A preparation based on plant extracts, with an antioxidant action which is particularly useful in the treatment of circulation and chronic degenerative problems and in the treatment of hypertension, characterized in that its active ingredients comprise Ginkgo biloba biflavones, catechin and/or epicatechin, cumarin and derivatives thereof and a component selected from among madecassic acid, asiatic acid, asiaticoside or combinations thereof.

This Application is a 371 of PCT/EP00/08876 filed Sep. 8, 2000 which claims foreign priority to Application number 1663/99 filed in Switzerland on Sep. 10, 1999.
The present invention relates to a preparation based on plant extracts which has an antioxidant effect and is particularly useful in the prevention and treatment of circulation and chronic-degenerative problems, and in the prevention and treatment of hypertension.
This object is achieved according to the invention by providing a preparation characterised in that its active ingredients include a combination of Ginkgo biloba biflavones, catechin and/or epicatechin, cumarin and derivatives thereof, and an ingredient chosen from asiaticoside, asiatic acid, madecassic acid and compounds thereof.
This object is achieved according to the invention by providing a preparation characterised in that its active ingredients include a combination of Ginkgo biloba biflavones, catechine and/or epicatechine, cumarine and derivatives thereof, and an ingredient chosen from asiaticoside, asiatic acid, madecassic acid and compounds thereof.
The preparation is obtained by mixing plant extracts which contain the above active principles.
It is known that extracts from the leaves of Ginkgo biloba contain important active principles and in particular flavonol glucosides, lactonic terpenes and dimeric biflavones or flavones. The flavonol glucosides and the lactonic terpenes constitute the active components of standardized Ginkgo biloba extracts currently available on the market and are, respectively, powerful antibxidants and stimulants of nitric oxide and of effective platelet aggregating factor (PAF) antagonists. Thanks to the combined action of the active principles they contain, standard Ginkgo biloba extracts have proved to have a powerful vaso-motor effect, able to improve both central and peripheral blood flow. However, these extracts do not contain the biflavone component which is not extracted during normal processing. The Ginkgo biloba extract used in preparations according to the present invention is highly enriched with the biflavone component and, as a possible option, with extracts containing flavonol glucosides and lactonic terpenes. Five biflavones in particular have been identified in the biflavone component of Ginkgo biloba: these are, in particular, amentoflavone, bilobetine, isoginkgetine, ginkgetine and sciadopisitine; the five said compounds differ only by the presence of methyl compounds in some positions and, like all flavones, are powerful antioxidants. However, from a pharmacological point of view, they are characterised by their anti-phosphodiesterase, anti-inflammatory, vasculokinetic and anti-allergy properties. Phosphodiesterases (PDE) are cell enzymes responsible for interacting with cyclic nucleotides so as to linearize them. Cyclic nucleotides are involved as second messengers in transmitting intercellular signals and are thus responsible for some phenomena which are very important from a biochemical point of view. They assist with the visual process and in the relaxation of smooth muscles, they stimulate lipolysis in adiposity and vasculo-motion in capillary arterioles. More specifically, it is sufficient to report that in inhibiting PDE depending on cyclic AMP, these biflavones demonstrate an IC50 of 1.2 micromoles.
The anti-inflammatory properties of biflavones, and in particular those of amenthoflavone, have been demonstrated both in vitro, by measuring the interaction of these biflavones with cyclo-oxygenase, lipo-oxygenase e phospholipase A2, and in vivo, using various models of inflammation in animals (carragineen oedema, Croton oil inflammation etc). The anti-inflammatory action of biflavones was confirmed both in models using local application and in those in which they were administered intraperitoneally. In these models, the biflavones always demonstrated an anti-inflammatory action equivalent to that of indomethacyn or prednisolone. This effectiveness can be explained by analizing the IC50 of cyclo-oxygenase inhibition, which is 3 micromoles for amentoflavone.
With regard to the microvascularkinetic activity of biflavones, it should be reported that, following acute treatment, these substances improve the size of the arterial sphygma wave and, following chronic treatment they improve capillary density in tissues with trophic-connective problems, such as those affected by panniculopathy and/or various degrees of sclerodermy. Biflavones also have clear anti-allergy properties; they inhibit the release of histamine by mast-cells stimulated by allergens: thereby reducing or countering the formation of oedemas resulting from vasodilation and increases in vascular permeability.
In the context of the invention it is convenient to use an extract of leucocyanidine or leucoanthocyanin derived from Vitis vinifera as the source of catechin or epicatechin. Leucoanthocyanins are procyanidolic oligomers derived from condensing monomeric units of flavan-3-ols and flavan-3,4-diols, these being either free or esterified with gallic acid; leucoanthocyanines are powerful antioxidants. They are able to protect the endothelial wall of vessels and the extra-cellular matrix surrounding capillary wail""s, as well as having anti-atherosclerotic properties owing to their antioxidant action on low-density lipoproteins (LDL) in blood.
The extracts are preferably used in a phytosomal form, in which the active components are complexed with phospholipids.
In the context of the invention, it is convenient to use an extract of leucocyanidine or leucoanthocyanin derived from Vitis vinifera as the source of catechin or epicatechin. Leucoanthocyanins are procyanidolic oligomers derived from condensing monomeric units of flavan-3-ols and flavan-3,4-diols, these being either free or esterified with gallic acid; leucoanthocyanines are powerful antioxidants. They are able to protect the endothelial wall of vessels and the extra-cellular matrix surrounding capillary walls, as well as having anti-atherosclerotic properties owing to their antioxidant action on low-density lipoproteins (LDL) in blood.
These active principles have a good bio-availability even when administered orally and their tropism have been demonstrated for the cardiovascular system and for all tissues, such as artery walls, which are rich in glycoamminoglycene.
Preferably, phytosomal forms of extracts are used, thus further enhancing the bioavailability of the active principles. In this form the procyanidines are complexed with phospholipids, particularly with soya distearoylphosphatidyecholine.
The preferable source of cumarin cumarine is an extract of Meliotus officinea, cumarin and its derivatives being the main active principles thereof; the main active principles of this extract are melilotine (3,4 dihydro-cumarine), melilotic acid (hydroxycumarinic acid), melilotoside (melilotin glucoside) and some flavonoids which act like vitamin P; the active ingredients contained in the extract are particularly effective in increasing capillary strength, in reducing vascular permeability, in stimulating venous circulation and improving lymphatic circulation.
Extract of Melilotus may be replaced or backed up, as a source of cumarine and its derivatives, by an extract of Aesculus hippocastanum (horse chestnut) in the same dosage or up to around twice the dose of Melilotus extract.
The most abundant active ingredient of Aesculus hippocastanum extract, obtained from the bark, the pericarp of the fruit, the leaves or the buds, is cumarine glucoside, esculoside (6-0-glucosil-7-hydroxy-cumarine).
Other cumarins ctziari ies acontained in the extract are fraxine (8-0-glycoside-7-hydroxy-6-mehoxycumarin) and aglicone, esculetine (6,7-dioxy-cumarin) and fraxetine (7,8-dioxy-6-methoxy-cumarin).
The preferred source of asiaticoside, asiatic acid and madecassic acid is an extract containing a triterpene fraction of centella (Centella asiatica) which contains a combination of the above three active principles. The extract should preferably be used in a phytosomal form, obtained by a reaction between the triterpene fraction of the Centella asiatica with a phospholipid. A main action of the triterpene fraction of centella consists in accelerating the uptake and metabolism of lysine and of proline, thus increasing the synthesis and the release of tropocollagen and stimulating the turnover of acid mucopolysaccharides in connective tissue.
The basic composition of the invention can thus be obtained by mixing a Ginkgo biloba biflavone extract (perhaps in combination with a standard Ginkgo biloba extract also containing flavonol glucosides and lactonic terpenes), leucocyanidine extract, Melilotus officinalis extract and Centella extract; these extracts preferably being in a phytosomal form except for the Melilotus officinalis extract.
With reference to the extracts normally available on the market, the basic composition is preferably made up by the following percentages by weight:
2.5-40% Ginkgo biloba biflavone extract;
15-80% of leucocyanidine extract;
2.5-60%, preferably 2.5-30% of Melilotus officinalis and/or Aesculus hippocastanum extract;
2.5-40% of centella extract; possibly in combination with:
2.5-40% of standard Ginkgo biloba extract containing flavonol glucosides and lactonic terpenes. In terms of the content of active principles, the composition of the invention preferably contains the following percentages by weight:
0.2-14%, preferably 0.8-5% of total biflavones, expressed as ginkgetine content,
0.5-16%, preferably 1.5-6% of catechin and/or epicatechin, expressed as catechin content;
0.1-6%, preferably 0.4-2% of cumarin and its derivatives;
0.3-18%, preferably 0.9-6% of asiaticoside;
0.4-26%, preferably 1.4-9 % of asiatic acid and/or madecassic acid;
and possibly one or more of the following substances:
0.2-10%, preferably 0.6-4%, of flavonol glucosides and
up to 1.3-2%, preferably up to 0.5%, of ginkgolide lactonic terpenes (bilobalide).
The composition can also contain active ingredients chosen from gamma-linolenic acid, eicosapentaenoic acid (EPA), docohexaenoic acid (DHA), ruscogenin and/or neoruscogenin, flavinoids such as vitexine, hyoside, proanthocyanidine, epicatechin and crategolic acid and mixtures thereof.
Gamma-linolenic acid is preferably introduced into the preparation in borage oil, added in quantities of 50 to 180% by weight with reference to 100 parts of basic mixture.
The preferred source of eicosapentaenoic acid (EPA) and of docohexaenoic acid (DHA) is fish oil which, with reference to 100 parts of the basic composition, may be added in quantities of 25 to 120% by weight.
The preferred source of ruscogenin and/or neoruscogenin is an extract of Ruscus aculeatus (Butcher""s broom), this extract is preferably added in quantities of 5 to 50% by weight, with reference to 100 parts of the basic mixture.
The preferred source of flavonoids is an oily maceration of hawthorn Crataegus oxyacantha which, with reference to 100 parts of the basic mixture, can be added in quantities from 25 to 100% by weight.

