A system and method for the acute non-invasive treatment of a migraine attack. The system includes at least one skin electrode for placement on the forehead of a patient, and is configured to provide consecutive biphasic electrical pulses via the at least one skin electrode to the supratrochlear and supraorbital nerves of the ophthalmic branch of the trigeminal nerve during a prolonged time span which may be for at least 10 minutes.

Migraine is a common neurobiological disorder characterized by recurrent episodes of headache accompanied by sensory hypersensitivity, which can significantly impair quality of life. Acute treatments are used during a migraine attack with the objective to abort or reduce headache pain and restore normal function, while preventive treatments are intended to reduce attack frequency and severity.
Current acute migraine treatments are primarily pharmacologic approaches, with the most commonly used medications being analgesics, non-steroidal anti-inflammatory drugs (NSAIDs) and triptans. These drugs bear several contraindications and are associated with moderate to severe side effects. In patients with frequent and/or prolonged migraine attacks, excessive consumption of acute migraine drugs may lead to headache chronification and medication overuse headache, which portends a worse outcome. Moreover, some patients (particularly those with chronic migraine) may become resistant to conventional migraine medications and thus do not achieve sufficient pain relief. Medication-related adverse effects and limited effectiveness highlight the need for non-pharmacologic therapies.
Recent studies suggest that neurostimulation may be a promising modality for the treatment of headache disorders. Several neuromodulation technics have been investigated for the treatment of primary headaches. Pain Physician 11(2), 187-200 (2008) discloses open trials wherein percutaneous occipital nerve stimulation (p-ONS) was effective for chronic migraine. Lancet Neurology 6(4), 314-321 (2007) discloses the effectiveness of p-ONS for chronic cluster headache. Cephalalgia 31(3), 271-285 (2011) discloses positive results for p-ONS in a controlled study for chronic migraine. Cephalalgia 30(3), 260-271 (2010) discloses that a combined occipital nerve and supraorbital nerve neurostimulation shows better efficacy than occipital nerve stimulation alone. Neuromodulation 19(5), 507-514 (2016) discloses that while patient functional status is improved in the perioperative period, it waned over the long-term follow-up. Cephalalgia 33(10), 816-830 (2013) discloses that sphenopalatine ganglion stimulation (SPG) yields positive results in several trials mainly for the treatment of cluster headache. However, although generally well tolerated, these invasive neuromodulation technics could be appropriate for intractable migraine and chronic cluster headaches, but may not be acceptable for less severe migraine patient categories. Cephalalgia 36(6), 534-546 (2016) discloses that non-invasive vagus nerve stimulation shows clinical benefits beyond those with standard of care for cluster headache. However, the Journal of Headache and Pain 16, 63 (2015) and Neurology 87(5), 529-538 (2016) report negative results for non-invasive vagus nerve stimulation from sham-controlled trials for chronic migraine.
BMC Neurology 11, 135 (2011) discloses a double-blind, sham-controlled, cross-over study with healthy subjects in which transcutaneous supraorbital neurostimulation was found to produce a sedative effect. Neurology 80(8), 697-704 (2013) discloses a subsequent multi-center, randomized, double-blind, sham-controlled trial which reveals the efficacy and safety of external trigeminal nerve stimulation (e-TNS) for the prevention of episodic migraine. The Journal of Headache and Pain 16, 69 (2015) discloses a larger open randomized trial in which the therapeutic efficacy in migraine prevention was corroborated. The Journal of Headache and Pain 14, 95 (2013) discloses a prospective study of 2313 patients in which safety and patient satisfaction have been further confirmed.
However, there remains a need in the art for a safe non-drug and non-invasive acute treatment for migraine attacks.
US 2009/0 210 028 discloses a device for the electrotherapeutic treatment of headaches such as tension headaches and migraines. An electrode support has a shape and is size selected so as to allow, independently from the subject, the excitation of the afferent paths of the supratrochlear and supraorbital nerves of the ophthalmic branch of the trigeminal nerve. An electrical circuit includes a programmable signal generator suitable for creating pulses of a duration of between 150 and 450 μs with a maximum increase in intensity of 0 to 20 mA at a rate of less than or equal to 40 μA/s and with a step up in intensity not exceeding 50 μA.
US 2009/0 210 028 does not disclose the use of the device for the acute treatment of migraine attacks. In addition, US 2009/0 210 028 does not disclose particular treatment durations.
US 2010/0 274 327 discloses an electrotherapy system for stimulating sensory nerves within skin tissue. The system comprises an electrode carrier, a pulse generator, an array of skin-penetrating electrodes and surface skin electrodes, a pulse conditioning circuit, and a power source. The system administers biphasic pulsed current at the surface skin electrodes and monophasic pulsed current at each skin-penetrating electrode. The document in particular discloses the combined use of the skin-penetrating and surface skin electrodes. The embodiments disclosed in US 2010/0 274 327 provide an applicable electrode patch combining both the surface skin electrodes and skin-penetrating electrodes within this same patch. Non-invasive treatment is not possible with such an electrode patch. The system and in particular the surface skin electrodes are configured for masking pain due to stimulation via the skin-penetrating electrodes. The document does not disclose the treatment of migraine. The document also does not disclose the ophthalmic branch of the trigeminal nerve.
The present invention aims to resolve at least some of the problems mentioned above.

External trigeminal nerve stimulation for the acute non-invasive treatment of migraine attacks


The present invention relates generally method of treating or alleviating cognitive impairment by administering an abuse-deterrent formulation containing dextroamphetamine sulfate.

Cognitive impairment can an prevent an individual from concentrating, recalling memories, and can lead to mental fatigue.
Cognitive impairment is not caused by any one disease or condition, nor is it limited to a specific age group. Cognitive impairment, effects one's quality of life and is complicated to treat because it can be caused by a long range of lifestyle problems, medications, or conditions.
However, new research is now suggesting that there may be long-term neurologic consequences in those who survive COVID infections, including more than seven million Americans and another 27 million people worldwide. Particularly troubling is increasing evidence that there may be mild—but very real—brain damage that occurs in many survivors, causing pervasive yet subtle cognitive, behavioral, and psychological problems. While sometimes the brain damage is obvious and leads to major cognitive impairment, more frequently the damage is mild, leading to difficulties with sustained attention.
Accordingly, a need exists for treatments for cognitive impairment, in particular in COVID 19 survivors.

Compositions and methods of treating cognitive impairment


An analytical method for computing a video hologram for a holographic reproduction device having at least one light modulation means is disclosed, wherein a scene split into object points is encoded as a whole hologram and can be seen as a reconstruction from a visibility region, located within a periodicity interval of the reconstruction. The visibility region, together with each object point of the scene to be reconstructed, defines a subhologram and the whole hologram is generated from a superposition of subholograms, wherein the complex hologram values of a subhologram are determined from the wave front of the respective object point to be reconstructed in a modulator region of the light modulation means, by calculating and evaluating the transmission or modulation functions of an imaging element formed in the modulator region. The object point to be reconstructed is located in the focal point of the imaging element.

