeutic benefit, it lessens the frequency and severity of side-effects associated with systemic cannabinoid administration because the amount of active compound circulating in the patient is reduced. The cannabinoid (e.g., cannabidiol) or cannabinoid prodrug (e.g., a cannabidiol prodrug) can be incorporated into a composition with an additional active moiety that is capable of improving the appearance and/or hydration of the skin.
Accordingly, a significant advancement in the art would occur with the development of a topical drug delivery system comprising a pharmaceutical composition, comprising a cannabinoid (e.g., cannabidiol) or a cannabinoid prodrug (e.g., a cannabidiol prodrug) and a microneedle array in the treatment of condition responsive to cannabinoid therapy.

Use of cannabidiol prodrugs in topical and transdermal administration with microneedles


The invention relates to an illumination system (10), a luminaire (102), a collimator (30), and a display device (200). The illumination system according to the invention comprises a light source (20) and the collimator. The light source is configured to emit a substantially Lambertian light distribution around an axis of symmetry (22). The refractive collimator is configured to redirect light from the light source so as to at least partially illuminate an illuminating surface (50), in which at least a part of the illuminating surface is substantially parallel to the axis of symmetry. The refractive collimator comprises a concave entrance window (34) and an at least partially convex exit window (40) for refracting light towards the illuminating surface.

Such illumination systems are known per se. They are used, inter alia, in luminaires for general lighting purposes, for example, for office or shop lighting or, for example, as shop window lights. Alternatively, these illumination systems are used for lighting (transparent or semi-transparent) plates of glass or (transparent) synthetic resin on which items, for example, jewelry are displayed. The illumination systems are also used for illuminating advertising boards, for example, advertising boards illuminating a partially transparent image from the back of the image.
The known illumination systems may also be used as light sources in backlighting systems in (picture) display devices, for example, for TV sets and monitors. Such illumination systems are particularly suitable for use as backlighting systems for non-emissive displays such as liquid crystal display devices, also denoted LCD panels, which are used in (portable) computers or (portable) telephones.
Recently, illumination systems comprising a light source having a substantially Lambertian emission profile, for example, light-emitting diodes (further also referred to as LEDs) have been more frequently used in general lighting applications, such as luminaires. Use of LEDs in luminaires has the advantage that the LEDs have a relatively high efficiency. Furthermore, there is a vast range of available LEDs for use in general light applications, offering excellent freedom of design with respect to emitted colors and aesthetic design of the luminaire. However, use of LEDs has the drawback that the light-emitting surface is typically relatively small and that light emitted from this relatively small surface has a high intensity. To prevent glare, it is important to shield a user of the luminaire from this light-emitting surface. Glare results from excessive contrast between bright and dark areas in the field of view. Glare can result, for example, from directly viewing a filament of an unshielded or badly shielded light source. Particularly when LEDs are used, direct view into the LEDs by a user near the luminaire should be prevented so as to reduce glare and improve the user's visual comfort. A luminaire comprising LEDs as a light source is known from, for example, WO 2007/054889. In this luminaire, the light emitted by the LEDs is emitted via a back-reflector so as to reduce glare and improve the uniformity of the light emitted from the luminaire. The known luminaire has the drawback that it has a relatively large height.

Illumination system, luminaire, collimator, and display device

Abstract: The illumination system according to the invention has the effect that a height of the illumination system may be reduced by virtue of the use of the refractive collimator.


The present invention provides a driving method for a liquid crystal display panel, comprising a timing-driven process, wherein the timing-driven process includes the steps of: generating an initial pulse signal, which has a first rising edge rising from a low voltage to a high voltage and a first falling edge falling from the high voltage to the low voltage; and generating a timing pulse signal, which has a second rising edge rising from a low voltage to an intermediate voltage, a third rising edge rising from the intermediate voltage to a high voltage, a second falling edge falling from the high voltage to the intermediate voltage, and a third falling edge falling from the intermediate voltage to the low voltage. At the same time, the present invention further provides a driving circuit for a liquid crystal display panel.

With development of the modern technology, more and more novel information products are available to the market so as to meet the requirements from the public. In the past, the display is generally made from cathode ray tube (CRT). However, not only has it a bulky size and extensive energy consumption, but also emit extensive radiation which is detrimental to the viewer if exposed for an extended period of time. Accordingly, the liquid crystal display (LCD) has gradually replaced the traditional CRT monitor.
Liquid crystal displays available in the market today are mainly referred to as backlit liquid crystal display, which includes a liquid crystal display panel and a backlight module. The liquid crystal display panel comprises scan lines and control lines crisscrossed with each other; wherein data lines are controlled by data-driven chips which receive data start signal TP1 (latched pulse) and then output the data voltage to the data lines of the liquid crystal display panel on the falling edge; and wherein the scan lines are controlled by scan-driven chips set on both sides of the liquid crystal display panel. Currently, there are three control signals for controlling the switch of scan-driven chips on each line of the liquid crystal display panel, such as shown in FIG. 1, including a start voltage pulse (STV) signal for controlling the initiation of scanning first line; a clock voltage pulse (CKV) signal for providing a shift register to the scan-driven chip, controlling the switching frequency of each line, and starting operation when detecting the STV of a rising edge is a high voltage; and an output enable (OE) signal, respectively, wherein the pulse signal of the OE signal includes the rising edge of the CKV signal. Because there is a parasitic capacitance in the liquid crystal display panel, delays will occur during the process of scanning output voltage to the liquid crystal display panel, and there is a problem of overlap between the lines and lines when switching, resulting in overlapping areas, and this will cause a problem of filling the incorrect data. After the OE is added, the high voltage of the OE will lower the scanning output voltage strongly. Hence, the OE is placed between lines and lines when switching, forcing the adjacent scan lines not to form the overlapping area caused by switching on simultaneously anymore, so the time of overlapping switch on is prevented, and thereby the problem of filling the wrong data is also prevented.
The control signal of the scan-driven chip will be transmitted from a printed circuit board assembly (PCBA), and transmitted to a glass of a liquid crystal display panel via a flexible circuit board of a data chip, and then reached to a scan-driven chip through a glass conducting trace. The current mainstream of the liquid crystal display panel is designed to a narrow-boarder frame, and the cost of increasing a signal is to increase one more conducting trace on the glass, so the edge of the glass will be occupied. In addition, there will be one more signal on a timing-controller (T-CON) chip, and the manufacturing cost will increase.