Anti-oxidant preparation based on plant extracts for the treatment of circulation and adiposity problems


A welding assembly including a current generator, a first electrode electrically coupled to the current generator, the first electrode including a first engagement surface, a second electrode electrically coupled to the current generator, the second electrode including a second engagement surface, a width-determining fixture positioned between the first electrode and the second electrode to define a welding volume having a width, and an electrically nonconductive material positioned to electrically insulate at least one of the first electrode and the second electrode from an electrical conductor outside the width.

Stranded metals and metal alloys (e.g., stranded cables and wires) find a wide variety of applications. Particularly, stranded aluminum and aluminum alloys find a wide variety of applications due to their favorable combination of electrical conductivity properties and mechanical properties, including strength-to-weight ratio, low temperature (cryogenic) properties, corrosion resistance and notch toughness.
The challenge with stranded aluminum and aluminum alloys is joining (by welding) the stranded cables or wires to one another and/or to a connector. During a welding operation (e.g., resistive welding), individual strands of the cable or wire may not consistently liquefy to form a solid welded workpiece. For example, strands located proximate the periphery of the cable or wire may liquefy; while strands located proximate the center of the cable or wire may not liquefy sufficiently to form a suitably solid weld. In order to sufficiently liquefy strands proximate the center of the cable or wire, the strands located proximate the periphery of the cable or wire may tend to burn and the whole welded assembly may tend to stick to the weld electrodes.
Accordingly, those skilled in the art continue with research and development efforts in the field of welding stranded metals and metal alloys.

This patent is subject to a terminal disclaimer.


Method and system are disclosed for assigning a relative value to a search result based on the personal preferences of the consumer. A consumer profile may be created for each consumer. The profile may contain the consumer's personal preferences for each one of the search criteria. A search value index may be derived for the search results based on the preferences in the consumer profile. The search value index may indicate to the consumer the value of a particular search result relative to other search results. Search results satisfying a consumer defined threshold may be retained, while the rest may be discarded.