The present invention relates to an analytic method for computing video holograms for a holographic display device in real time.
Such a holographic display device is substantially based on the principle that a sub-hologram is defined together with each object point of the scene to be reconstructed and that the entire hologram is formed by superposition of sub-holograms, with the help of at least one light modulator means on which a scene which is divided into object points is encoded as an entire hologram and where the scene can be seen as a reconstruction from a visibility region which lies within one periodicity interval of the reconstruction of the video hologram. In general, the principle is to reconstruct mainly that wave front that would be emitted by an object into one or multiple visibility regions. In detail, such a device is based on the principle that the reconstruction of an individual object point only requires a sub-hologram as a subset of the entire hologram encoded on the light modulator means. The holographic display device comprises at least one screen means. The screen means is either the light modulator itself, where the hologram of a scene is encoded, or an optical element—such as a lens or a mirror—onto which a hologram or wave front of a scene encoded on the light modulator is imaged.
The definition of the screen means and the corresponding principles for the reconstruction of the scene in the visibility region are described in other documents filed by the applicant. In documents WO 2004/044659 and WO 2006/027228, the light modulator itself forms the screen means. In document WO 2006/119760, titled "Projection device and method for holographic reconstruction of scenes", the screen means is an optical element onto which a hologram which is encoded on the light modulator is imaged. In document DE 10 2006 004 300, titled "Projection device for the holographic reconstruction of scenes", the screen means is an optical element onto which a wave front of the scene encoded on the light modulator is imaged. Document WO 2006/066919 filed by the applicant describes a method for computing video holograms.
A 'visibility region' is a limited region through which the observer can watch the entire reconstruction of the scene at sufficient visibility. Within the visibility region, the wave fields interfere such that the reconstructed scene becomes visible for the observer. The visibility region is located on or near the eyes of the observer. The visibility region can be moved in the x, y and z directions and is tracked to the actual observer position with the help of known position detection and tracking systems. It is possible to use two visibility regions, one for each eye. Generally, more complex arrangements of visibility regions are also possible. It is further possible to encode video holograms such that individual objects or the entire scene seemingly lie behind the light modulator for the observer.
In this document, the term 'light modulator means' or 'SLM' denotes a device for controlling intensity, colour and/or phase of light by way of switching, gating or modulating light beams emitted by one or multiple independent light sources. A holographic display device typically comprises a matrix of controllable pixels, which reconstruct object points by modifying the amplitude and/or phase of light which passes through the display panel. A light modulator means comprises such a matrix. The light modulator means may for example be an acousto-optic modulator AOM or a continuous-type modulator. One embodiment for the reconstruction of the holograms by way of amplitude modulation can take advantage of a liquid crystal display (LCD). The present invention also relates to further controllable devices which are used to modulate sufficiently coherent light into a light wave front or into a light wave contour.
The term 'pixel' denotes a controllable hologram pixel of the light modulator, it represents a discrete value of the hologram point and is addressed and controlled discretely. Each pixel represents a hologram point of the hologram. In the case of an LC display, a pixel is a discretely controllable display pixel. In the case of a DMD (Digital Micro-mirror Device), such as a DLP (Digital Light Processor), a pixel is a discretely controllable micro-mirror or small group of such mirrors. In the case of a continuous light modulator means, a pixel is an imaginary region which represents the hologram point. In the case of a colour representation, a pixel is typically subdivided into multiple sub-pixels, which represent the primary colours.
The term 'transformation' shall be construed such to include any mathematical or computational technique which is identical to or which approximates a transformation. Transformations in a mathematical sense are merely approximations of physical processes, which are described more precisely by the Maxwellian wave equations. Transformations such as Fresnel transformations or the special group of transformations which are known as Fourier transformations, describe second-order approximations. Transformations are usually represented by algebraic and nondifferential equations and can therefore be handled efficiently and at high performance using known computing means. Moreover, they can be modeled precisely using optical systems.
Document WO 2006/066919 filed by the applicant describes a method for computing video holograms. It generally includes the steps of slicing the scene into section planes which are parallel to the plane of a light modulator, transforming all those section planes into a visibility region and to add them up there. Then, the added results are back-transformed into the hologram plane, where also the light modulator is disposed, thus determining the complex hologram values of the video hologram.
Document DE 10 2006 042 324 describes a method for the real-time generation of video holograms. That method uses the principle that the reconstruction of a single object point only requires a sub-hologram as a subset of the entire hologram which is encoded on the SLM. It is characterised in that for each object point the contributions of the sub-holograms can be retrieved from look-up tables, and that said sub-holograms are accumulated so to form an entire hologram in order to reconstruct the entire scene.
The former method for the generation of video holograms for interactive real-time representations can only be realised with great efforts being put into resources. Moreover, because of the great number of complex computing steps, the generation of the video holograms causes a great computational load and requires high performance and costly computing units. As a result of the long computation times there is the risk that video sequences and interactive three-dimensional real-time applications cannot be provided with the desired refresh frequency.
As in conventional video technologies, a high image refresh rate is desired and indispensable when displaying computer-generated video holograms. The cited methods further exhibit the disadvantage that hologram values can only be generated for object points, which represent certain discrete positions or positions of discrete section layers.

This patent is subject to a terminal disclaimer.

Analytic method for computing video holograms in real time


A bicycle twist-grip shift control device includes a base member for attachment to the bicycle; a twist-grip operating member rotatably supported relative to the base member for rotating in first and second directions around an operating member axis; a transmission control member rotatably mounted relative to the base member for controlling the pulling and releasing of a transmission control element in response to rotation of the operating member, and an intermediate member that moves in a direction of an intermediate member axis in response to rotation of the operating member. The transmission control member rotates around a transmission control member axis that is substantially parallel to the operating member axis, and the intermediate member includes an intermediate member detent for maintaining a rotational position of the operating member and the transmission control member.

The present invention is directed to bicycles and, more particularly, to a bicycle twist-grip shift control device that uses parallel gearing to communicate rotational power from a twist-grip to a transmission control element.
Twist-grip shift control devices have been used with bicycles to pull and release transmission control elements in response to rotation of a twist-grip operating member that rotates coaxially with a handlebar axis. An example of such a device is shown in U.S. Pat. No. 5,315,891. The device disclosed in that patent includes a twist-grip operating member that rotates coaxially around a handlebar axis, a drive gear that rotates coaxially with the operating member, a driven gear that meshes with the drive gear and rotates around an axis that is parallel to the handlebar axis, and a cable reel that rotates coaxially with the driven gear for winding and unwinding a transmission control cable. The operating member rotates in clockwise and counterclockwise directions from a home position to correspondingly rotate the cable reel. A retainer mechanism maintains the cable reel in the selected position so that the operating member may return to the home position after each operation.

Bicycle twist-grip shift control device with parallel gearing


Imaging elements, such as photographic, electrostatographic and thermal imaging elements, are comprised of a support, an image-forming layer and an electrically-conductive layer comprising a dispersion in a film-forming binder of fine particles of an electronically-conductive metal antimonate. Use of metal antimonate particles provides a controlled degree of electrical conductivity and beneficial chemical, physical and optical properties which adapt the electrically-conductive layer for such purposes as providing protection against static or serving as an electrode which takes part in an image-forming process.