Driving method and circuit for liquid crystal display panel

Shenzhen China Star Optoelectronics Technology Co., Ltd


An image sensor includes a pixel array in which a plurality of pixels, first and second row selection lines separated from each other, and first and second column lines separated from each other are disposed and a column selecting circuit configured to connect the first and second column lines using a column selection signal. The pixel array includes a first pixel which is connected to the first row selection line and the first column line and a second pixel which is disposed in the same row as the first pixel and connected to the second row selection line and the second column line.

1. Field
At least some example embodiments relate to an image sensor.
2. Description of the Related Art
An image sensor is one of the semiconductor devices that convert optical information into an electrical signal. Examples of the image sensor include a charge coupled device (CCD) image sensor and a complementary metal-oxide semiconductor (CMOS) image sensor.
Research is being conducted on an image sensor that performs both a full mode operation and a binning mode operation.
The full mode operation is an operation of sensing an image using information of all pixels included in a pixel array. On the other hand, the binning mode operation is an operation of collecting information of selected pixels and sensing an image using the collected information.

Image sensor having multiple operation modes


An opening roller assembly for an open-end spinning device of a textile machine, wherein an opening roller (12) is mounted on a bearing shaft (17) which is fixed in a bearing bracket (14) of an opening roller housing (11) in such a manner that the shaft can be easily removed. A drive (28) for rotating the opening roller is provided by a single electrical motor formed as an external rotor. A contact lead device (18) is mounted on the bearing shaft and includes leads (19) which are connected to the electrical motor, and a contact shoe housing (50) is provided which includes contact shoes or contact pins (21) which are connected to a power supply (27) of a corresponding textile machine and which can be selectively brought into contact with the leads (19) of the contact lead device (18).

The invention relates to an open-end spinning machine of the type having a stationary rotor housing which mounts a rotating rotor cup and a sliver opening unit which includes an opening roller assembly.
In connection with open-end spinning machines e.g. of rotor spinning machines, different embodiments of opening rollers are known.
In DE 35 43 428 A1, for example, an opening roller is described which comprises a bearing shaft at its rear side and is mounted with this bearing shaft in the bearing bracket of an opening roller housing. The bearing shaft has on its end a so-called drive whorl which is driven by a tangential belt having the same length as the machine and which is connected via a shaft to the base plate of the opening roller. On the opening roller's base plate mounted in such a manner that it can rotate, a so-called trimming ring is fixed in such a manner that it can be replaced. To replace the trimming ring the opening roller can be pivoted away from the tangential belt and subsequently dismounted from the opening roller housing at the front.
Furthermore, for example, opening rollers which are driven by a single motor are also known from DE 40 36 017 A1 or DE 100 54 697 A1. Such opening roller drives are formed as external rotors which are fixed by their stator to the opening roller housing and connected via the electric lines to the power supply of the textile machine. On this external rotor a trimming ring is also disposed in such a manner that it can be replaced.
However, it is disadvantageous in the case of these opening rollers driven by a single motor that to replace the trimming ring the drive of the opening roller must also be dismounted and in so doing electric lines or corresponding plug-in connectors must be disconnected. On re-mounting of the opening roller these plug-in connectors must then be carefully connected once again. The mounting and dismounting of opening rollers of this type thus prove to be relatively complicated and time-consuming.
Finally, in DE 196 50 597 and corresponding U.S. Pat. No. 5,850,730 an open-end spinning device is described whose opening roller with its bearing shaft is mounted in the bearing bracket of an opening roller housing and comprises a single drive formed as an external rotor. On the end of the bearing shaft of this opening roller a whorl is disposed which can be acted on by a brake element. The known opening roller is fixed in the bearing bracket by a spring wire which engages in an annular groove of the bearing shaft. Furthermore, a locking and unlocking device is present which can be actuated by a toggle switch disposed in front of the opening roller housing, said toggle switch being connected via a shaft to connecting links toward the rear. That is, by means of the toggle switch, connecting links which comprise different switching surfaces can be turned so that the brake is pressed onto the whorl and at the same time the power supply of the opening roller drive is interrupted. In an additional switching position the arresting of the bearing shaft of the opening roller in the bearing bracket can be discontinued and the brake once again released.
Also in the case of this known opening roller, as described above, in dismounting and mounting of the opening roller plug-in contacts must first be disconnected in a laborious and time-consuming manner and later connected once again.
Proceeding from the aforementioned state of the art, the objective of the invention is to provide an opening roller which is driven by a single motor but, e.g. for replacing a trimming ring, can be mounted and dismounted from its bearing bracket on the opening roller housing securely and without difficulty.

Opening roller assembly for an open-end spinning machine


When processing a primitive when generating a render output in a graphics processor, the vertices for the primitive are loaded by a vertex loader, but before a primitive setup stage generates per-primitive data for the primitive using the loaded vertices for the primitive, an early culling test is performed for the primitive using data of the loaded vertices for the primitive. When the primitive passes the early culling test, the primitive is sent onwards to the primitive setup stage and to a rasteriser for rasterising the primitive, but when the primitive fails the early culling test, it is discarded from further processing at the early culling test.