1. Field of the Invention
The present invention is related to the evaluation of information searches and, more particularly, to a method and system for assigning relative value to the results of such information searches.
2. History of the Related Art
A number of search options are available to help consumers find goods and services. For example, in the travel planning industry, a professional travel agent can help the consumer find available flights, hotel rooms, car rentals, and the like. Typically, the travel agent accesses one or more public or private reservation databases available from travel services providers (e.g., airlines, hotels, car rental agencies) to obtain several possible travel solutions that are presented to the consumer for evaluation. The consumer can also directly search for these services via a travel Web site that specializes in finding such services. In the latter case, the consumer simply provides information such as the origination, destination, and dates of his travel. A search engine associated with the Web site thereafter queries the appropriate databases to obtains several possible travel solutions that are presented to the consumer for evaluation.
The success of such consumer targeted Web sites has given rise to the development of specialty search engines that focus on finding certain types of information. For example, in the travel planning industry, Low Fare Search Engines (LFSE) have been developed that specialize in finding inexpensive fares. These LSFE produce multiple fare solutions by performing iterative searches of fare pricing databases and comparing the results with search results from fare availability databases. A number of constraints such as the application of certain fare validity rules and also data processing limitations combine to produce a subset of the total possible fare solutions. The solutions are then presented to the consumer in order of the lowest fares first.
Specialty search engines and search engines in general, however, can sometimes provide too many solutions for the consumer to thoroughly evaluate in a reasonable amount of time. Thus, some of the search results may initially appear unusable to the consumer based on his personal preferences, but may actually turn out to be very acceptable when properly evaluated, and vice versa. Referring to the travel planning industry again as an example, a travel solution requiring several connecting flights may be rejected at first glance by a traveler who prefers a non-stop trip. However, other aspects of the itinerary such as frequent flyer miles, a low fare, meals, movies, seating, and the like, may cause the traveler to reconsider when properly evaluated. On the other hand, some travel solutions may have aspects that are so out of line with the traveler's preferences that, a non-stop trip notwithstanding, they should not be included at all in order to save time. Therefore, it is desirable to be able to present the results of an information search in such a way that the consumer may quickly evaluate the search results in accordance with his preferences. More particularly, it is desirable to be able to assign a relative value to each one of the search results based on the preferences of the consumer in order to facilitate selection therefrom.
One method of listing the results of an information search is by the number of search criteria for which a match was found. Under this approach, search results in which every search criteria were found are listed ahead of search results in which less than all search criteria were found. The number of criteria found in a given search result is usually indicated using a percentage. For example, if a particular search found four out of five specified criteria, the result would be listed as an 80 percent match.
Another method of listing the results of an information search is by the number of "hits" or matches found for a particular criterion. This method is premised on the assumption that results containing a higher number of hits are more likely to be relevant or desirable. Under this approach, search results containing 10 hits of a particular criterion, for example, are listed ahead of search results containing fewer than 10 hits.
None of the aforementioned methods, however, provide a way to assign a relative value to a search result based on the personal preferences of the consumer.


A fastener driving apparatus is disclosed which comprises a vibrating feed hopper, a fastener feed assembly for receiving the fasteners from the hopper and serially delivering the fasteners to a discharge tube which leads to an automatic screwdriver. The fastener feed assembly comprises a body member which mounts a slide for transverse sliding movement between a first position wherein the fastener is received in a notch in the slide, and a second position where the fastener is delivered to a discharge opening which leads to the discharge tube and to the screwdriver. A first air line system is provided for moving the slide toward the first or fastener receiving position, and for concurrently injecting air into the discharge opening to move a fastener previously positioned in the tube to the screwdriver. A second air line is provided for directing a stream of air into contact with the fastener at the second position so as to positively move the fastener into the discharge opening.

Power driven fastener driving apparatus for serially driving fasteners into a workpiece are known in the art. Typically, such apparatus comprise a vibrating feed hopper, and a feed or escapement assembly for receiving the fasteners from the delivery chute of the hopper, and for serially delivering them through a discharge tube to a power driven tool. Apparatus of this general type are disclosed, for example, in the U.S. Pat. No. 4,278,184 to Willis and U.S. Pat. No. 3,247,874 to MacDonald.
While the known apparatus of the described type are generally suitable for their intended use, the known feed or escapement assemblies are structurally complex, in that they utilize mechanical mechanisms to feed the fasteners into the discharge tube leading to the screw-driver. This complexity increases the cost of the assembly and reduces its reliability.
It is accordingly an object of the present invention to provide a fastener feed assembly of the described type which is of relatively simple construction, so as to minimize its cost and increase its reliability.
It is a more particular object of the present invention to provide a fastener feed assembly of the described type which has a simplified mechanism for moving the fastener into the delivery tube.


The invention relates to the isolation of the prepro form of cathepsin L, of its leader sequence, of cathepsin L and of the affiliated propeptide from ciliates, in particular Paramecium, to the use of these peptides and to a process for preparing cathepsin L from ciliates.