Problems associated with the formation and discharge of electrostatic charge during the manufacture and utilization of photographic film and paper have been recognized for many years by the photographic industry. The accumulation of charge on film or paper surfaces leads to the attraction of dust, which can produce physical defects. The discharge of accumulated charge during or after the application of the sensitized emulsion layer(s) can produce irregular fog patterns or "static marks" in the emulsion. The severity of static problems has been exacerbated greatly by increases in the sensitivity of new emulsions, increases in coating machine speeds, and increases in post-coating drying efficiency. The charge generated during the coating process results primarily from the tendency of webs of high dielectric polymeric film base to charge during winding and unwinding operations (unwinding static), during transport through the coating machines (transport static), and during post-coating operations such as slitting and spooling. Static charge can also be generated during the use of the finished photographic film product. In an automatic camera, the winding of roll film out of and back into the film cassette, especially in a low relative humidity environment, can result in static charging. Similarly, high-speed automated film processing can result in static charge generation. Sheet films are especially subject to static charging during removal from light-tight packaging (e.g., x-ray films).
It is generally known that electrostatic charge can be dissipated effectively by incorporating one or more electrically-conductive "antistatic" layers into the film structure. Antistatic layers can be applied to one or to both sides of the film base as subbing layers either beneath or on the side opposite to the light-sensitive silver halide emulsion layers. An antistatic layer can alternatively be applied as an outer coated layer either over the emulsion layers or on the side of the film base opposite to the emulsion layers or both. For some applications, the antistatic agent can be incorporated into the emulsion layers. Alternatively, the antistatic agent can be directly incorporated into the film base itself.
A wide variety of electrically-conductive materials can be incorporated into antistatic layers to produce a wide range of conductivities. Most of the traditional antistatic systems for photographic applications employ ionic conductors. Charge is transferred in ionic conductors by the bulk diffusion of charged species through an electrolyte. Antistatic layers containing simple inorganic salts, alkali metal salts of surfactants, ionic conductive polymers, polymeric electrolytes containing alkali metal salts, and colloidal metal oxide sols (stabilized by metal salts) have been described previously. The conductivities of these ionic conductors are typically strongly dependent on the temperature and relative humidity in their environment. At low humidities and temperatures, the diffusional mobilities of the ions are greatly reduced and conductivity is substantially decreased. At high humidities, antistatic backcoatings often absorb water, swell, and soften. In roll film, this results in adhesion of the backcoating to the emulsion side of the film. Also, many of the inorganic salts, polymeric electrolytes, and low molecular weight surfactants used are water-soluble and are leached out of the antistatic layers during processing, resulting in a loss of antistatic function.
Colloidal metal oxide sols which exhibit ionic conductivity when included in antistatic layers are often used in imaging elements. Typically, alkali metal salts or anionic surfactants are used to stabilize these sols. A thin antistatic layer consisting of a gelled network of colloidal metal oxide particles (e.g., silica, antimony pentoxide, alumina, titania, stannic oxide, zirconia) with an optional polymeric binder to improve adhesion to both the support and overlying emulsion layers has been disclosed in EP 250,154. An optional ambifunctional silane or titanate coupling agent can be added to the gelled network to improve adhesion to overlying emulsion layers (e.g., EP 301,827; U.S. Pat. No. 5,204,219) along with an optional alkali metal orthosilicate to minimize loss of conductivity by the gelled network when it is overcoated with gelatin-containing layers (U.S. Pat. No. 5,236,818). Also, it has been pointed out that coatings containing colloidal metal oxides (e.g., antimony pentoxide, alumina, tin oxide, indium oxide) and colloidal silica with an organopolysiloxane binder afford enhanced abrasion resistance as well as provide antistatic function (U.S. Pat. Nos. 4,442,168 and 4,571,365).
Antistatic systems employing electronic conductors have also been described. Because the conductivity depends predominantly on electronic mobilities rather than ionic mobilities, the observed electronic conductivity is independent of relative humidity and only slightly influenced by the ambient temperature. Antistatic layers have been described which contain conjugated polymers, conductive carbon particles or semiconductive inorganic particles.
Trevoy (U.S. Pat. No. 3,245,833) has taught the preparation of conductive coatings containing semiconductive silver or copper iodide dispersed as particles less than 0.1 .mu.m in size in an insulating film-forming binder, exhibiting a surface resistivity of 10.sup.2 to 10.sup.11 ohms per square. The conductivity of these coatings is substantially independent of the relative humidity. Also, the coatings are relatively clear and sufficiently transparent to permit their use as antistatic coatings for photographic film. However, if a coating containing copper or silver iodides was used as a subbing layer on the same side of the film base as the emulsion, Trevoy found (U.S. Pat. No. 3,428,451) that it was necessary to overcoat the conductive layer with a dielectric, water-impermeable barrier layer to prevent migration of semiconductive salt into the silver halide emulsion layer during processing. Without the barrier layer, the semiconductive salt could interact deleteriously with the silver halide layer to form fog and a loss of emulsion sensitivity. Also, without a barrier layer, the semiconductive salts are solubilized by processing solutions, resulting in a loss of antistatic function.
Another semiconductive material has been disclosed by Nakagiri and Inayama (U.S. Pat. No. 4,078,935) as being useful in antistatic layers for photographic applications. Transparent, binderless, electrically semiconductive metal oxide thin films were formed by oxidation of thin metal films which had been vapor deposited onto film base. Suitable transition metals include titanium, zirconium, vanadium, and niobium. The microstructure of the thin metal oxide films is revealed to be non-uniform and discontinuous, with an "island" structure almost "particulate" in nature. The surface resistivity of such semiconductive metal oxide thin films is independent of relative humidity and reported to range from 10.sup.5 to 10.sup.9 ohms per square. However, the metal oxide thin films are unsuitable for photographic applications since the overall process used to prepare these thin films is complicated and costly, abrasion resistance of these thin films is low, and adhesion of these thin films to the base is poor.
A highly effective antistatic layer incorporating an "amorphous" semiconductive metal oxide has been disclosed by Guestaux (U.S. Pat. No. 4,203,769). The antistatic layer is prepared by coating an aqueous solution containing a colloidal gel of vanadium pentoxide onto a film base. The colloidal vanadium pentoxide gel typically consists of entangled, high aspect ratio, flat ribbons 50-100 .ANG. wide, about 10 .ANG. thick, and 1,000-10,000 .ANG. long. These ribbons stack flat in the direction perpendicular to the surface when the gel is coated onto the film base. This results in electrical conductivities for thin films of vanadium pentoxide gels (about 1 .OMEGA..sup.-1 cm.sup.-1) which are typically about three orders of magnitude greater than is observed for similar thickness films containing crystalline vanadium pentoxide particles. In addition, low surface resistivities can be obtained with very low vanadium pentoxide coverages. This results in low optical absorption and scattering losses. Also, the thin films are highly adherent to appropriately prepared film bases. However, vanadium pentoxide is soluble at high pH and must be overcoated with a nonpermeable, hydrophobic barrier layer in order to survive processing. When used with a conductive subbing layer, the barrier layer must be coated with a hydrophilic layer to promote adhesion to emulsion layers above. (See Anderson et at, U.S. Pat. No. 5,006,451.)
Conductive fine particles of crystalline metal oxides dispersed with a polymeric binder have been used to prepare optically transparent, humidity insensitive, antistatic layers for various imaging applications. Many different metal oxides--such as ZnO, TiO.sub.2, ZrO.sub.2, SnO.sub.2, Al.sub.2 O.sub.3, In.sub.2 O.sub.3, SiO.sub.2, MgO, BaO, MoO.sub.3 and V.sub.2 O.sub.5 --are alleged to be useful as antistatic agents in photographic elements or as conductive agents in electrostatographic elements in such patents as U.S. Pat. Nos. 4,275,103, 4,394,441, 4,416,963, 4,418,141, 4,431,764, 4,495,276, 4,571,361, 4,999,276 and 5,122,445. However, many of these oxides do not provide acceptable performance characteristics in these demanding environments. Preferred metal oxides are antimony doped tin oxide, aluminum doped zinc oxide, and niobium doped titanium oxide. Surface resistivities are reported to range from 10.sup.6 -10.sup.9 ohms per square for antistatic layers containing the preferred metal oxides. In order to obtain high electrical conductivity, a relatively large amount (0.1-10 g/m.sup.2) of metal oxide must be included in the antistatic layer. This results in decreased optical transparency for thick antistatic coatings. The high values of refractive index (>2.0) of the preferred metal oxides necessitates that the metal oxides be dispersed in the form of ultrafine (<0.1 .mu.m) particles in order to minimize light scattering (haze) by the antistatic layer.
Antistatic layers comprising electro-conductive ceramic particles, such as particles of TiN, NbB.sub.2, TiC, LaB.sub.6 or MoB, dispersed in a binder such as a water-soluble polymer or solvent-soluble resin are described in Japanese Kokai No. 4/55492, published Feb. 24, 1992.
Fibrous conductive powders comprising antimony-doped tin oxide coated onto non-conductive potassium titanate whiskers have been used to prepare conductive layers for photographic and electrographic applications. Such materials are disclosed, for example, in U.S. Pat. Nos., 4,845,369 and 5,116,666. Layers containing these conductive whiskers dispersed in a binder reportedly provide improved conductivity at lower volumetric concentrations than other conductive fine particles as a result of their higher aspect ratio. However, the benefits obtained as a result of the reduced volume percentage requirements are offset by the fact that these materials are relatively large in size such as 10 to 20 micrometers in length, and such large size results in increased light scattering and hazy coatings.
Use of a high volume percentage of conductive particles in an electro-conductive coating to achieve effective antistatic performance can result in reduced transparency due to scattering losses and in the formation of brittle layers that are subject to cracking and exhibit poor adherence to the support material. It is thus apparent that it is extremely difficult to obtain non-brittle, adherent, highly transparent, colorless electro-conductive coatings with humidity-independent process-surviving antistatic performance.
The requirements for antistatic layers in silver halide photographic films are especially demanding because of the stringent optical requirements. Other types of imaging elements such as photographic papers and thermal imaging elements also frequently require the use of an antistatic layer but, generally speaking, these imaging elements have less stringent requirements.
Electrically-conductive layers are also commonly used in imaging elements for purposes other than providing static protection. Thus, for example, in electrostatographic imaging it is well known to utilize imaging elements comprising a support, an electrically-conductive layer that serves as an electrode, and a photoconductive layer that serves as the image-forming layer. Electrically-conductive agents utilized as antistatic agents in photographic silver halide imaging elements are often also useful in the electrode layer of electrostatographic imaging elements.
As indicated above, the prior art on electrically-conductive layers in imaging elements is extensive and a very wide variety of different materials have been proposed for use as the electrically-conductive agent. There is still, however, a critical need in the art for improved electrically-conductive layers which are useful in a wide variety of imaging elements, which can be manufactured at reasonable cost, which are resistant to the effects of humidity change, which are durable and abrasion-resistant, which are effective at low coverage, which are adaptable to use with transparent imaging elements, which do not exhibit adverse sensitometric or photographic effects, and which are substantially insoluble in solutions with which the imaging element typically comes in contact, for example, the aqueous alkaline developing solutions used to process silver halide photographic films.
It is toward the objective of providing improved electrically-conductive layers that more effectively meet the diverse needs of imaging elements--especially of silver halide photographic films but also of a wide range of other imaging elements--than those of the prior art that the present invention is directed.

Imaging element comprising an electrically-conductive layer containing particles of a metal antimonate


The invention provides novel compounds, composition comprising said compounds and methods for inhibiting CK1 as well as methods of treating CK1 related disorders such as Alzheimer's disease comprising administering a therapeutically effective amount of a CK1 inhibitor to a patient in need thereof.

Alzheimer's disease (AD) is an irreversible, progressive brain disease characterized by the loss of cognitive functioning, e.g., memory and reasoning, and behavioral abilities. AD is estimated to affect more than 25 million people in the world and is reported in the 2010 World Alzheimer Report to have annual societal costs of US$604 billion, or 1% of the aggregated worldwide Gross Domestic Product (GDP). Existing AD medications aim to treat symptoms of AD only and do so rather poorly. Existing AD medications do not address the progression of the disease. New therapeutic agents that slow (or reverse) the disease and that target multiple aspects of the disorder are urgently needed.
Studies have shown that the etiology of AD includes a range of clear genetic predispositions involving amyloid precursor protein (APP), Tau phosphorylation, gamma-secretase (GS), apolipoprotein E (ApoE) and genes involved in circadian rhythms. There is strong evidence which indicates the importance of Tau hyper-phosphorylation, excessive amyloid beta (Aβ) formation and desynchrony of circadian rhythms in Alzheimer's disease. There is also clear evidence of a cell loss in the suprachiasmatic nucleus, the brain region involved in regulating circadian rhythms that coincides with development of the dementia stage of AD. AD patients suffer a plethora of symptoms including serious and progressive cognitive decline, sleep disturbances and agitation.
Casein Kinase 1 is a member of a unique class of protein serine/threonine kinases that are only distantly related to other kinase families. Comparing CK1 sequence identities to other kinase families, glycogen synthase kinase 3 (GSK3) is the closest related kinase outside the CK1 family and is only 20% identical in the catalytic domain. The CK1 family has seven isoforms with various splice variants. The role of CK1 in AD is substantially documented in recent reviews. See Buee et al., Brain Res. Rev. (2000) 33(1):95-130; See also Perez et al., Med. Res. Rev. (2010) 31(6):924-54. It has been observed that CK1 delta mRNA is elevated 30-fold in the hippocampus of AD patients' brains. Yasojima et al., Brain Res. (2000) 865(1):116-20. The beneficial effect of CK1 inhibitors to reverse Aβ formation has also been shown. Flajolet et al., Proc. Natl. Acad. Sci. U.S.A. (2007) 104(10):4159-64. With regard to the phosphorylation of various Tau forms, there are multiple sites of phosphorylation of Tau and a number of putative Tau kinases are involved. Although the role of various kinases in this process is complex, the importance of critical priming kinases is generally accepted as driving the hyper-phosphorylation co-incident with the formation of paired helical filaments (PHF) that are the universal pathology associated with AD. It is well documented that CK1 is a "major Tau kinase" with priming functions and is associated with paired helical filaments (PHF). Hanger et al., J. Biol. Chem. (2007) 282(32):23645-54. Most importantly, there is substantial evidence for a fundamental role of CK1 controlling circadian rhythm and metabolic state through phosphorylation and regulation of a series of transcription factors including CLOCK, BMAL-1, and Perl-3; with CK1 and CK2 collectively considered the "clock genes". Ebisawa T., J. Pharmacol. Sci. (2007) 103(2):150-4. CK1 delta and epsilon gene variations are also associated with circadian rhythms changes.
Highly specific CK1 inhibitors have been developed and have served to further validate the role of CK1 in AD related pathologies. Several examples of potent and selective inhibitors are known. Using potent and selective CK1 inhibitors in rodent and monkey animal models, profound influences on phase shifts in circadian rhythms are discovered that substantially validate the hypothesis of CK1 involvement in the biological clock. Sprouse et al., Psychopharmacology (Berl) (2010) 210(4):569-76; Sprouse et al., Psychopharmacology (Berl) (2009) 204(4):735-42. All of these studies therefore support the critical role of CK1 as therapeutic target in AD.
In view of the important role of CK1, further potent and selective CK1 inhibitors are needed in the fight against AD and other CK1 related diseases.