The technology described herein relates to computer graphics processing, and in particular to the processing of graphics primitives when generating a rendering output on a graphics processor.
Graphics processing is normally carried out by first splitting the desired render output, such as a frame (image) to be displayed, into a number of similar basic components or "primitives", which primitives are then subjected to the desired graphics processing operation. The graphics primitives are usually in the form of simple polygons, such as lines, triangles or quadrilaterals.
Each primitive is usually defined by and represented as a set of vertices. Each vertex for a primitive has associated with it a set of data (such as position, colour, texture and other attributes data) representing the vertex. This data is then used, e.g., when rasterising and rendering the primitive(s) to which the vertex relates, e.g. for display.
Once primitives and their vertices have been generated and defined, they can be processed by the graphics processor in order, e.g., to render the desired render output, e.g. frame. This process basically involves determining which sampling positions of an array of sampling positions covering the output area to be processed are covered by a primitive, and then determining the appearance that each sampling point should have (e.g. in terms of colour, etc.) to represent the primitive at that sampling position. These processes are commonly referred to as rasterising and rendering, respectively.
The rasterising process typically determines the sampling points that should be used for a primitive (i.e., the (x, y) sampling positions for sampling points to be used to represent the primitive in the render output, e.g. frame to be displayed).
The rendering process then derives the data, such as red, green and blue (RGB) colour values and an "alpha" (transparency) value, necessary to represent the primitive at the sampling positions (i.e. "shades" each sampling point). This can involve applying textures, and blending sampling point data values, etc.
In graphics literature, the term "rasterisation" is sometimes used to mean both primitive conversion to sampling points and rendering. However, herein "rasterisation" will be used to refer to converting primitive data sampling point addresses only.
The rasterisation process basically maps the primitives defining the render output to be generated to the sampling points that will be used to render the output. This is typically done by determining, for each sampling point, whether the sampling point position is covered by the primitive in question or not. This determination is typically done by testing the sampling points' positions against the edges of a primitive, to see if the sampling points are covered by the primitive. To do this, graphics processors typically derive (line) equations representing each of the edges of a primitive (e.g. using the defined vertices of the primitive), and then test the sampling points' positions using these edge equations. If a sampling point "passes" the edge test, it is taken to be within the primitive.
The (line) equations representing each of the edges of a primitive are typically derived from the vertices defined for a primitive in a so-called primitive (triangle) setup operation (stage), prior to the rasterisation operation (stage). The primitive setup operation may also derive other per-primitive data for use by later graphics processing operations.
The rasterisation process is typically carried out by testing sets of one or more sampling points. For each set of one or more sampling points found to include a sampling point that is covered by the primitive in question (that is being tested), a discrete graphical entity, usually referred to as a graphics "fragment", on which the subsequent graphics processing operations (such as rendering) are to be carried out, is generated by the rasteriser and sent to the remainder of the graphics processing pipeline (such as the renderer) for processing.
One drawback of graphics processing systems is that because primitives are processed sequentially, and typically not in perfect front-to-back order, a given sampling position (and hence pixel) may be shaded multiple times as a render output is generated. This occurs when a first received and rendered primitive is later covered by a subsequently received and rendered primitive, such that the rendered first primitive is not in fact seen at the sampling position(s) and pixel(s) in question. Primitives can be overwritten many times in this manner, and this typically leads to multiple, ultimately redundant, graphics processing (rendering) operations being carried out for each render output, e.g. frame, being rendered. This phenomenon is commonly referred to as "overdraw".
Techniques have therefore been proposed to try to reduce the amount of "overdraw" (the amount of redundant processing of hidden surfaces) that is performed when processing a render output.
For example, early occlusion culling, such as early depth (Z) and/or stencil(s) testing processes, may be used to try to cull fragments that are issued by the rasteriser before they are sent for rendering.
These arrangements try to identify, e.g., fragments and/or sampling points, for a new primitive that will be occluded by already processed primitives (and therefore that do not need processing) before the fragments and/or sampling points are issued to the rendering pipeline. In these arrangements, the depth value at a sampling position of a new primitive that has been rasterised is compared to the depth value of the current primitive that has been rendered to that sampling position, to see if the new primitive is occluded at the sampling position in question or not. This can help to avoid sending fragments that are occluded by already processed primitives through the rendering pipeline.
FIG. 1 shows an exemplary graphics processing pipeline that may be executed by a graphics processor to perform graphics processing to generate a render output that can operate in the above manner.
As shown in FIG. 1, the graphics processing pipeline 1 includes a vertex loader 2 that is operable to load vertex positions for primitives to be processed by the graphics processing pipeline.
The vertices loaded by the vertex loader 2 are then used by a primitive (triangle) setup unit 3 to perform any required per-primitive computations and to derive any required per-primitive data, using the vertices for the primitive loaded by the vertex loader 2.
The so-"setup" primitives are then rasterised by the rasteriser 4 to generate corresponding fragments representing the primitive. The fragments are then subjected to an early depth and stencil test 5 to see if any of them can be identified at that stage as being occluded and so discarded.
Any fragments that pass the early depth and stencil test 5 are then rendered 6 (e.g. by executing an appropriate fragment shader program for the fragments).
The rendered fragments are then subjected to a final "late" depth and stencil test 7 before being output, e.g., to memory or directly for display (if they pass the late depth and stencil test 7).
The Applicants believe that there remains scope for improvements to the processing of graphics primitives when generating a render output in a graphics processor.
Like reference numerals are used for like features throughout the drawings, where appropriate.

Processing of primitives in a graphics processor


A spray head is provided that includes a housing having a water inlet, at least one water guide, and a housing bottom, in which jet outlet openings are arranged, wherein the water guide is used as a connection between the water inlet and a number of jet outlet openings and a valve element for sealing a valve opening is provided for the water guide. The valve element is movably mounted on both sides and a control device having at least one control element that acts on the valve element is provided, wherein the control element defines a translational movement of the valve element by a valve stroke.

Field of the Invention
The invention relates to a spray head.
Description of the Background Art
Different jet outlet openings are often provided in overhead or hand showers at the spray base to generate different spray patterns or spray types. A plurality of changeover devices are known for changing from one jet type to another.


A touch control panel comprises a transparent substrate, a contact layer, a first transparent electrode formed over the transparent substrate and a second transparent electrode formed over the contact layer facing the first transparent electrode. The space between the first transparent electrode and the second transparent electrode contains a plurality of spacers. The transparent substrate or the contact layer or both have ultra-violet ray shielding capability.