1. Field of the Invention
The invention relates to the isolation of the prepro form of cathepsin L, of its leader sequence, of cathepsin L and of the affiliated propeptide from ciliates, in particular Paramecium to the use of these peptides and to a process for preparing cathepsin L from ciliates.
2. Description of the Related Art
The finding that propeptides of different proteases can, after they have been liberated by activation of the protease zymogens, act as protease inhibitors is known. For example, once splitting-off has taken place, the propeptide of Pseudomonas aeruginosa elastase attaches to elastase and thereby gives rise to inactivation of the enzyme (Kessler and Safrin, 1994, J. Biol. Chem., 269, 22726). The propeptides of papain and of papaya proteinase IV act selectively as inhibitors of the mature papaya proteases and of the related B and L cathepsins from rat liver (Taylor et al., 1995, Biochem. Soc. Trans., 23, 80). The propeptides of other cathepsins can also act as protease inhibitors. Thus, the synthetically prepared propeptide of human procathepsin D inhibits bovine cathepsin D (Vagner et al., 1993, Collect. Czech. Chem. Commun., 58, 435).
Cathepsin L, a protease, plays an important role in various syndromes. First, this enzyme is probably of crucial importance for the invasiveness of tumors and the formation of metastases (Pike, 1991, Dissertation Abstr. Intern., 53, 4645). This protease can also be involved in the penetration of pathogenic bacteria or parasitic protozoa into the host tissue. Cathepsin L is also involved in the degradation of bone matrix. This enzyme therefore appears to be a rewarding target in connection with the treatment of osteoporosis (Pharma Japan, September 1995, 1468, 23).
Finally, it may be mentioned that cathepsin L is also involved in the development of inflammatory diseases such as arthritis.
The identification of suitable cathepsin L inhibitors could represent an important step in the development of suitable preparations for the therapy of the said diseases. Furthermore, it would be very advantageous to have a suitable source for isolating relatively large quantities of cathepsin L. This is because the enzyme could be employed in screening systems for finding suitable protease inhibitors. Over and above this, it could be employed, for example, in wound ointments, where it could catalyze the degradation of necrotic tissue.
The present invention consequently relates to a cathepsin L prepro form which can be obtained from ciliates, preferably from Paramecium, particularly preferably from Paramecium tetraurelia, and to the DNA sequence encoding such a protein.
The invention furthermore relates to a cathepsin L from ciliates, preferably from Paramecium, particularly preferably from Paramecium tetraurelia, and the affiliated DNA sequence, to a process for its preparation from ciliates, and to its use for preparing a pharmaceutical for treating wounds.
The cathepsin L according to the present invention can furthermore be used for identifying suitable inhibitors, for example by means of so-called molecular modeling.
Furthermore, the present invention provides a cathepsin L propeptide, and its DNA sequence, from ciliates, preferably from Paramecium, particularly preferably from Paramecium tetraurelia.
The propeptide of the cathepsin L from ciliates is a highly specific inhibitor of this cathepsin L and is consequently suitable for preparing pharmaceuticals for treating inflammatory diseases, metastasizing tumors, bacterial infections, infections with parasitic protozoa, or osteoporosis.
The present invention furthermore provides a presequence, corresponding to the leader sequence or signal ef the sequence of the cathepsin L from ciliates, preferably from Paramecium, particularly preferably from Paramecium tetraurelia, which presequence is translated into the corresponding leader sequence or signal sequence when recombinant peptides or proteins are expressed, thereby resulting in the secretion of the recombinantly expressed peptides or proteins from the ciliate cells.
The present invention is clarified below and with the aid of examples.

Cathepsin L, its prepro form and the corresponding propeptide from ciliates

Nutrinova Nutrition Specialties and Food Ingredients GmbH


A chip package assembly and method for fabricating the same are provided which utilize a composite stiffener selected to provide excellent resistance to warpage without detrimentally imposing excessive stress on a package substrate of the package assembly. In one example, the chip package assembly includes an integrated circuit die stacked on a top surface of a package substrate, and a composite stiffener coupled to a first edge of the package substrate. The composite stiffener includes a first stiffener member and a second stiffener member. The first stiffener member has a bottom surface bonded to the top surface of the package substrate. The second stiffener member is disposed over the first stiffener member. The second stiffener member has a bottom surface bonded to the top surface of the package substrate. The second stiffener member has a Young's modulus that is less than a Young's modulus of the first stiffener member.

Electronic devices, such as tablets, computers, copiers, digital cameras, smart phones, control systems and automated teller machines, among others, often employ electronic components which leverage chip package assemblies for increased functionality and higher component density. Conventional chip packaging schemes often utilize a plurality of integrated circuit (IC) dice to be mounted to a single package substrate. The IC dice may include memory, logic or other IC devices.
Out of plane deformation of the chip package assembly can be problematic to conventional chip packaging schemes. In many instances, a stiffener is utilized to stiffening the chip package assembly against out of plane deformation. However, particularly in larger chip package assemblies, the stiffener itself may bend or twist, or even become delaminated from chip package assembly, thus still permitting undesirable warpage and bending during manufacture and/or use. Such warpage and bending of the chip package assembly can lead to solder connection failure or other damage to the components and devices of the chip package assembly, which may detrimentally effect device performance and reliability.
In large chip package assemblies, simply utilizing a heavy duty (e.g., "stiffer") stiffener has not shown to be a robust solution. Particularly, heavy duty stiffeners that rigidly hold the chip package assembly extremely flat without any flexibility induce large stresses on the interconnect substrate to which the dice are mounted. Such large stresses can lead to solder connection failure or other damage to the components and devices of the chip package assembly, even if the substrate itself doesn't warp or bend. Solder connection failure is particularly problematic when lead-free solder is utilized to make the electrical connections between the interconnect substrate and dice, as lead-free solder is not a strong as the more commonly used tin-lead (Sn—Pb) solders, which have greater tensile and shear strengths.
Therefore, a need exists for an improved chip package assembly, and in particular, to a chip package assembly having an improved stiffener.

Chip package assembly with composite stiffener


An apparatus includes a processor, and a non-transitory computer-readable storage medium coupled to the processor, and configured to store programmable instructions. When executed by the processor the programmable instructions cause the apparatus to maintain a transmission status of a previous data packet of a first access stratum entity, and adjust a transmission parameter of a current data packet, in response to the transmission status of the previous data packet being a transmission failure.