A method for network access is provided. The method includes establishing a secure link between a user equipment (UE) and a wireless local area network (WLAN) when an authentication and authorization server determines that credentials provided by the UE to the authentication and authorization server allow the UE secure access to the WLAN. The method further includes establishing a secure link between the UE and an application access server via the WLAN when the application access server, using the same credentials, determines that the UE is allowed secure access to the application access server.

As used herein, the terms "user equipment", "UE", "device", "electronic device", and the like can refer to mobile equipment such as telephones, smart phones, personal digital assistants, handheld or laptop computers, and similar devices that have wireless telecommunications capabilities. Such a device might include an associated removable memory module, such as but not limited to a Universal Integrated Circuit Card (UICC) that includes a Subscriber Identity Module (SIM) application, a Universal Subscriber Identity Module (USIM) application, or a Removable User Identity Module (R-UIM) application. A UE might be capable of connecting wirelessly to one or more different types of networks, such as a Wireless Local Area Network (WLAN), a secure corporate WLAN, a virtual private network (VPN), a WLAN hotspot, and/or a home network. In addition, a UE might connect to various types of servers, such as network access servers, authentication servers, and/or other types of servers. A UE might also connect to an application access server in order to gain access to internet-related applications, such as email.

Simplified authentication via application access server


The present invention generally relates to interior trim parts such as door panels that are attached to an interior sheet in a motor vehicle. In accordance with the preferred embodiment of the present invention, a method of forming the trim part having an outer surface and an inner surface is disclosed. The method comprises providing a substrate having a first side and a second side and disposing the substrate in a molding tool, the molding tool has an upper mold and a lower mold. Engaging the first side of the substrate with the upper mold and the second side of the substrate with the lower mold. The first side is subject to compression molding such that the first side forms the outer surface of the trim part and injection molding an attachment surface to the second side of the substrate.

This invention generally relates to a trim parts installed in the interior of a motor vehicle. More specifically to a trim part having an attachment surface and a method of forming the attachment surface on the trim part.
Automotive interior molded panel components, such as trim part inserts such as door panels, are typically manufactured with a covered substrate and with backside attachment methods for sheet metal. The sheet metal is then attached to other components of the trim part. Typically, these door panels are made by compression molding a substrate to the desired form of the door panel. With the use of compression molding techniques, it is very difficult to mold in the backside the attachment points.
Therefore, in order to attach these attachment points at the back of the substrate forming the door panel, a two step process is involved where these attachment points are purchased components and are assembled to the substrate by means of placing/locating each attachment piece into the molding tool before the molding process. Alternatively, these attachment tools are attached after removing the substrate from the molding tool and fastening the attachment by secondary operations such as heat staking, sonic welding, vibration welding or with the help of an adhesive. However present methods used to secure these attachments entail additional product cost, therefore, adding to the overall cost of the automobile. In some cases, over time, these attachments points contribute to the degradation in the noise, vibration and harshness (NVH) characteristics of an automobile.
Hence, there is a need in the automotive industry to manufacture door panels that have integrated attachment points that will reduce the overall cost and manufacturing time of a door panel.
The present invention generally relates to interior trim parts such as door panels that are attached to an interior sheet in a motor vehicle. In accordance with the preferred embodiment of the present invention, a method of forming the trim part having a outer surface and an inner surface is disclosed. The method comprises providing a substrate having a first side and a second side and disposing the substrate in a molding tool, the molding tool has an upper mold and a lower mold. Engaging the first side of the substrate with the upper mold and the second side of the substrate with the lower mold. The first side is subject to compression molding such that the first side forms the outer surface of the trim part and injection molding an attachment surface to the second side of the substrate.

Method of attaching thermoplastic attachments to a substrate


A compact, lightweight manipulation system that excels in operability and has a force feedback capability is provided. When automatic operation of a slave manipulator 105 that follows manual operation of a master manipulator 101 is bilaterally controlled by means of communication, the force acting on the slave manipulator is fed back to the master manipulator by operating the master manipulator primarily under electrically-driven speed control and the slave manipulator primarily under pneumatically-driven force control. Therefore, in the master manipulator, it is not necessary to compensate for the dynamics and the self-weight of the master manipulator in the motion range of a user, allowing highly accurate, broadband positional control, which is specific to an electrically-driven system, and in the slave manipulator, nonlinearity characteristics specific to a pneumatically-driven system presents passive softness, provides a high mass-to-output ratio, and produces a large force.

In recent years, surgical operations have been widely practiced in the form of endoscopic surgery to improve QOL (Quality of Life), such as reduction in patient's pain, hospitalization period, and size of the scar associated with the surgery. Endoscopic surgery is performed in such a way that an operator inserts forceps or other related tools through a thin tube (trocar) and performs the surgery while observing images from a laparoscope. Since the scar is smaller than that in open surgery, the burden on the patient is smaller. However, since the operator moves the forceps or other related tools using the abdominal wall as a pivotal point, sufficient degrees of freedom are not provided at the tip of the forceps and hence it is not easy to freely approach the site to be treated. Such a situation requires a highly skilled operator. To reduce the burden on the operator, studies on multi-DOF forceps system have been actively underway, in which robotics technology is used to impart multiple degrees of freedom to the tip of forceps.
The master-slave concept used in commercially available multi-DOF forceps systems has advantages of, for example, capability of remotely and intuitively operating the forceps. To provide more accurate, safer workability, it is desirable to provide force feedback to the operator. To this end, studies on forceps with a force sensor provided in the vicinity of the tip of the forceps are underway. However, such a multi-DOF forceps system using electric actuators to drive the master and slave portions not only cannot feed a minute force back to the operator because of a high reduction ratio, but also has an insufficient movable range and results in a bulky apparatus. Further, attaching a force sensor to the forceps is not an easy task in consideration of practical factors, such as reduction in size, sterilization, and calibration.
To address the above problems, the inventors of the present application have conducted studies on multi-DOF forceps systems, in which pneumatic actuators are used to drive the master and slave portions. A pneumatic actuator, which has nonlinear characteristics, is inferior to an electric actuator in terms of controllability, but has advantages of, for example, presenting passive softness, having a high mass-to-output ratio, and producing a large force without a reduction gear train. For example, a multi-DOF forceps system has been proposed (see the non-patent document 1: "Bilateral control of multi-DOF forceps system having force sensing capability using pneumatic servo technology", Japan Society of Computer Aided Surgery, pp. 25-31, (2005), Kotaro Tadano, Kenji Kawashima), in which the slave portion includes a 3-DOF forceps manipulator using pneumatic cylinders and the pressure in each of the pneumatic cylinders is used to estimate the external force acting on the tip of the forceps instead of using a force sensor. The entire disclosures of the aforesaid non-patent reference 1 are incorporated herein by reference. Further, a multi-DOF forceps system has been proposed (see the non-patent document 2: "Development of master-slave system having force feedback capability using pneumatically-driven multi-DOF forceps: Development of manipulator for holding forceps", Conference on Robotics and Mechatronics, 1A1-A03, (2006), Kotaro Tadano, Kenji Kawashima), which includes a 3-DOF pneumatic manipulator that holds and drives the 3-DOF forceps manipulator described in the non-patent document 1 in a region outside the abdomen. The entire disclosures of the aforesaid non-patent reference 2 are incorporated herein by reference.
However, in the multi-DOF forceps systems proposed in the above mentioned study, the forceps manipulator has only three degrees of freedom, which does not allow the motion of the human hand to be reproduced. In the multi-DOF forceps systems described in the non-patent documents 1 and 2, the forceps manipulator includes a mechanism that converts the linear motion of a pneumatic cylinder into rotational motion, so that reduction in weight of the forceps manipulator is difficult to achieve. Further, the master and the slave portions are configured in the same manner (both are controlled pneumatically), which does not necessarily provide an optimum structure in terms of operability.
The invention has been conceived and completed through the above mentioned studies conducted by the inventors of the present application. An object of the invention is to provide a compact, lightweight manipulation system that excels in operability and has a force feedback capability.