1. Field of Invention
The present invention relates to a touch control device. More particularly, the present invention relates to a touch control panel capable of withstanding ultra-violet rays.
2. Description of Related Art
Due to the persistent progress in semiconductor technologies, the level of integration of circuits and their operating speed increases at an ever-increasing rate. The modern world is filled with digital electronic products. However, before the transmission of digital data or signals required by a digital control device, an input mechanism for inputting data is necessary. Digital data is commonly input through a keyboard using a high-level language format. For example, the computer keyboard is able to input text and instructions. Nevertheless, keyboard is not the best data input method under all circumstances.
To ease digital data input and control, another common input method is a touch control panel. In a system incorporating a touch control panel, data and instructions can be fed into a system by touch. In fact, the touch control panel provides a user with a free and convenient method of input. For example, transparent touch control panel may be adhered to certain display region of a flat panel display screen. Rather than inputting data through a keyboard, data is directly fed into a system by touching the display panel. Unlike a keyboard, the touch panel is an input device that receives signals and hence may transmit pictures and textual writings. Because of such conveniences, touch control panel is also used in many electronic devices.
However, a conventional touch control panel has little resistance for the passage of ultra-violet rays. When the touch control panel is used in outdoor activities or in areas having a high ultra-violet index, the ultra-violet rays can easily penetrate into the light-channeling board or backlight panel. In general, the light-channeling board is made of polycarbonate (PC) or polymethyl methacrylate (PMMA). Since PC and PMMA may decompose in the presence energetic light rays, prolonged illumination by ultra-violet light may lead to deterioration such as the fogging of the display screen.
FIG. 1 is a schematic cross-sectional view of a conventional touch control panel 110. As shown in FIG. 1, the touch control panel 110 includes a transparent substrate 100. A transparent electrode 102 is formed over the substrate 100. In general, the transparent electrode 102 is made of an indium-tin-oxide (ITO) compound. An adhesion layer 103 is formed near the edges of the transparent electrode 102. A contact layer 104 is attached to the adhesion layers 103. At present, the contact layer 104 is mostly made from material such as polyester or glass. The contact layer 104 also has a layer of transparent electrode 102 on the side facing the transparent. substrate 100. A plurality of spacers 108 is formed in the space between the transparent substrate 100 and the contact layer 104. The spacers prevent direct contact of the transparent electrode 102 attached to the transparent substrate 100 with the transparent electrode 102 attached to the contact layer 104 due to sagging as a result of self-weight. The spacers 108 are formed over the transparent electrode 102 of the transparent substrate 100 by printing, for example. The outer surface of the contact layer 104 may further include a hard coating 106 for protecting the contact layer 104 and increasing its hardness. When the contact layer 104 is touched so that the transparent electrode 102 on the transparent substrate 100 is contacted, the position of the contact point is registered through a difference in resistive value at the point of contact.
The aforementioned touch control panel 110 has no special provision for blocking out ultra-violet light and hence ultra-violet rays will illuminate the devices underneath the panel. When the touch panel 110 and a liquid crystal display panel are used together, ultra-violet rays can still penetrate into the light-channeling panel causing the aging problem.
FIG. 3 is a schematic cross-sectional view of a conventional liquid crystal display panel with a touch panel structure therein. As shown in FIG. 3, a conventional touch control panel 110 is disposed over a display panel 206. In general, the touch control panel 110 is attached to the edges of the display panel 206 through a double-sided tape 208. The display panel 206 is a liquid crystal display panel, for example. Since a conventional touch control panel 110 has no provision for resisting ultra-violet light, ultra-violet light can easily penetrate into the light-channeling panel (not shown) inside the display panel 206. Prolonged illumination to ultra-violet light rays may lead to aging of the light-channeling panel and result in a hazy display panel.


A fuel-efficient hydraulic fluid has a lower viscosity than a standard hydraulic fluid, a pressure loss decreases, and thus, when control based on a standard model is exercised, the speeds of various actuators increase. However, the speeds need not be increased beyond the speeds of the standard model. Instead, it is preferred that fuel efficiency be improved. As a result, an engine revolution speed decreases by 50 rpm and a pump torque decreases by 5%. This reduces an engine output. Therefore, when a hydraulic fluid is changed from the standard hydraulic fluid to the fuel-efficient hydraulic fluid, the fuel efficiency can be improved while maintaining operability equivalent to that of the standard model. Hence, the fuel efficiency can be improved while maintaining the operability when an item affecting the fuel consumption is replaced. In addition, the settings can be changed with ease by a service technician.

A construction machine such as a hydraulic excavator generally includes a diesel engine. The diesel engine drives a hydraulic pump of a variable displacement type. A hydraulic fluid discharged from the hydraulic pump drives a plurality of hydraulic actuators to perform necessary operations. The engine includes a fuel injection device. The fuel injection device controls a fuel injection amount, thereby controlling an engine revolution speed and an output torque.
Meanwhile, pump torque control is exercised over the hydraulic pump, which is rotationally driven by the engine, in order to prevent the engine from being excessively loaded. The pump torque control is exercised to prevent the maximum torque of the hydraulic pump from exceeding a setting by reducing the displacement volume of the hydraulic pump in accordance with an increase in the load pressure of the hydraulic pump.
A predetermined revolution speed is basically selected for the engine by using an engine control dial. Besides, the revolution speed of the engine is controlled depending on the situation. An appropriate pump toque is then set in accordance with such revolution speed control.
Optimizing the engine revolution speed setting and the pump torque setting makes it possible to provide improved fuel efficiency while maintaining the operability of the hydraulic excavator.
A control device for controlling an engine and a pump of a construction machine is disclosed, for instance, in Patent Document 1. The control device provides improved fuel efficiency by automatically controlling an engine revolution speed and a pump torque in accordance with the work to be performed.
The control device (control system) is a construction machine control device that controls the engine revolution speed by displacing the rack of an all-speed governor to increase or decrease the fuel injection amount, uses the engine to drive the pump, and controls the torque of the pump with a torque setup regulator. The control device includes a controller that detects the amount of displacement with a rack sensor and calculates an effective engine load factor by performing a stabilization process on the displacement amount of the rack. Further, work modes for multiple stages, which depend on the combinations of the engine revolution speed and pump torque, are set in the controller so as to control an engine revolution speed setting device and a torque setup regulator in accordance with a work mode designated by the controller. Furthermore, intermediate work modes included in the multiple stage work modes are provided with a region for switching to a next-stage work mode, a stabilized region, and a region for switching to a previous-stage work mode. Moreover, a highest-stage work mode is provided with a stabilized region and a region for switching to a previous-stage work mode. A lowest-stage work mode is provided with a region for switching to a next-stage work mode and a stabilized region. In addition, a switching region of each work mode has a portion that overlaps with a stabilized region in the next or previous stage work mode designated by the switching region. Meanwhile, when the effective engine load factor is above a predetermined value and a switching region in a certain work mode persists for a period not shorter than a predetermined period of time, control is exercised to switch to the next or previous stage work mode designated by the switching region.

HITACHI CONSTRUCTION MACHINERY CO., LTD.


A multi-channel or bidirectional optoelectronic device comprises a two or more optoelectronic components, e.g., a photodetector and a light source. A protective encapsulant can be applied to the optoelectronic device that includes hollow dielectric microspheres to reduce electrical cross-talk, and that can further include an optical absorber to reduce optical cross-talk.