In an industrial control scenario, motion control is relatively challenging due to a relatively high requirement on communication. A motion controller is responsible for controlling and moving or rotating a part (for example, a mechanical arm) of a machine to complete a task, for example, delivering goods or assembling parts. A communication mode between the motion controller and the controlled part may be wired communication or wireless communication. An advantage of the wireless communication is that no line is deployed between the controller and the controlled part. This reduces costs, and increases support of a system for mobility, so that the controlled part can move anywhere. In addition, for some plant areas and factories, production lines are customized and reorganized based on requirements at any time. It is more convenient to reorganize a production line equipped with a wireless communications system. As a 5G communications system develops, communication performance of the wireless communication becomes better, and is sufficient to meet a low-latency and high-reliability communications requirement in the industrial control scenario. Therefore, 5G communication will be one of main communications technologies in the future industrial control field.
In the industrial control scenario, a requirement on a communications indicator is relatively high, and control signaling is transmitted with high reliability assurance in short time. In the control scenario, the controller usually transmits an instruction to the controlled unit periodically, to instruct the controlled unit how to perform an action. Because 100% reliability cannot be achieved for communication, when an application layer is designed, an error is usually allowed to occur in one instruction, but errors are not allowed to occur in two consecutive instructions. If two pieces of consecutive control signaling are lost or transmitted incorrectly, the application layer performs consecutive actions according to incorrect instructions or disconnects a connection. This may cause device damage or production line stoppage, resulting in huge property loss or personal safety accidents.

Method and apparatus for avoiding failure of transmitting consecutive data packets


The present invention is a visual prosthesis for stimulating visual neurons to create the perception of light. The visual prosthesis electrically stimulating the retina with implanted electrodes exhibits interaction between electrodes stimulated closely together in both space and time. The visual prosthesis of the present invention includes means for determining a minimum distance at which spatiotemporal interactions occur, determining a minimum time at which spatiotemporal interactions occur, and avoiding stimulation of electrodes within the minimum distance during the minimum time. The minimum are ideally established for each individual patient. Alternatively, approximate minimums have been established by the applicants at 2 mm and 1.8 milliseconds.

Retinitis pigmentosa (RP) and age-related macular degeneration (AMD) are photoreceptor diseases that cause substantial vision loss and lead to subsequent blindness in over 15 million people worldwide. After the loss of the photoreceptor layer, the spatial organization of the inner nuclear and ganglion cell layers can become disorganized and inner nuclear and ganglion cell layers begin to thin. However, the inner nuclear and ganglion cell layers maintain relatively high cell density and some functional circuitry remains. These findings of residual function within the inner layers of the retina have inspired a variety of research focused on sight restoration technologies that interface with remaining retinal cells.
A great deal of progress has been made in treating one type of RP (i.e., Leber's Congenital Amaurosis; RPE65 mutation) using a gene replacement therapy. However, current gene therapies focused on restoring function within photoreceptors necessarily require the maintenance of photoreceptors and are specific to a single gene mutation gene mutation. This limits the utility of this approach for many types of RP since photoreceptor cells generally die off as a function of the disease process, and the genetics of RP is highly heterogeneous. Over 180 different gene mutations have been positively identified as being involved with photoreceptor disease and this number is likely an underestimate. One recent estimate is that there are likely to be over 400 gene mutations associated with photoreceptor disease.
A second approach to treatment is genetically targeting bipolar and/or ganglion cells with engineered photo-gates or light-sensitive proteins such as channelrhodopsin-2 (ChR2), which has the advantage of not needing to be specific to a given gene mutation. Still, ChR2 activation requires light stimulation levels that are 5 orders of magnitude greater than the threshold of cone photoreceptors and has a substantially limited dynamic range (2 log units). An ideal therapy would be able to treat blindness independent of the genetic mutation, in the absence of photoreceptors, and with reasonable response sensitivity.
One typical application of neural tissue stimulation is in the rehabilitation of the blind. Some forms of blindness involve selective loss of the light sensitive transducers of the retina. Other retinal neurons remain viable, however, and may be activated in the manner described above by placement of a prosthetic electrode device on the inner (toward the vitreous) retinal surface (epiretinal). This placement must be mechanically stable, minimize the distance between the device electrodes and the visual neurons, and avoid undue compression of the visual neurons.
In 1986, Bullara (U.S. Pat. No. 4,573,481) patented an electrode assembly for surgical implantation on a nerve. The matrix was silicone with embedded iridium electrodes. The assembly fit around a nerve to stimulate it.
Dawson and Radtke stimulated cat's retina by direct electrical stimulation of the retinal ganglion cell layer. These experimenters placed nine and then fourteen electrodes upon the inner retinal layer (i.e., primarily the ganglion cell layer) of two cats. Their experiments suggested that electrical stimulation of the retina with 30 to 100 uA current resulted in visual cortical responses. These experiments were carried out with needle-shaped electrodes that penetrated the surface of the retina (see also U.S. Pat. No. 4,628,933 to Michelson).
The Michelson '933 apparatus includes an array of photosensitive devices on its surface that are connected to a plurality of electrodes positioned on the opposite surface of the device to stimulate the retina. These electrodes are disposed to form an array similar to a "bed of nails" having conductors which impinge directly on the retina to stimulate the retinal cells. U.S. Pat. No. 4,837,049 to Byers describes spike electrodes for neural stimulation. Each spike electrode pierces neural tissue for better electrical contact. U.S. Pat. No. 5,215,088 to Norman describes an array of spike electrodes for cortical stimulation. Each spike pierces cortical tissue for better electrical contact.
The art of implanting an intraocular prosthetic device to electrically stimulate the retina was advanced with the introduction of retinal tacks in retinal surgery. De Juan, et al. at Duke University Eye Center inserted retinal tacks into retinas in an effort to reattach retinas that had detached from the underlying choroid, which is the source of blood supply for the outer retina and thus the photoreceptors. See, e.g., E. de Juan, et al., 99 Am. J. Ophthalmol. 272 (1985). These retinal tacks have proved to be biocompatible and remain embedded in the retina, and choroid/sclera, effectively pinning the retina against the choroid and the posterior aspects of the globe. Humayun, U.S. Pat. No. 5,935,155 describes the use of retinal tacks to attach a retinal array to the retina. Alternatively, an electrode array may be attached by magnets or glue. U.S. Pat. No. 5,109,844 to de Juan describes a flat electrode array placed against the retina for visual stimulation.
Any device for stimulating percepts in the retina must receive a signal describing a visual image along with power to operate the device. The device can not be powered by wires as any connection through the skin will create the risk of infection. Battery power is not practical as batteries are bulky and surgery is required to replace them. Such signal and power may be transmitted into the eye inductively as shown in Humayun U.S. Pat. No. 5,935,155. Humayun uses a primary (external) coil in front of the eye, possibly encased within the rim of a pair of glasses, and a secondary (internal) coil within the lens capsule or around the sclera just under the conjunctiva. Implanting within the lens capsule is difficult surgery and only allows for a small diameter coil. Larger coils are more efficient, can receive more power with less resulting temperature rise per unit of power received. Implanting around the sclera under the conjunctiva and near the surgical limbus (that is at the front of the eye) allows for a larger coil but may cause irritation or damage to the conjunctiva if the coil is placed in front near the cornea.
U.S. patent application Ser. No. 09/761,270, Ok, discloses several coil configurations including a configuration where the coil is offset about 45 degrees from the front of the eye. The offset configuration allows the primary and secondary coils to be placed closer together allowing for better inductive coupling. The bridge of nose partially blocks placement of a primary coil when placed directly in front of the eye.
A better configuration is needed allowing for close physical spacing of relatively large primary and secondary coils, without causing physical damages such as erosion of the conjunctiva.
Several groups have recently developed microelectronic retinal prostheses with the ultimate goal of restoring vision in blind subjects by stimulating the remaining retinal cells with spatiotemporal sequences of electrical pulses. Analogous to cochlear implants, these devices are designed to directly stimulate remaining retinal neurons with pulsing electrical current. To date, both semi-acute and long-term implanted devices have been demonstrated to be safe and capable of generating visual percepts in human subjects. Note, however, that only the Second Sight Argus trials have thus far allowed use of the system outside of the clinic in subject's daily lives. The ultimate goal of these projects is to generate useful vision in blind patients by presenting a spatial and temporal sequence of electrical pulses that represent meaningful visual information, such as a continuous video stream that uses electrical pulses rather than pixels.
Here we examine how systematic variations in spatiotemporal patterns of multi-electrode retinal stimulation influence the perceived brightness in our prosthesis patients. It is well known that for cochlear implants the precise timing of stimulation across electrodes has perceptual consequences as a result of both electrical field. However, to date, only limited data have been reported examining how electrodes interact during spatiotemporal stimulation in the retina. Earlier work from our group demonstrated significant interactions between pairs of electrodes, even when they are stimulated non-simultaneously. Here we systematically examined how these interactions affect perceived brightness and we present a simple computational model that describes these data.