Maneuvering system having inner force sense presenting function


A device and method are provided for therapy and treatment of biological tissue such as muscle, tendon, and ligament tissue, by use of a device and method in which therapeutic vibrational frequency resonance patterns are transmitted to tissues of a patient. The resonance frequencies originate from many resonance domains, including vitamins, minerals, herbs, amino acids, and fatty acids. Each domain includes therapeutic frequency resonance patterns. These resonance patterns may be passively excited and transmitted to a patient to enhance tissue function, to decrease the normal rehabilitation time of damaged tissue, and provide therapeutic benefits for muscle tissue dysfunction. Therapeutic frequency resonance patterns may also be actively excited by a delivery mechanism that uses electromagnetic or mechanical waves to interact with the device. The actively excited device transmits the therapeutic frequency resonance patterns to the patients for similar enhancements and therapeutic benefits.

Stimulation and exercise of muscle tissue is necessary for the rehabilitation and continued development of damaged and/or poorly functioning muscle tissue. The failure to stimulate and exercise muscle tissue inevitably results in muscle atrophy, and long periods of muscle inactivity can result in permanent damage.
There are a number of existing devices and methods that are used for muscle stimulation and rehabilitation, primarily in the field of neuromuscular electrical stimulation (NMES). NMES is known to provide many therapeutic benefits such as prevention or retardation of disuse atrophy, pain relief, improvement of blood circulation, and others. Most forms of electrical stimulation involve the delivery of intermittent and repeating series of electrical pulses to the targeted muscle tissue(s). In many systems, the pulses are delivered transcutaneously by surface electrodes that are placed on the patient's skin over the targeted muscle area(s).
Included within this body of knowledge regarding NMES are a number of patent references. One example includes the U.S. Pat. No. 8,265,763. This reference discloses systems and methods for neuromuscular electrical stimulation. Stimulation electrodes are provided on a stimulation pad, configured to provide electrical stimulation to a targeted tissue. A system for neuromuscular electrical stimulation also includes a pressure generating mechanism to provide a compressive force to a region of the targeted tissue, thereby removing excess fluid from the region.
Another example of a US patent reference includes the U.S. Pat. No. 8,315,711. This reference discloses a method and apparatus using resonant pulses to treat diabetes, carpal tunnel syndrome, arthritis, and other maladies by applying a stimulating signal to promote and manipulate blood flow. The stimulating signal may include a resonant sequence that includes at least three pulses, where the pulses of the resonant sequence are spaced relative to one another such that each pulse subsequent to a first pulse in the sequence is effective to progressively stimulate and create tension in a musculature that includes the muscle inwardly from the electrodes and towards the center of the musculature, while maintaining the tension created in at least a portion of the musculature by each preceding pulse in the resonant sequence.
Yet another example of a US patent reference that discloses an invention in this field is the U.S. Pat. No. 8,145,318. This reference generally discloses an apparatus for electrical stimulation of muscle tissue, including an electrode system with an electrode array. The array has a plurality of electrode pads and is placed in electrical contact with the targeted muscle tissue. The electrode system further includes a sensor for sensing a property of the muscle tissue. This property forms a measure for the activity of the muscle tissue. The apparatus includes an electrode selector for selecting one or more stimulating electrode pads. A signal generator is connected to the electrode array for providing an electrical stimulation signal to the stimulation electrode pad. A signal processor is connected to the sensor for determining from the sensor signal a value of the muscle activity, and outputting the value to a human perceptible form. This reduces the accuracy required to position the electrode system and increases the accuracy of measuring muscle tissue activity.
As further background, it is helpful to understand basic muscle physiology. When a muscle is activated during muscle testing, the muscle has "locked" because the level of neurological information flow between the muscle and the central nervous system is sufficient to maintain muscle contraction in opposition to the dynamic pressure applied. If the muscle is unable to withstand the applied pressure during muscle monitoring, the muscle "unlocks" because of insufficient neurological flow between the muscle and the central nervous system, or overt inhibition. During the muscle testing, the muscle is typically monitored in terms of the feedback to and from the muscle to check the integrity of the neurological flow between the muscle sensors (spindle cells and Golgi tendon organs) and the central nervous system. Muscle strength is defined in terms of the number and size of muscle fibers in a muscle, and the resulting force depends on alpha motor neurons, which activate the muscle fibers. Inputs from the alpha motor neurons can be excitatory or inhibitory and can come from sensory organs (e.g., the muscle spindle or Golgi Tendon Organ, or from supraspinal areas of the cerebral cortex, cerebellum, or brainstem or reflexe). Muscle strength can be measured by the weight that can be lifted by that muscle or force that can be exerted by the muscle (e.g. as measured on a dynamometer). A "strong" muscle is one that when "locked" can hold against a large weight, while a "weaker" muscle is "over powered" by the same weight even when all muscle fibers are "locked". Thus, the "weaker" muscle can still "lock", that is, maintain sufficient neurological flow to hold against all pressures up to that which over powers it. An "unlocked" muscle, however, cannot maintain sufficient neurological flow to hold its position even at pressures far below that which are needed to overpower it. When the muscle is inhibited, too few muscle fibers can contract to equal the pressure applied and thus the appendage containing the muscle being tested will begin to move in the direction of pressure. This failure of the muscle is not caused by the muscle being "weak" but rather, is caused by the muscle experiencing poor functioning by problems associated with the inputs to the muscle from some other part of the nervous system.
All muscles in the body with few exceptions (the diaphragm being one) are arranged in antagonistic pairs of muscles. This arrangement of muscles can be referred to as reciprocal facilitation/inhibition, because whenever one of the pair is facilitated or turned on, its antagonist (or antagonists as there may be several) is automatically inhibited or turned off. Hence, the turning on or "locking" and turning off or "unlocking" are both normal states of muscle function. When a muscle "locks" during muscle monitoring, neurologically, signals are sent to the "prime mover" (PM) to hold the position of the body part by consciously facilitating (turning on) the PM. Then as the pressure on the body part (e.g. an arm held horizontal) is increased during muscle monitoring the muscle sensors (spindle cells) in the PM respond by a spinal reflex arc referred to as the "load reflex". The load reflex increases the degree of PM contraction, while at the same time inhibiting their antagonists and facilitating their synergists. Synergists are muscles that help the PM in holding the arm up, but are not in their position of optimal mechanical advantage. Synergists contribute much less than the PM to establishing and maintaining this position. A muscle circuit can be defined as the PM and all other muscles, both synergists and antagonists, to which it is "wired" both at the level of the brain and spinal reflex arcs.
FIG. 1 provides an example of a simplified muscle circuit. More specifically with respect to a muscle circuit, each muscle in the body has antagonists (usually more than one) that oppose its action. The agonist or PM and its antagonist(s) are neurologically wired together via the spindle cells in the belly of these muscles. This neurological wiring is such that when a PM is facilitated (turned on) it sends signals to automatically inhibit (turn off) its antagonist(s) to the same degree it has been facilitated. At the same time, if the load is sufficiently large it facilitates its synergists. In this way, the limb moves in the direction of contraction, unopposed by its antagonist(s), permitting smooth and rapid movement of the limb. Likewise, facilitation of an antagonist will inhibit the PM, as the spindle cells of the antagonist(s) need to inhibit the PM in order to move the limb in the opposite direction from the action of the PM. Referring to FIG. 1, it illustrates a muscle circuit consisting of an agonist or prime mover (biceps), one antagonist (triceps) and one synergist (brachioradialis). The spindle cell of the PM is wired to both its antagonist, which it inhibits, and its synergist, which it facilitates. Not shown is the reciprocal spindle cell circuitry for the antagonist, the triceps. When the triceps is facilitated, spindle cells in the belly of the triceps send signals to inhibit the biceps and its synergists the brachioradialis.
During a series of muscle contractions and relaxations, information on this series of activity is also sent to subconscious parts of the brain, e.g. the basal ganglia and thalamus which control "pre-recorded" muscle programs, and the cerebellum where comparisons are made of intended actions and actual actions. If an intended action is to keep the arm held at horizontal, but the arm moves downward due to the increasing pressure of a dynamic load, the subconscious brain centers augment the automatic spinal load reflex and orders additional contraction of the PM to offset movement, thereby helping the arm to remain horizontal. As long as the flow of information from muscle sensors to and from the brain remains "clear" with no interruptions, the muscle can "lock" and maintain its "lock" under continued loading until the muscle reaches its full power of contraction. If loading continues above this point, the arm will move down as the PM is overpowered by the downward pressure of the dynamic load.
During muscle testing, the pressure applied is far less force than needed to overpower the PM. A muscle with full neurological integrity should therefore "lock" during muscle monitoring. That is, unless something interferes with the neurological flow of information between the muscle and the central nervous system, the muscle should be facilitated sufficiently to maintain its physical position even under increasing load. This capability of the muscle to "lock" indicates a muscle that can be considered in "balance" with its neurological circuitry. If there is interference or a disruption in the flow of information between a muscle and the central nervous system, the muscle will not be able to coordinate and match its degree of facilitation to the increasing loading taking place during muscle testing/monitoring. Accordingly, the arm will move downward appearing to fail under the monitoring pressure, resulting in the "unlocked" muscle state. A muscle that becomes unlocked such as by inhibited feedback from muscle spindle cells, tendon and joint sensors or inhibitory feedback from subconscious emotional brain centers, can be described as being "under-facilitated" relative to the pressure being applied. This unlocking of the muscle may be observed simply as the muscle being weak (i.e. failing under the monitoring pressure). However, the muscle is not weak, but rather inhibited or under-facilitated to resist the monitoring pressure.
As additional background, muscle function is controlled by a number of different sensors in the muscles themselves, their tendons and the ligaments of the joints among others. Together these sensors that sense position, length, and tension of muscles are called "proprioceptors". There are several types of proprioceptors that provide the central nervous system (CNS) with feedback with regard to what is happening in the muscles, body position and equilibrium. The feedback from these sensors, which are actually specialized nerve endings, goes entirely to the spinal column and subconscious parts of the brain, e.g. spinal segments, brainstem, basal ganglia, thalamus, cerebellum, etc. This provides the body with information on the state of muscle contraction, muscle and tendon tension, position and activity of joints and equilibrium. When stimulated, many of these proprioceptors adapt quickly and provide information on instantaneous change and rate of change in muscle activity and body position. Others adapt only slowly to stimulation and therefore provide steady-state information about muscle and body position. Working together they provide the information necessary for coordinated muscle action and movement and the maintenance of posture.
For muscle to function properly, they require a number of different nutrients, including vitamins, minerals, and trace elements in sufficient concentrations to maintain the required energy production for muscle function. Muscle tissue also requires a variety of amino acids for structural integrity and repair, and to provide energy for proper muscle function. When any of the components of this nutritional matrix is deficient, it may reduce the effectiveness of muscle function. Additionally, the proper ratios and concentrations of the nutrients within this matrix are necessary for maintenance of on-going muscle function. One of the problems of aging is a decrease in the effectiveness with which the body both assimilates and utilizes nutrients and thus muscle function is often affected by these nutrient imbalances due to these natural processes.
While there may be a tremendous amount of information available regarding traditional techniques and therapies for improving muscle function, the great majority of this information relates to electrical or chemical methods of treatment. Muscle stimulation by NMES has proven to provide certain benefits. Providing a patient with an improved diet and/or supplementation of vitamins, minerals, and other nutrients that were shown to be lacking has also proven to provide certain benefits.
However, nutritional supplementation, stimulation and exercise alone are often not enough to strengthen "weak" muscles due to inhibition of the muscle via muscle spindle cell, Golgi tendon organ and Golgi ligament organ receptors whose job it is to "protect" the structural integrity of the muscle and its related tendons and ligaments should tension on the muscle exceed a threshold level. Often injury or even simply slipping or an unusual activity can "unset" this threshold for inhibition such that the Spindle cell, Golgi tendon organ or Golgi ligament organ receptors now inhibit the muscle action long before there is any likelihood of damage to the muscle, tendon or ligament. Thus, when the person now tries to use this muscle it appears "weak" as it just cannot develop much power.
A muscle in this "inhibited" state responds very poorly to normal rehabilitation even using the electrical stimulating devices because according to Wolf's Law in physiology, in order to build more strength, and muscle must develop more tension. This is because tension is the signal for the muscle to make more muscle fibers, which is what increases its strength. If, however, the muscle is inhibited at a specific level of tension (even one that does not approach tension that would be harmful) by the "unset" Spindle cell, Golgi tendon or Golgi ligament organ receptors, this inhibition prevents the development of further tension, and thus the muscle is not given the signal to make more muscle fibers. Muscles inhibited in this way, even when exercised regularly can never get stronger, and thus present as chronic muscle problems. Until the "unset" receptors are "reset", this problem will persist.
Thus, traditional techniques and therapies for improving muscle function still may not provide optimal results for many patients that have certain imbalances or maladies manifesting in poor muscle function. Therefore, there is still a need to provide an alternative form of treatment and therapy for muscle tissue that does not rely upon traditional techniques/therapies.