The field of the present invention relates to bidirectional or multi-channel optoelectronic devices, including bidirectional optoelectronic transceivers. In particular, (i) a light source drive circuit, (ii) multi-function encapsulation, and (iii) a light-trapping structure formed on a waveguide substrate are disclosed herein for reducing cross-talk in a bidirectional optoelectronic device.
A bidirectional optoelectronic transceiver is a device that can simultaneously (i) receive one or more input optical signals and generate corresponding output electrical signals and (ii) receive one or more input electrical signals and generate corresponding output optical signals. More generally, a multi-channel optoelectronic device is one that can simultaneously handle such conversion between electrical and optical signals for two or more such pairs of corresponding signals (each pair comprising a "channel"). Such multi-channel devices can be "unidirectional" (i.e., wherein all input signals are optical and all corresponding output signals are electrical, or vice versa) or "bidirectional" (already described above).
In general, the input and output signals (optical and electrical) can be transmitted and received in any suitable way, including, e.g., free-space propagation (optical or electrical), electrical conduction by conductive wire, cable, or trace (electrical), or propagation as a guided mode in an optical fiber or waveguide (optical). It is common in telecommunications devices for the optical signals (input and output) to be received from or transmitted into an optical fiber or waveguide, and for the electrical signals to be received from or transmitted to a conductive wire, cable, or trace.
In this context, each signal (electrical or optical) typically comprises a carrier wave modulated according to a given scheme to encode digital or analog information (e.g., a digital data stream, an analog or digital video signal, or an analog or digital audio signal). The correspondence referred to above (i) between the input optical signal and the output electrical signal, and (ii) between the input electrical signal and the output optical signal, is a correspondence of the information encoded according to their respective modulation schemes. Many modulation schemes exist for encoding information onto an electrical or optical carrier signal. One common example of an electrical modulation scheme includes baseband digital amplitude modulation; another common example includes amplitude modulation of a radio frequency (RF) electrical carrier wave. One common example of an optical modulation scheme includes amplitude modulation of a visible or near-infrared optical carrier wave. Multiple electrical or optical modulation schemes can in some instances be used together or overlaid on one another. In some examples, by using differing carrier frequencies for input and output signals (electrical or optical), both input and output signals can be carried by a common transmission medium (e.g., input and output optical signals carried by a common optical fiber or waveguide, or input and output electrical signals carried by a common conductive wire, cable, or trace). In other examples, input and output electrical signals can be carried by separate conductive wires or traces, or input and output optical signals can be carried by separate optical fibers or waveguides.
Typically, care must be taken to limit the effects of cross-talk in a multi-channel or bidirectional optoelectronic device. Electrical cross-talk refers to an electrical signal (input or output) adversely affecting reception or generation of another electrical signal, and optical cross-talk refers to an optical signal (input or output) interfering with reception or generation of another optical signal. In principle, a cross-talk problem can arise in either or both directions (i.e., input affecting output, output affecting input, or both), and limiting cross-talk in both directions can be advantageous. In practice, in a bidirectional device, an input electrical signal (that drives the light source to generate the output optical signal) typically is larger in absolute magnitude than an output electrical signal (generated by photodetection of a typically weak input optical signal). As a result, the input electrical signal typically affects the output electrical signal (or its generation from the input optical signal) to a greater degree than the output electrical signal affects the input electrical signal (or generation of the output optical signal therefrom). Similarly, in a bidirectional device, the output optical signal typically is larger in absolute magnitude than the input optical signal. As a result, the output optical signal typically affects the input optical signal (or generation of the output electrical signal therefrom) to a greater degree than the input optical signal affects the output optical signal (or its generation from the input electrical signal).
Cross-talk in a multi-channel or bidirectional optoelectronic device can manifest itself in a variety of ways. In one example, electrical cross-talk can result in decreased sensitivity, in the presence of an input electrical signal, for reception of an input optical signal and generation of a corresponding output electrical signal by the photodetector. In another example, optical cross-talk can result in decreased sensitivity, in the presence of an output optical signal, for reception of an input optical signal and generation of a corresponding output electrical signal by the photodetector. In those examples and in others, such decreased sensitivity can manifest itself, e.g., as decreased signal-to-noise ratio, increased bit error rate for a digital signal, or increased noise floor. Sensitivity is simply the minimum optical power needed to ensure sufficiently faithful encoding on the output electrical signal of information encoded on the input optical signal (e.g., to guarantee a bit error rate below a specified limit for a digital data signal; various suitable criteria can be established for various types of signals). The sensitivity of the photodetector is typically degraded in the presence of an input electrical signal applied to the light source or the resulting output optical signal, relative to its sensitivity in the absence of an input electrical signal or output optical signal. Such degradation can be referred to or quantified generically as a "cross-talk penalty," expressed as a ratio of the sensitivity of the photodetector with versus without the input electrical signal applied to the light source (or expressed as a difference between sensitivities given as dBm, for example). Reduction of optical or electrical cross-talk is a way to improve the photodetection performance of the bidirectional optoelectronic device, and can in some instances be imperative for meeting photodetection performance requirements of the device. Analogously, a cross-talk penalty can be quantified for faithful encoding on the output optical signal of information encoded on the input electrical signal in the presence of an input optical signal or an output electrical signal.

This patent is subject to a terminal disclaimer.

Cross-talk reduction in a bidirectional optoelectronic device


Absorbent article, such as a sanitary towel, a panty liner, an incontinence pad or the like, which article has two transverse end edges, two longitudinal side edges, a liquid-permeable surface layer, an essentially liquidtight backing layer, and an absorbent core located between the liquid-permeable surface layer and the essentially liquidtight backing layer and also side flaps at the longitudinal side edges on both sides of the absorbent core, the side flaps being folded and detachably tacked to the surface layer, said tacking being mechanical.