Multi-electrode integration in a visual prosthesis


A gas sensor in one form comprises a housing including a base and a top defining an interior space. The housing includes a gas entry hole and first and second electrical terminals. First and second electrodes in the housing interior space each comprise a membrane having a layer of platinum black catalyst on one side. The second electrode includes a lower amount of platinum black catalyst than the first electrode. A separator is placed between the first and second electrodes. Current collectors electrically connect the first and second electrodes to the respective first and second electrical terminals whereby sensor current represents concentration of gas while minimizing cross sensitivity.

Electrochemical toxic gas sensors, in one form, are designed to be maintenance free and stable for long periods. They have a direct response to volume concentration of gas rather than partial pressure. The simplest form of electrochemical toxic gas sensor comprises two electrodes, a sensing electrode and a counter electrode separated by a thin layer of electrolyte. This structure is enclosed in a plastic housing that has a small capillary to allow gas entry to the sensing electrode and includes pins which are electrically attached to both electrodes and allow easy external interface. These pins may be connected to a simple resistor circuit that allows a voltage drop resulting from any current flow to be measured. Gas diffusing into the sensor is either oxidized or reduced at the sensing electrode and, coupled with a corresponding counter reaction at the other electrode, a current is generated through the external circuit. Since the rate of gas entering into the sensor is controlled by the capillary diffusion barrier, the current generated is proportional to the concentration of gas present outside the sensor and gives a direct measure of the toxic gas present.
One known carbon monoxide sensor suffers from a high or variable level of hydrogen cross sensitivity which can be an issue. A large variation has been observed, depending on catalyst batches used. Such a known sensor consists of a sensing electrode made from normal platinum and a counter electrode made from high surface area platinum and higher and weight of platinum. Two different catalysts were used to ensure that there was enough stability of potential and the like to last throughout the life of the product. Because the catalysts were not exactly matched there can be subtle but important differences in their behavior within the sensor environment.
The present disclosure is directed to improvements in cross sensitivity in a gas sensor.

Carbon monoxide sensor with reduced hydrogen cross sensitivity


A spectroscopic measuring apparatus with monitoring capability includes a first optical path that extends from a measuring object through an optical system and a slit of a slit-mirror block to a spectroscope main body and a second optical path that extends from the measuring object through the optical system and a mirror face of the slit-mirror block to a two-dimensional photographing unit. The slit and spectroscope main body are integrated into a spectroscopic unit.

There is known a system of scanning and spectroscopically measuring a measuring object, to early diagnose a skin disease such as a melanoma. A spectroscopic measuring apparatus has a spectroscope (first optical device) and an autofocus controller (second optical device) and arranges a slit mirror in the vicinity of a focus of an objective optical system. Reflected light from the slit mirror is detected with a position sensor, to autofocus-control the objective optical system. Transmitted light straight from the slit is made incident to the spectroscope and is spectroscopically measured with a diffraction grating. Scanning the measuring object provides two-dimensional spectroscopic information about the measuring object. With the use of part of the reflected light from the slit mirror, it is possible to monitor, with a two-dimensional camera, the measuring object other than the spectroscopically measured field. Related arts are, for example, Japanese Unexamined Patent Application Publications No. 2001-289619, No. 2001-208979, No. 2004-145372, and No. 2007-086470.

Spectroscopic measuring apparatus with monitoring capability


An assembly includes a photovoltaic module including a solar cell and a cooling system including a heat pipe adapted to dissipate heat from the solar cell. A method includes dissipating heat from the solar cell using the heat pipe. The photovoltaic module may be disposed on a vehicle to convert solar energy into electricity.