A vehicle cargo area lighting system includes, among other things, a cover assembly and at least one cargo area light. The cover assembly is movable back and forth between a closed position and an open position. The cover assembly covers a cargo area of a vehicle when the cover assembly is in the closed position. The cover assembly has a top portion and a wall portion. The wall portion extends vertically downward from the top portion when the cover assembly is in the closed position. The cargo area light is secured to an interior side of the wall portion. The cargo area light is configured to illuminate the cargo area when the cover assembly is in the open position.

Many electrified vehicles do not include an internal combustion engine. These electrified vehicles can include a front storage compartment, which is also known as a front trunk or "frunk." Because there is no need to package an internal combustion engine at a front of the vehicle, this area is available to hold cargo.

Vehicle cargo area lighting system and cargo area lighting method


An electric strike having a keeper arranged to pivot about a shaft extending in a longitudinal direction, a lock lever for locking the keeper in a door-locking position, the lock lever being arranged to pivot about a second shaft extending in a direction that is transverse to the longitudinal direction and parallel to the backside of the strike; and an actuation mechanism for actuating the lock lever. The strike is provided with a bearing element arranged to bear against the lock lever. The bearing element acts as a stop against possible lateral motions of the lock lever. Such motions may be induced by trying to force open the door lock when the lock lever is in the locking position. By providing the bearing element, it is avoided that the forces due to these lateral motions are exerted onto the second shaft that connects the lock lever to the strike.

Strikes are generally used in conjunction with a door to selectively retain the door in a closed position. In some instances, the strike is electric, enabling the electric release of a locked mechanism. An electric strike typically has a latch bolt holding mechanism that comprises one keeper that forms a side wall of the latch bolt cavity. The lock lever is arranged horizontally above the keeper. The electromagnet is located on top of the keeper, between the keeper and the lock lever. A compression spring is provided to urge the lock lever away from the electromagnet into the door-releasing position to unlock the keeper. A torsion spring is provided to urge the keeper into its door-locking position. When the lock lever is in its releasing position, opening the closure member urges the latch bolt against the keeper thereby pivoting the keeper, against the force of the torsion spring, to enable the latch bolt to exit the latch bolt cavity. To lock the keeper, the electromagnet is energized thereby pulling the lock lever, against the force of the compression spring, towards the keeper. A protrusion on the lock lever then engages an opening in the keeper thereby preventing a pivoting motion of the keeper.
In conventional strikes, when the lock lever is in its locking position and the keeper is in its door-locking position, someone may try to force the door open. In such a case, the latch bolt will be urged against the keeper to try to pivot the keeper. This force will be transmitted to the lock lever, as this is locked with its protrusion in a hole in the keeper. The force on the lock lever is a pulling force that tries to pull the lock lever away from its pivot axis, e.g., away from its axle.
Another example of a conventional strike includes a lock lever with a protrusion that locks into the keeper. When the lock lever is in its locking position and the keeper is in its door-locking position, someone may try to force the door open. In such a case, the latch bolt will be urged against the keeper to try to pivot the keeper. This force will be transmitted to the lock lever, as this is locked with its protrusion in the keeper. The force on the lock lever is again a pulling force that tries to pull the lock lever away from its pivot axis, e.g., away from its axle. Furthermore, in this strike, the axle is formed by two separate pins and not by a continuous axle.
A downside of some conventional strikes is that, when someone tries to force open the door, the forces associated therewith all have to be borne by the axle used to fix the lock lever to the strike frame. Due to the fact that relatively large forces may be exerted onto the axle, the axle should be arranged so that the lock lever only exerts pulling forces onto the axle. As this axle is a small element, when compared to the rest of the strike, it may be damaged due to excessive forces which might be exerted thereon for example when the lock lever would be forced in a direction parallel to the axle. Due to the required orientation of the axle, the design freedom of the strike is limited.
Another example of a conventional strike includes a keeper arranged to cooperate with a latch bolt of a door lock. The lock lever is formed as a pivotable locking bar having a flat surface that contacts against a flat surface of the keeper. When the lock lever is released, opening the door pushes the latch bolt against the keeper thereby pivoting the keeper from the door-locking to the door-releasing position. The pivoting motion of the keeper also pivots the released locking bar to its unlocking position. Two springs are provided to return the keeper and the locking bar back to their initial position, e.g., a first spring is used to return the keeper to its door-locking position and a second spring is used to return the locking bar to its locking position. To unlock the keeper, two electromagnets are provided that can each displace an anchor element. The anchor elements retain the locking bar in the locking position. Specifically, when both electromagnets are not energized, the anchor elements engage with the locking bar thereby preventing the locking bar, and thus the keeper, from pivoting. When the electromagnets are energized, the anchor elements are rotated by the electromagnets until they do not engage with the locking bar thereby enabling the locking bar, and thus the keeper, to pivot to release the latch bolt.
A drawback of some conventional electric strikes is that, when the locking bar is locked by the anchor elements, the opening force of the door is transmitted to the anchor elements, which are small when compared to the strike. As such, when a large force is exerted on the door, e.g. when a person tries to force the door open, this large force is exerted onto the small anchor elements which may be damaged due to the excessive pressures resulting in a defective strike.