1. Technical Field
The present invention relates to an absorbent article, such as a sanitary towel, a panty liner, an incontinence pad or the like, which article has two transverse end edges, two longitudinal side edges, a liquid-permeable surface layer, a liquidtight backing layer, and an absorbent core located between the liquid-permeable surface layer and the liquidtight backing layer, and also side flaps at the longitudinal side edges on both sides of the absorbent core.
2. Background of the Invention
Some modern conventional sanitary towels and similar products have side flaps. The purpose of the side flaps is to attach the article to the briefs so that it does not lie askew by being folded around the edges of the briefs in the crotch portion and attached to the outside of the briefs. Another reason for providing a sanitary towel or the like with side flaps is that the risk of leakage occurring is reduced. Leakage often occurs in sanitary towels without side flaps as a result of the edges of the briefs in the crotch area becoming turned in over the upper side of the article. This usually happens when the sanitary towel is narrower than the width of the briefs in their crotch portion. Leakage can also occur when there is insufficient time for liquid to be absorbed in the central portion of the sanitary towel, and it runs out on the surface towards and over the side edges of the article where the liquid comes into contact with the underwear. An article with side flaps assists with positioning in the briefs and reduces the occurrence of leakage. An example of a document which describes the attachment of the sanitary towel is EP 0 359 501.
On supply to the consumer, sanitary towels and similar products are often folded for packing and packed. In this context, "folded for packing" means that the side flaps are folded over the product so that they come to lie against the liquid-permeable surface layer in the central part of the product when supplied, and that the product is folded one or more times in the transverse direction or longitudinal direction in order that its size is reduced so that the product is easier to handle. Generally, the products are supplied packed, for example multipacked or individually packed. A multipacked product is characterized by a number of products lying side by side, packed in a common outer packing. An individually packed product is characterized by each individual product first being packed in its own packing which is then packed together with further individually packed products to form a larger unit in a common outer packing. Suitable materials for individual packing of the product can include, for example, an essentially liquidtight plastic film, a tissue layer or a similar thin flexible material. The common outer packing can include, for example, cardboard or plastic.
A product folded for packing is considerably smaller and significantly easier for the consumer to store and carry in a bag, trouser pocket or the like. If the products are moreover individually packed, the possibility of keeping the products hygienically is improved, so that they do not become soiled by dirt and dust when they are stored in, for example, a bag, pocket or the like.
Products with side flaps have generally been difficult to fold and pack in controlled ways during manufacture compared with products without side flaps. At a slow production rate, the side flaps of the products can be folded in a controlled manner but, at an increased production rate, this becomes difficult. The reason why the side flaps are incorrectly folded may be, for example, that the folding unit in the production machine does not function mechanically at a high rate. Another reason for the side flaps being incorrectly folded may be that the materials from which the products are made and of which the surfaces come to lie against one another when the side flaps are folded over the article have too low friction against one another. Low friction between the materials means that they do not cling to one another but slide apart.
However, the comfort to the wearer can be improved if material surfaces which will lie against the skin of the consumer have low friction. Low friction of a material means a nice, soft surface. As it is considerably more important to supply products which feel comfortable to the consumer, it is important for the problem of folding products for packing to be solved without it being necessary to forgo the quality of the material.
An incorrectly folded side flap, which projects from the product in some way, increases the likelihood of machine stoppage occurring because projecting side flaps catch on machine parts on the way through the production machine, which can lead to production being disrupted.
Another problem which can arise when the side flaps of the product are incorrectly folded is that packing the article in an individual packing is made difficult. For example, when the packing material is sealed outside the edges of the product folded for packing so as to form an individual packing, incorrectly folded side flaps can accidentally end up in the seal. A product with its side flaps caught in the seals of the individual packing is unfortunately not always detected during product control but is discovered only when the consumer is about to use the product. A product with its side flaps caught in the seals of the individual packing will be pulled apart on opening and has to be discarded by the consumer. A product with incorrectly folded side flaps moreover creates a slipshod impression which may give the consumer the impression that the functioning of the product would be worse than is actually the case.
Another problem which can arise when the side flaps are incorrectly folded is an increased risk of the protective layer on the means of attachment of the side flaps being creased or turned up from the adhesive surfaces so that the adhesive surfaces become exposed and attach themselves to surfaces other than the adhesive protective layers. Products with the adhesive surfaces of their side flaps attached to surfaces other than the protective layers may be spent and not useable by the consumer.
A further problem can arise in instances when relatively rigid material is used for the side flaps of the product. Incorrect folding of the side flaps may then become lasting, which makes it difficult to fold the side flaps around the edges of the briefs in the crotch area.
One way of reducing the problem of side flaps being incorrectly folded during production is described in, for example, EP 0 527 171. In an illustrative embodiment in EP 0 527 171, the side flaps are folded down over the liquid-permeable surface layer of the article and are held in place by a skin-friendly adhesive. One disadvantage of the illustrative embodiment described in EP 0 527 171 is the increased cost for the adhesive which is to hold the side flaps in place. Another disadvantage is that it is extremely difficult to control the strength of the adhesive so that the side flap lies sufficiently firmly against the liquid-permeable surface layer of the product. If the side flap is attached too loosely to the liquid-permeable surface layer, it will come loose during manufacture and packing. In instances when the side flap lies excessively firmly against the liquid-permeable surface layer of the product, there is a great risk that the liquid-permeable surface layer of the product and/or the side flap will be torn apart when the side flap is lifted up from the liquid-permeable surface layer. Another disadvantage is that the adhesive impairs the capacity of the product for admitting liquid into the product.
A further disadvantage of using adhesive as the means of attachment of the side flaps to the liquid-permeable surface layer of the product is that the adhesive areas which remain on the liquid-permeable surface layer after the side flaps have been lifted up from the liquid-permeable surface layer can feel uncomfortable to the consumer as the adhesive area does not have the same surface characteristics as the rest of the upper side.

Absorbent article with detachably connected side flaps having indentations and openings


Disclosed are high throughput assay systems and methods for identifying agents that alter the level of surface expression of integral membrane proteins, such as cardiac ion channels, in mammalian cells. Also disclosed are therapeutic methods of using agents identified using such methods.