The need to improve the energy efficiency of automotive vehicles has been well documented. Efforts have therefore been untaken to utilize alternative energy sources to power vehicle loads. For example, vehicles equipped with photovoltaic modules, or solar panels, utilize solar energy captured from the sun. The photovoltaic modules convert the solar energy into electricity for charging the vehicle battery or for powering various other electrical loads. The operating temperatures of solar cells increase during the photovoltaic conversion process. Solar cell performance often decreases as its operating temperature increases.

Systems and methods for passively cooling photovoltaic modules


An apparatus for reducing drag on a transport vehicle, which comprises retractable aerodynamic panels for deployment at the rear of the vehicle, behind the cabin, or both. When these panels are deployed, they provide an aerodynamic design, thereby reducing drag and turbulence as the vehicle travels, for example, down a highway, which in turn, reduces energy costs associated with transportation. When not in use, the panels retract adjacent to the planar surfaces of the vehicle (for example, the sides, top and bottom surfaces). The retracted panels are housed either on the outside surface of the vehicle; the inside surface of the vehicle, or within the walls of the vehicle. The retracted position of the panels allows for easy unloading of cargo from the rear of the vehicle when it is docked.

As a vehicle increases its speed, so too does the amount of aerodynamic drag, which in turn, increases the amount of fuel consumption required for transport. This inefficiency leads to a direct increase in operating costs. As a result, there have been many efforts to reduce aerodynamic drag, particularly on transport vehicles which are not sufficiently streamlined to minimize aerodynamic drag.
In particular, transport vehicles, such as trucks, are susceptible to aerodynamic drag, due to the shape of the cabin and/or trailer. The drag is associated both with the rear of the truck, and in the case of tractor-trailer combinations, with the space between the cabin and trailer. Often, the rear-end of a trailer is a large planar surface, which results in an area of reduced pressure to be created behind the trailer box as it travels, for example, down a highway. This in turn, generates a retarding force that must be counteracted by additional engine power.
It follows that there have been many efforts to streamline the rear of such vehicles, through the use of airfoils and other similar devices mounted at the rear of the vehicle.
U.S. Patent Application No. 20080093886 (Nussbaum) discloses a retractable air deflection apparatus for reduction of vehicular air drag, comprising at least three air deflection elements, each of which is contoured in a wing-like shape, and each of which is disposed adjacent one of the angular trailing corner edges of the vehicle. This apparatus requires a complex series of mechanical linkages.
There have been other devices that essentially comprise panels at the rear of the vehicle, which fold up onto the rear doors when not in use (see, e.g. U.S. Patent Application Nos. 20090179456; 20080309122; and 20090200834; and U.S. Pat. Nos. 6,309,010; 6,485,087; 6,666,498 and 6,799,791). These panels are fully exposed to the elements, and do not deploy in a coordinated manner. Often, manual deployment by the vehicle operator is required. Furthermore, these devices are not easily adapted for reducing the aerodynamic drag in the space between the rear of a cabin and the front surface of an attached trailer.
Breidenbach discloses in U.S. Pat. No. 7,380,868 an aerodynamic drag reducing apparatus that includes a series of successively nesting shapes and/or frameworks that extend rearward for use in a drag reducing configuration and collapse for use in a space saving configuration. The apparatus is bulky when fully deployed, and is attached to the rear doors of the vehicle. Such an apparatus cannot be easily adapted to providing drag reduction in the space between a cabin and an attached trailer. Care must be taken not to damage the apparatus when opening the rear doors to load/unload cargo. In addition, the nesting elements require a large number of complex mechanical linkages for operation.
It would be advantageous to provide a drag reducing device that is relatively simple in construction, with aerodynamic panels that deploy in a coordinated manner (either manually or automatically), for use at the rear of the vehicle and/or the space between the rear of cabin and the front of an attached trailer. When used at the rear of the vehicle, the apparatus should not couple with the rear doors of the vehicle, so as to permit easy loading/unloading of vehicular cargo. Furthermore, when not in use, the apparatus should be shielded from the elements, and also, retracted so as not to create a traffic hazard.


A semiconductor image sensor includes a substrate having a first side and a second side that is opposite the first side. An interconnect structure is disposed over the first side of the substrate. A plurality of radiation-sensing regions is located in the substrate. The radiation-sensing regions are configured to sense radiation that enters the substrate from the second side. A plurality of isolation structures are each disposed between two respective radiation-sensing regions. The isolation structures protrude out of the second side of the substrate.

Semiconductor image sensors are used to sense radiation such as light. Complementary metal-oxide-semiconductor (CMOS) image sensors (CIS) and charge-coupled device (CCD) sensors are widely used in various applications such as digital still camera or mobile phone camera applications. These devices utilize an array of pixels (which may include photodiodes and transistors) in a substrate to absorb (i.e., sense) radiation that is projected toward the substrate and convert the sensed radiation into electrical signals.
A back side illuminated (BSI) image sensor device is one type of image sensor device. These BSI image sensor devices are operable to detect light from the backside. Compared to front side illuminated (FSI) image sensor devices, BSI image sensor devices have improved performance, especially under low light conditions. However, traditional methods of fabricating BSI image sensor devices may still lead to certain shortcomings for BSI image sensor devices. For example, traditional BSI image sensors may require two types of isolation structures—for example a trench isolation as well as a metal grid—to provide sufficient isolation between adjacent pixels so as to reduce cross-talk. However, the need for having two different types of isolation devices result in more complicated (and lengthier) fabrication processes, which may increase fabrication costs. In addition, the two types of isolation structures need to be accurately aligned, and any misalignment may lead to substandard device performance and may even result in device failures.
Hence, while existing BSI image sensor devices have been generally adequate for their intended purposes, they have not been entirely satisfactory in every aspect.

Back side illuminated image sensor with deep trench isolation structures and self-aligned color filters

TAIWAN SEMICONDUCTOR MANUFACTURING COMPANY, LTD.