Two circuits, an original and a modified, are being recognized, with the original circuit having a first logic and the modified circuit having a second logic. The second logic contains at least one desired logic change relative to the first logic. An equivalence line is detected in the original circuit such that the first and second logic are equivalent from the circuit inputs to the equivalence line. At least one point of change is located amongst the logic gates that are neighboring the equivalence line. The points of change are accepted as verified if an observability condition is fulfilled. The observability condition is checked within a Boolean Satisfiability (SAT) formulation. Substitute logic for the verified points of change is derived using SAT and Boolean equation solving techniques, in such manner that the first logic becomes equivalent to the second logic.

The present invention relates to integrated circuit (IC) design. In particular, it relates to making logic changes in an already implemented circuit, which logic changes in some sense are small.
It is known that in existing design flows, even a small change in the specification, such as would be usual for an engineering change order (ECO), can lead to large changes in the implementation. There is a need for computer-aided design (CAD) methodologies to handle relatively minor logic changes specified for an existing circuit, without restarting the entire logic synthesis process.

International Business Machines Corporation


A combined roof spraying and seaming assembly that is easy, safe, and efficient to operate. The assembly is able to provide consistent coating thickness to the surface of a roof, while being able to fully coat all surfaces on the roof. The assembly can readily seam various types of roof surface conditions, such as those having channeled, corrugated, and/or ribbed surfaces.

Roofs, particularly metal roofs, need to be regularly maintained in order to prevent leaks, cracks, and deterioration. Some of the regular maintenance includes painting/coating of the roof. Commonly used methods for painting roofs include manually applying paint through brushes, sprayers, and the like. However, these techniques are slow and labor intensive, requiring a number of individuals to be on the roof at the same time. In addition to being inefficient, these techniques present increased safety risks to the individuals on the roof.
Commonly used spraying/coating methods and assemblies often result in inconsistent coating of the roof. Many of these assemblies do not allow the spraying tips to be readily adjusted or controlled. As a result, these assemblies need to be continuously adjusted and rearranged. These assemblies still fail to coat certain areas on a roof, such as channeled, corrugated, or ribbed surfaces.
Consequently, there is a need for a combined roof spraying and seaming assembly that is easy, safe, and efficient to operate, provides consistent coating thickness to the surface of the roof, and that is able to fully coat all surfaces on the roof.


An operation input device includes a base part including a placement surface on which an inductor is placed; a displacement member including a first surface facing the placement surface and a second surface configured to receive application of a force, and configured to cause the inductance of the inductor to vary with the approach of the first surface to the placement surface due to the application of the force on the second surface; a support member configured to support the displacement member in such a manner as to allow the displacement of the displacement member; a detection part configured to detect a variation in the inductance by feeding a first pulse signal to the inductor; and a control part configured to generate a magnetic field to displace the second surface by feeding a second pulse signal different in phase from the first pulse signal to the inductor.

1. Field of the Invention
The present invention relates generally to operation input devices that receive an operator's input and methods of controlling the same, and more particularly to an operation input device configured to provide an operator with vibrations and a method of controlling the same.
2. Description of the Related Art
Conventionally, an input device is known that detects an input position and a pressure at the time of pressing with an operator's finger using a resistive touchscreen panel and provides the touchscreen panel with vibrations. (See, for example, Japanese Laid-Open Patent Application No. 2005-275632.) This input device detects the input position and the pressure with a voltage measuring circuit while providing a user with vibrations using a vibrating motor.

Operation input device and method of controlling same


This invention relates to methods of inhibiting a Cav3 calcium channel in a cell using a C2-C10 alkyl alcohol, or mixtures thereof. This invention further relates to methods of treating a thalamocortical dysrhythmia disorder in a mammal and for treating a neurological disorder in a mammal associated with the thalamocortical dysrhythmia using a C2-C10 alkyl alcohol, a lipophilic molecule with a partition coefficient substantially similar to that of a C2-C10 alkyl alcohol, or mixtures thereof, or a pharmaceutical composition comprising the same.

Neurological disorders that affect the central nervous system, the peripheral nervous system, and the autonomic nervous system strick millions of people worldwide. These varied disorders include, but are not limited to, thalamocortical dysrhythma, neurogenic pain, obsessive-compulsive disorder, depression, panic disorder, Parkinson's disease, schizophrenia, rigidity, dystonia, tinnitus, tremor, and epilepsy. In particular, these and other neurological disorders occur when the coordinate, controlled electrical activity at the cortical level of the brain becomes disrupted, thereby leading to uncoordinated electrical activity and abnormal neuronal oscillation.
In particular, thalamocortical dysrhythmia refers to a neurological and/or psychiatric condition arising from the abnormal rhythmicity in particular components of the thalamocortical circuit Winds et al. (1999) Proc. Natl. Acad. Sci. USA, 96:15222-15227). At the cellular level, the abnormal activity of the thalamic neurons is caused by an increase of low frequency oscillatory activity due to protracted activation of the T type calcium channels because of direct modification of the channel properties or more commonly, abnormal hyperpolarization of the thalamic neurons due to excess inhibition or deafferentation. Such abnormal activity is transmitted to the related cortical area to which the given thalamic neurons are oscillating generating a recurrent attractor that is maintained by the recursive nature of the circuit. At the macrocellular level, the abnormal rhythmicity interferes with the communication among and between different regions of the brain, and thereby impairs the motor and cognitive skills that are controlled by those regions of the cortex.
Spike output in neuronal cell types is affected by low-voltage-activated Cav3-type calcium currents arising from the Cav channels. Low-voltage-activated (LVA) calcium currents provide an important contribution to spike output patterns of neurons. Cav3-type channels are recognized as key determinants of LVA calcium-dependent responses, including low-threshold calcium spikes (LTS), bistable behavior, rebound depolarizations and augmentation of synaptic responses. Cav3-type channels are important to cell and circuit functions that range from sensory and pain transmission through thalamocortical sleep-wake cycles. The three isoforms of the Cav3-type calcium channel, i.e., Cav3.1, Cav3.2, and Cav3.3, can differ in their voltage-dependent and kinetic properties, demonstrating the potential to differentially affect spike output. In thalamus, differences in the distribution and kinetic properties of Cav3-type currents have been shown to be capable of influencing the nature of oscillatory output of principal cells and inhibitory interneurons involved in the sleep-wake cycle, suggesting a selective distribution or modulation of Cav3 channel isoforms over discrete regions of the cell axis.
There are many drugs currently available for treating neurological disorders. These include, but are not limited to, anticonvulsants, antiepileptics, barbiturates, barbituric acid derivatives, anesthetic agents, tinnitus-treating agents, selective serotonin reuptake inhibitors, antidepressant agents, neuroleptic agents, antihypertensive agents, antipsychotic agents, calcium channel blockers, ACE inhibitors, and beta-blockers. However, many of such drugs are limited in their effectiveness and by their significant side effects. For example, some of these drugs are known to cause lightheadedness, depression insomnia, weakness, fatigue, hallucinations, side-effects which severely limit their use in human population. In particular, beta blockers, anticonvulsants, and benzodiazepines have been shown to be partially beneficial to some patients. However, beta blockers can cause changes in blood pressure and heart rate, and are contraindicated in patients with heart block, asthma, and congestive heart failure.
In addition, some anticonvulsants can cause acute nausea and vomiting, fatigue, sleepiness, confusion and incoordination, while others can cause memory and speech abnormalities, sedation, incoordination, and metabolic dysfunction.
Physical trauma has been used to treat some neurological disorders. For example, certain surgical procedures have been used in the most severe cases of essential tremor, destroying a part of the brain including, the globus pallidus pars interna (GPi) nucleus in the basal ganglia or implanting electrodes into the same area of the brain including connecting them to a pacemaker-like battery that stimulates regions of the brain to diminish the tremor. Such procedures carry a high risk of infection and bleeding or equipment malfunction. Additionally, many existing treatments for some neurological disorders are poorly effective in that they do not stop the disorders completely, and in most instances, they do not prevent or even delay the progression of the disease.
Thus, there is a need for more effective treatments of neurological disorders that have reduced or no side-effects.

Methods and compositions for treating thalamocortical dysrhythmia


In a fuel supply apparatus for vehicles, a fuel pump is supported in a sub tank through cushioning members. Each cushioning member includes a plurality of resilient parts having a wavy shape in cross section in a radial direction and a plate width in an axial direction. The resilient parts thus support the fuel pump resiliently to absorb vibrations of the fuel pump caused in the radial direction, while withstanding the weight of the fuel pump and the reaction force generated upon fuel discharge operation of the fuel pump. The cushioning members are resin-molded unitarily with an inlet-side cover and an outlet-side cover which are fitted in the axial side ends of the fuel pump. The cushioning members have respective engagement parts which are fitted with the sub tank. The sub tank has stoppers which restrict the fuel pump from moving in the axial direction under a condition that the fuel pump is assembled with the sub tank.