1. Field of the Invention
The present invention relates to high throughput assay systems and methods for identifying agents that alter the level of surface expression of integral membrane proteins, such as cardiac ion channels, in mammalian cells. The present invention also relates to therapeutic methods of using agents identified using such methods.
2. Background of the Related Art
A. Assays
Human Ether-a-go-go Related Gene (HERG) is the pore-forming potassium channel subunit that underlies the cardiac repolarizing current IKr and consists of six transmembrane segments (S1–S6) and cytoplasmic amino- and carboxyl-termini. HERG has been linked to both congenital and drug-induced long QT syndrome, a serious and potential fatal heart condition.
Mutations in hERG produce functionally impaired channels and/or trafficking defective channels, both of which reduce IKr currents. Mutations spanning most of the molecule have been identified in different long QT families. This suggests that hERG plays a critical role in cardiac physiology.
Most of the drugs associated with long QT syndrome (drug-induced) are hERG blockers. See, e.g., Vandenberg et al, Trends Pharmacol Sci. 22:240–246 (2001). Since the cardiotoxicity of the non-sedating antihistamine terfenadine (Seldane) was linked to hERG block in 1996 (see Roy et al, Circulation 94:817–823 (1996)), a wide variety of drugs having diverse structures, including antiarrhythmics, antibiotics, antipsychotics as well as antihistamines, have been shown to be potent hERG blockers.
Accordingly, hERG has become an important target for cardiac safety testing of new therapeutic agents. The US Food & Drug Administration currently recommends that pharmaceutical companies seeking approval for novel therapeutic compounds have them screened for potential hERG blocking.
Presently, hERG cardiac safety testing involves eletrophysiology and consits of patch clamp recording of hERG currents in HEK 293 cells which stably overexpress hERG. This assay, however, is expensive, time-consuming and requires considerable expertise. Consequently, it is usually done relatively late in the drug development process. Unfortunately, at that time, discovery that a novel therapeutic compound is a potent hERG blocker would be potentially devastating to the prospects of that compound being approved and used therapeutically. As a result, there is considerable interest in the pharmaceutical industry for assays for hERG blockers that are both less expensive and faster, and that can be employed much earlier in the drug development process.
The limitations of the patch clamp assay has led to alternative methods for preclinical screening of drugs for potential hERG interactions. Several methods have been described, but are limited, for example, in sensitivity, throughput capacity and/or false-postive rates (see Xu et al., Drug Discover Today 6:1278–1287 (2001)).
For example, one type of assay uses membrane potential sensitive fluorescent dyes, such as DiBAC4 or FMP. Since these assays measure changes in membrane potential and not hERG activity, the risk of false positives (i.e. drugs which change membrane potential but do not block hERG) is great. A recent evaluation of such assays (fang et al., J. Biomol. Screen. 6:325–331 (2001)) indicates a signficant problem with false positives and, to a lesser extent, false negatives. In addition, sensitivity is reduced about 100-fold. Moreover, the rank order of hERG blocker potency differs with membane potential assays relative to patch clamp measurements, limiting the use of such fluorescent assays to identifying potential hERG channel blockers without providing useful information as to their potency. Finally, dye/drug interactions have also caused problems in this assay.
A second assay suggested as a potential high throughput preclinical screen for hERG interactions is [3H]-dofelitide binding to membranes for hERG transfected cells. (See Finlayson etaz., Eur. J. Pharm 430:147–148 (2001)). This binding assay is nonfunctional and relies on the ability of drugs to compete with [3H]-dofelitide for binding to hERG channels. In preliminary experiments, however, the rank order of hERG blockers identified by patch clamp methods was not replicated in the [3H]-dofelitide binding assay. Also, the requirements for purified cell membranes as binding substrate and radio-labelled dofelitide limit the usefulness of this assay.
A third assay that has been suggested involves the measurement of rubidium (Rb) flux through cells expressing hERG (see Terstappen, Anal Biochem. 272:149–155 (1999)). These cells ate loaded with Rb channels and activated with high potassium levels, and Rb released into the medium is measured. The rank order of potency obtained by this method, however, does not correlate with patch clamp data (see Tang et al, J. Biomol. Screen., 6:325–331 (2001)). In addition, throughput is limited and sensitivity reduced 10-fold.
Accordingly, there remains a need for assay systems for identifying blockers of integral membrane proteins, including cardiac ion channels such as hERG.
B. Cardiac Arrhythmias
Atrial flutter and/or atrial fibrillation (AF) are the most commonly sustained cardiac arrhythrnlas in clinical practice, and are likely to increase in prevalence with the aging of the population. Currently, AF affects more than 1 million Americans annually, represents over 5% of all admissions for cardiovascular diseases and causes more than 80,000 strokes each year in the United States. While AF is rarely a lethal arrhythmia, it is responsible for substantial morbidity and can lead to complications such as the development of congestive heart failure or thromboembolism. Currently available Class I and Class III anti-arrhythmic drugs reduce the rate of recurrence of AF, but are of limited use because of a variety of potentially adverse effects, including ventricular proarrhythmia. Because current therapy is inadequate and fraught with side effects, there is a clear need to develop new therapeutic approaches.
Ventricular fibrillation (VF) is the most common cause associated with acute myocardial infarction, ischemic coronary artery disease and congestive heart failure. As with AF, current therapy is inadequate and there is a need to develop new therapeutic approaches.
Although various anti-arrhythmic agents are now available on the market, those having both satisfactory efficacy and a high margin of safety have not been obtained. For example, anti-arrhythmic agents of Class I, according to the classification scheme of Vaughan-Williams ("Classification of antiarrhythmic drugs", Cardiac Arrhythmias, edited by: E. Sandoe, E. Flensted-Jensen, K. Olesen; Sweden, Astra, Sodertalje, pp 449–472 (1981)), which cause a selective inhibition of the maximum velocity of the upstroke of the action potential (Vmax) are inadequate for preventing ventricular fibrillation because they shorten the wave length of the cardiac action potential, thereby favoring re-entry. In addition, they have problems regarding safety, i.e. they cause a depression of myocardial contractility and have a tendency to induce arrhythmias due to an inhibition of impulse conduction. The CAST (coronary artery suppression trial) study was terminated while in progress because the Class I antagonists had a higher mortality than placebo controls. β-adrenergenic receptor blockers and calcium channel (ICa) antagonists, which belong to Class II and Class IV, respectively, have a defect in that their effects are either limited to a certain type of arrhythmia or are contraindicated because of their cardiac depressant properties in certain patients with cardiovascular disease. Their safety, however, is higher than that of the anti-arrhythmic agents of Class I.
Anti-arrhythric agents of Class III are drugs that cause a selective prolongation of the action potential duration (APD) without a significant depression of the maximum upstroke velocity (Vmax). They therefore lengthen the save length of the cardiac action potential increasing refractories, thereby antagonizing re-entry. Available drugs in this class are limited in number. Examples such as sotalol and ariodarone have been shown to possess interesting Class III properties (Singh B. N., Vaughan Williams E. M., "A third class of anti-arrhythmic action: effects on atrial and ventricular intracellular potentials and other pharmacological actions on cardiac muscle of MJ 1999 and AH 3747", Br. J. Pharmacol 39:675–689 (1970), and Singh B. N., Vaughan Williams E. M., "The effect of amiodarone, a new anti-anginal drug, on cardiac muscle", Br. J. Pharinacol 39:657–667 (1970)), but these are not selective Class III agents.
Sotalol also possesses Class II (β-adrenergic blocking) effects which may cause cardiac depression and is contraindicated in certain susceptible patients.