The present invention relates to a structure for supporting a rotary device for a fuel supply apparatus.
A fuel pump for supplying an internal combustion engine with fuel is installed within a fuel tank of a vehicle or a sub tank accommodated within the fuel tank. The fuel pump comprises a mechanical pump unit and an electromagnetic drive unit (electric motor) for driving the pump unit. The fuel pump is supported in various ways within the sub tank or the fuel tank. For instance, it is supported in such a manner that its axis extends vertically, inclinedly or horizontally.
The electric motor generates vibrations during its rotation, and its first-order and higher-order components of the frequency of rotation cause vibrations of the sub tank or the side walls or bottom wall of a casing, thus generating noise sounds. Therefore, a rubber cushion member made of an oil-resistive rubber material is interposed between the outer peripheral surface of the fuel pump and the bottom wall of the casing. The rubber cushioning member must be rigid or high density-type to some extent to maintain its shape against the weight of the fuel pump and the reaction force of the same generated in response to the fuel discharge operation. As a result, the vibrations cannot be reduced sufficiently.
It is proposed to support the fuel pump from the side wall of the sub tank or the casing while interposing the rubber cushioning member between the outer peripheral surface of the fuel pump and the bottom wall. The side wall of the sub tank or the casing vibrates largely in a direction perpendicular to the side walls, because the vibration absorbing performance of the rubber cushioning member is limited due to its rigid or high density-type construction. Further, the assembling work for fixing the fuel pump to the side wall through the rubber cushioning member is complicated, because the rubber cushioning member must be fixed to both of the fuel pump and the side wall.

Rotary device support structure for fuel supply apparatus


An ophthalmic solution, which comprises diquafosol tetrasodium salt and is free from benzalkonium chloride, treats onset and/or exacerbation of dry eye symptom caused by wearing soft contact lenses.

Although dry eye is a disease that initially exhibits merely unpleasant symptoms such as dryness of the eyes or eyes that feel sandy or gritty, as the condition worsens, it causes considerable difficulties during the course of daily life. The number of the dry eye patients is increasing year by year with advent of an aging society and the increase in video display terminal (VDT) work such as personal computers, the estimated number of patients in the United States is over 10 million people, and in Japan, it is said to be more than 8 million people.
Although the pathology of dry eye is not completely clear, it is thought that the main cause is the decrease of lacrimal secretion and the increase of lacrimal evaporation accompanied by the decrease of the stability of the tear film. That is, these cause pathological symptom and/or findings such as eye discomfort, eye dryness, eye fatigue, hyperemia, keratoconjunctival epithelial disorders and the like. If these pathological symptoms and/or findings progress, vision abnormalities are ultimately generated, so that it is extremely important to treat the dry eye at an early stage and properly.
Wearing a soft contact lens leads to decrease in the stability of the tear film, so wearing soft contact lenses for dry eye patients may lead to exacerbation of dry eye symptoms. In addition, dry eye also may develop by wearing soft contact lenses. However, even with such a dry eye patient, there are cases where it is not desired to stop wearing soft contact lenses from the viewpoint of convenience.
On the other hand, in Japan, there are no widely recognized pharmaceuticals for treating onset and/or exacerbation of dry eye symptom caused by wearing soft contact lenses. Rather, in Japan, with regard to "DIQUAS® ophthalmic solution 3%", "Hyalein® ophthalmic solution 0.1%" and "Hyalein® ophthalmic solution 0.3%" which have widely been used for dry eye patients, the use themselves for soft contact lens wearers is contraindicated.
By the way, the above-mentioned "DIQUAS® ophthalmic solution 3%" contains diquafosol tetrasodium salt at a concentration of 3% (w/v) as an active ingredient, and further contains benzalkonium chloride as a preservative. Diquafosol is a purinergic receptor agonist also called as P1,P4-di(uridine-5′) tetraphosphate or Up4U, and it has been known to have a lacrimation-promoting function as disclosed in Patent Document 1. However, it has not been known what effect diquafosol has on the onset and/or exacerbation of dry eye symptom caused by wearing soft contact lenses.

Therapeutic agent for dry eye characterized by being applied to eye of dry eye patient wearing soft contact lens


The present invention is directed to a method for improving the performance of an electrophoretic display, which method comprises adding a fluorinated quaternary nitrogen salt in either the internal phase or the continuous phase in a microencapsulation process for the formation of pigment-containing microparticles. One or more of the following materials may be further added to the internal phase or continuous phase in the microencapsulation process: a fluorinated protective colloid, a second charge controlling agent or a second monomer or oligomer.

1. Field of the Invention
This invention relates to a method for improving the performance of an electrophoretic display and a microparticle forming process for the preparation of an electrophoretic dispersion. The dispersion may be used in all types of electrophoretic displays including transmissive, reflective and transflective displays. It may also be used in an electrophoretic display having the traditional up/down switching mode, the in-plane switching mode, or the dual switching mode, and in the total internal reflection (TIR) type of electrophoretic displays.
2. Description of Related Art
The electrophoretic display (EPD) is a non-emissive device based on the electrophoresis phenomenon influencing charged pigment particles suspended in a colored dielectric solvent. This type of display was first proposed in 1969. An EPD typically comprises a pair of opposed, spaced-apart plate-like electrodes, with spacers predetermining a certain distance between the electrodes. At least one of the electrodes, typically on the viewing side, is transparent. For the passive type of EPDs, row and column electrodes on the top (the viewing side) and bottom plates respectively, are needed to drive the displays. In contrast, an array of thin film transistors (TFTs) on the bottom plate and a common, non-patterned transparent conductor plate on the top viewing substrate are required for the active type EPDs. An electrophoretic dispersion composed of a colored dielectric solvent with charged pigment particles dispersed therein is enclosed between the two plates.
When a voltage difference is imposed between the two plates, the pigment particles migrate by attraction to the plate of polarity opposite that of the pigment particles. Thus, the color showing at the transparent plate, determined by selectively charging the plates, can be either the color of the solvent or the color of the pigment particles. Reversal of plate polarity will cause the particles to migrate back to the opposite plate, thereby reversing the color. Intermediate color density (or shades of gray) due to intermediate pigment density at the transparent plate may be obtained by controlling the plate charge through a range of voltages.
EPDs of different pixel or cell structures have been reported previously, for example, the partition-type EPD (M. A. Hopper and V. Novotny, IEEE Trans. Electr. Dev., 26(8):1148–1152 (1979)), the microencapsulated EPD (U.S. Pat. Nos. 5,961,804 and 5,930,026) and the total internal reflection (TIR) type of EPD using microprisms or microgrooves as disclosed in M. A. Mossman, et al, SID 01 Digest pp. 1054 (2001); SID IDRC proceedings, pp. 311 (2000); and SID′02 Digest, pp. 522 (2002).
An improved EPD technology was recently disclosed in U.S. application Ser. No. 09/518,488 (WO 01/67170), Ser. No. 09/606,654 (WO 02/01281), Ser. No. 09/784,972 (US Published Application No. 2002/0182544, WO 02/65215). The improved EPD comprises isolated cells formed from microcups of well-defined shape, size and aspect ratio and filled with charged pigment particles dispersed in a dielectric solvent, preferably a fluorinated solvent or solvent mixture. The filled cells are individually top-sealed with a polymeric sealing layer, preferably formed from a composition comprising a material selected from a group consisting of thermoplastics, thermosets and precursors thereof.
The microcup EPDs may have the traditional up/down switching mode, the in-plane switching mode or the dual switching mode. In the display having the traditional up/down switching mode or the dual switching mode, there are a top transparent electrode plate, a bottom electrode plate and a plurality of isolated cells enclosed between the two electrode plates. In the display having the in-plane switching mode, the cells are sandwiched between an insulator layer and an electrode plate.
For all types of the EPDs, the dispersion contained within the individual cells of the display is undoubtedly one of the most crucial parts of the device. The dispersion, as stated earlier, usually is composed of pigment particles dispersed in a dielectric solvent. The composition of the dispersion determines, to a large extent, the lifetime, contrast ratio, switching rate, response waveform and bistability of the device. In an ideal dispersion, the pigment particles remain separate and do not agglomerate or stick to the electrodes under all operating conditions. Furthermore, all components in the dispersion must be chemically stable and compatible not only with each other but also with the other materials present in an EPD, such as the electrodes and sealing materials.
The pigment particles in the dispersion may exhibit a native charge, or may acquire a charge when suspended in the dielectric solvent or may be charged using a charge controlling agent (CCA).
Halogenated solvents of high specific gravity have been widely used in EPD applications particularly in those involving an inorganic pigment, such as TiO2, as the charged white or colored particles. The halogenated solvents of high specific gravity are very useful in reducing the rate of sedimentation of the pigment particles in the solvent. Fluorinated solvents are among the most preferred because they are chemically stable and environmentally friendly. However, most CCAs and dispersants suitable for use in hydrocarbon solvents are not effective for dispersions in fluorinated solvents, particularly high boiling-point perfluorinated solvents. This could be due to poor solubility or charge separation of the CCAs in these solvents. As a result, pigment particles are very difficult to disperse in perfluorinated solvents. Therefore, EPDs based on perfluorinated dielectric solvents typically show poor stability and switching performance.
To improve the stability and display performance of EPDs based on fluorinated solvents, an electrophoretic dispersion comprising 22.5 to 44.25% by weight of a hydrocarbon solvent, 54.42–75.20% by weight of at least one chlorine-free fluorinated solvent and 0.1 to 1.5% by weight of a fluorinated surfactant, was disclosed in U.S. Pat. No. 5,573,711. The presence of a hydrocarbon solvent such as phenylxylylethane, phenyloctane, decahydronaphthalene or xylene was claimed to result in a stronger solvent system that gives a better display performance. However, the use of a hydrocarbon solvent in any significant amount is undesirable because it lowers the specific gravity of the solvent and, as a result, increases the sedimentation rate of the pigment particles particularly when a pigment of high specific gravity, such as TiO2, is used.
The whole content of each document referred to in this application is incorporated by reference into this application in its entirety.

Microencapsulation processes and compositions for electrophoretic displays