Amiodarone also is not a selective Class III antiarrhythmic agent because it possesses multiple electrophysiological actions and is severely limited by side effects. (Nademanee, K., "The Amiodarone Odyssey", J. Am. Coll. Cardiol. 20:1063–1065 (1992)) Drugs of this class are expected to be effective in preventing ventricular fibrillation. Selective Class III agents, by definition, are not considered to cause myocardial depression or an induction of arrhythmias due to inhibition of conduction of the action potential as seen with Class I antiarrhythmic agents.
Class III agents increase myocardial refractoriness via a prolongation of cardiac action potential duration (APD). Theoretically, prolongation of the cardiac action potential can be achieved by enhancing inward currents (i.e. Na+ or Ca2+ currents; hereinafter INa and ICa, respectively) or by reducing outward repolarizing potassium K+ currents. The delayed rectifier (IK)K+ current is the main outward current involved in the overall repolarization process during the action potential plateau, whereas the transient outward (Ito) and inward rectifier (IKI)K+ currents are responsible for the rapid initial and terminal phases of repolarization, respectively.
Cellular electrophysiologic studies have demonstrated that IK consists of two pharmacologically and kinetically distinct K+ current subtypes, IKr (rapidly activating and deactivating) and IKs (slowly activating and deactivating). (Sanguinetti and Jurkiewicz, "Two components of cardiac delayed rectifier K+ current. Differential sensitivity to block by Class III anti-arrhythmic agents", J Gen Physiol 96:195–215 (1990)). IKr is also the product of the human ether-a-go-go gene (hERG). Expression of hERG cDNA in cell lines leads to production of the hERG current which is almost identical to IKr (Curran et al., "A molecular basis for cardiac arrhythmia: hERG mutations cause long QT syndrome," Cell 80(5):795–803 (1995)).
Class III anti-arrhythmic agents currently in development, including d-sotalol, dofetilide (UK-68,798), almokalant (H234/09), E-4031 and methanesulfonamide-N-[1′-6-cyano-1,2,3,4-tetrahydro-2-naphthalenyl)-3,4-dihydro-4-hydroxyspiro[2H-1-benzopyran-2,4′-piperidin]-6yl], (+)-, monochloride (MK-499) predominantly, if not exclusively, block IKr. Although, amiodarone is a blocker of IKs (Balser J. R. Bennett, P. B., Hondeghem, L. M. and Roden, D. M. "Suppression of time-dependent outward current in guinea pig ventricular myocytes: Actions of quinidine and amiodarone", Circ. Res. 69:519–529 (1991)), it also blocks INa and ICa, effects thyroid function, is as a nonspecific adrenergic blocker, acts as an inhibitor of the enzyme phospholipase, and causes pulmonary fibrosis (Nademanee, K. "The Amiodarone Odessey". J. Am. Coll. Cardiol. 20:1063–1065 (1992)).
Reentrant excitation (reentry) has been shown to be a prominent mechanism underlying supraventricular arrhythmias in man. Reentrant excitation requires a critical balance between slow conduction velocity and sufficiently brief refractory periods to allow for the initiation and maintenance of multiple reentry circuits to coexist simultaneously and sustain AF. Increasing myocardial refractoriness by prolonging APD, prevents and/or terminates reentrant arrhythmias. Most selective, Class III antiarthythmic agents currently in development, such as d-sotalol and dofetilide predominantly, if not exclusively, block IKr, the rapidly activating component of IK found both in atrium and ventricle in man.
Since these IKr blockers increase APD and refractoriness both in atria and ventricle without affecting conduction per se, theoretically they represent potential useful agents for the treatment of arrhythmias like AF and VF. These agents have a liability in that they have an enhanced risk of proarrhythmia at slow heart rates. For example, torsade de pointes, a specific type of polymorphic ventricular tachycardia which is commonly associated with excessive prolongation of the electrocardigraphic QT interval, hence termed "acquired long QT syndrome", has been observed when these compounds are utilized (Roden, D. M. "Current Status of Class III Antiarrhythrnic Drug Therapy", Am J. Cardiol, 72:44B–49B (1993)). The exaggerated effect at slow heart rates has been termed "reverse frequency-dependence" and is in contrast to frequency-independent or frequency-dependent actions. (Hondeghem, L. M., "Development of Class III Antiarrhythmic Agents", J. Cardiovasc. Cardiol. 20 (Suppl. 2):S17–S22). The pro-arrhythmic tendency led to suspension of the SWORD trial when d-sotalol had a higher mortality than placebo controls.
The slowly activating component of the delayed rectifier (IKs) potentially overcomes some of the limitations of IKr blockers associated with ventricular arrhythmias. Because of its slow activation kinetics, however, the role of IKs in atrial repolarization may be limited due to the relatively short APD of the atrium. Consequently, although IKs blockers may provide distinct advantage in the case of ventricular arrhythmias, their ability to affect supra-ventricular tachyarrhythmias (SVT) is considered to be minimal.
Another major defect or limitation of most currently available Class III anti-arrythmic agents is that their effect increases or becomes more manifest at or during bradycardia or slow heart rates, and this contributes to their potential for proarrhythmia. On the other hand, during tachycardia or the conditions for which these agents or drugs are intended and most needed, they lose most of their effect. This loss or diminishment of effect at fast heart rates has been termed "reverse use-dependence" (Hondeghem and Snyders, "Class III antiarrhythmic agents have a lot of potential but a long way to go: Reduced effectiveness and dangers of reverse use dependence", Circulation, 81:686–690 (1990); Sadanaga et al., "Clinical evaluation of the use-dependent QRS prolongation and the reverse use-dependent QT prolongation of class III anti-arrhythmic agents and their value in predicting efficacy" Amer. Heart Journal 126:114–121 (1993)), or "reverse rate-dependence" (Bretano, "Rate dependence of class III actions in the heart", Fundam. Clin. Pharmacol. 7:51–59 (1993); Jurkiewicz and Sanguinetti, "Rate-dependent prolongation of cardiac action potentials by a methanesulfonanilide class III anti-arrhythmic agent: Specific block of rapidly activating delayed rectifier K+ current by dofetilide", Circ. Res. 72:75–83 (1993)). Thus, an agent that has a use-dependent or rate-dependent profile, opposite that possessed by most current class III anti-arrhythmic agents, should provide not only improved safety but also enhanced efficacy.
In view of the problems associated with current class III anti-arrhythmic agents, there remains a need for an effective treatment of cardiac arrhythrmias in mammals.

High throughput assay systems and methods for identifying agents that alter surface expression of integral membrane proteins


Techniques are described for dynamic translation of data access statements. A first set of statements is sent by an executing process to access a first data storage that supports a first query language. The first set of statements is intercepted and translated into a second set of statements configured to access a second data storage that supports a second query language. The second set of statements may be executed on the second data storage, and the result data set may be sent to the executing process that generated the first set of statements. The first and second storages may employ different data storage formats, such as relational and non-relational storage formats. The behavior of the executing process may be monitored to determine the feasibility of modifying the source code of the process to employ a different query language.

Applications, libraries, and other types of software modules may include hard-coded statements written in a particular query language to access data stored on a particular type of data storage device. In some cases, an organization that operates or maintains the software modules may migrate data from one type of data storage device to another type of data storage. In cases where existing software modules include hard-coded statements in a particular query language, the software modules may not function properly when attempting to access a data storage device that supports a different query language or that implements a different transaction model.
Certain implementations and embodiments will now be described more fully below with reference to the accompanying figures, in which various aspects are shown. However, various aspects may be implemented in many different forms and should not be construed as limited to the implementations set forth herein. Like numbers refer to like elements throughout.