In a regenerative reforming facility using a series of moving beds, a direct supply of regenerated catalyst, optionally reduced is passed into at least two of the reactors of the series. Spent catalysts from different reactors are passed into a common mixing apparatus so as to provide a homogeneous degree of coke on the spent catalysts which are thereafter passed to a regenerator. The feedstock and the intermediate effluents continue to circulate in succession relative to the reactors. The invention makes it possible in particular to reduce the operating pressure of the units to less than 0.2 MPa.

The invention relates to the moving-bed processes such as gasoline reforming (reforming according to English terminology) for the improvement of the octane number of petroleum fractions that are located in the range of gasolines, i.e., at the starting point between 70° C. and 110° C., and at the end boiling point between 150° C. and 180° C. More generally, the invention relates to any process that uses a series of moving-bed reactors such as are found in the aromatizing process or the process for dehydrogenating normal paraffins. The following description refers to the reforming process with continuous regeneration that will be designated by the name of regenerative reforming. The process for reforming gasolines started in the 1950s and has since known important technological developments that are often linked to the appearance of new generations of catalysts according to three successive stages. The appearance of catalyst was based on platinum on alumina in the 1950s. The units worked at pressures on the order of 5 MPa, and the catalyst was regenerated about every 6 months. Toward the end of the 1960s, the bimetallic catalysts that would allow the operating pressure to be lowered to around approximately 3 MPa appeared. Finally, at the beginning of the 1970s, the appearance of the continuous regeneration of catalyst made it possible to reach operating pressures only on the order of 1 MPa.
Currently, the regenerative reforming units operate at pressures of several bar (1 bar=0.1 MPa), typically 3 bar (0.3 MPa), on very selective catalysts that produce maximum hydrogen and on feedstocks that have a tendency of becoming more narrow.
The general tendency that emerges from this development is the continuous reduction of the pressure whose impact on the reformate yields is very significant.
The chemical reactions that are involved in the reforming process are numerous. The main one among them is the dehydrogenation of naphthenes into aromatic compounds, which is the most desired chemical family, since it is the one that promotes high octane numbers. The dehydrocyclization of paraffins into aromatic compounds and the isomerization of paraffins and particularly paraffins with a carbon atom number of 5 or 6 are also desired, since they also accompany an increase in the octane number. Among the unfavorable reactions, i.e., that do not lead to an improvement of the octane number, it is possible to cite the hydrocracking of paraffins and naphthenes.
The thermodynamic data show that the equilibrium of various chemical families is shifted toward the low-pressure aromatic compounds, which explains the technological development of units toward increasingly weaker operating pressures, while maintaining a certain partial hydrogen pressure that makes it possible to limit the deactivation of the catalyst by the coke. Actually, the coke is a compound of high molecular weight, characterized by a low H/C ratio, generally between 0.3 and 1.0, which is deposited on the active sites of the catalyst. Although the transformation selectivity of the hydrocarbons into coke is very low, the contents of coke accumulated on the catalyst can be very significant. Typically, for the units in a moving bed, these contents are between 3 and 10% by weight at the outlet of the last reactor.
The current technology of the catalytic reforming units is that of the moving bed that appeared in the 1970s in two main forms: the one that is described in U.S. Pat. No. 4,119,526 that is characterized by a vertical stacking of reactors through which the feedstock passes in succession, and that of the applicant that is characterized by reactors that are placed side by side.
In the two cases, the effluents that are obtained from a reactor are heated in a furnace before being introduced at the top of the next reactor since, overall, the reactions that are involved are endothermic and the reactors are operated at the same starting temperature. In the technology with vertical stacking of the reactors, the catalyst flows by gravity from one reactor to the next, then it is picked up by a lift line or a pneumatic transport line at the outlet of the last reactor to be introduced at the top of the regenerator in which it also flows by gravity. At the bottom of the regenerator, it is picked up by a second lift line to be introduced at the top of the first reactor.
In the technology of the applicant, the reactors are placed side by side, and the catalyst also flows by gravity inside each reactor and is transported from the bottom of a reactor to the top of the next reactor via a lift line. It is picked up by a lift line at the bottom of the last reactor to be introduced at the top of the regenerator in which it also flows by gravity. At the bottom of the regenerator, the catalyst is also picked up by a lift line to be introduced at the top of the first reactor. A detailed description of the circulation of the catalyst is indicated in Patent FR 2 657 087.
In short, in the current technology of the regenerative reforming reactors with moving beds, the catalyst circulates in succession from one reactor to the next, the same as the intermediate effluents that pass from one reactor to the next. This means that the catalyst that enters a reactor, other than the first, is a catalyst that is already coked by the reactions that have taken place in the preceding reactors. A loss in catalytic activity, penalizing the operation of each reactor and causing the following reactors to be operated at a higher temperature than the one that could be used if there were no coke deposition on the catalyst that enters the reactors, results therefrom. At the outlet of each reactor, the effluents are sent into a reheating furnace so as to enter the next reactor at a temperature level that is generally essentially identical to that of the preceding reactor, but sometimes slightly different if the operation of the unit thus requires.
The typical operating conditions of a moving-bed reforming unit are as follows: operating pressure of between 0.3 MPa and 0.8 MPa, volumetric flow rate, i.e., ratio between the catalyst mass in a reactor and mass rate of the feedstock, between 1 and 4 h−1, molar ratio of hydrogen to hydrocarbons (H2/HC) of between 3 and 10, and more particularly between 3 and 5, mean starting temperature of the reactors of between 480 and 550° C.
This invention makes it possible to redefine the circulation of the catalyst so that the catalyst that enters all or part of the successive reactors is a catalyst that is at least partially regenerated, regardless of the technology that is used for the arrangement of the reactors. This invention can therefore be used with a technology of reactors placed side by side, or a technology of reactors that are stacked vertically on one another. In other words, the circulation of the catalyst becomes at least partially a circulation in parallel relative to the reactors, whereas that of the feedstock and effluents continues to be in series. Various embodiments of this circulation type will be presented in the text below.


Apparatus and methods for automatically handling die carriers are disclosed. In one example, a disclosed apparatus includes: at least one load port each configured for loading a die carrier operable to hold a plurality of dies; and an interface tool coupled to the at least one load port and a semiconductor processing unit. The interface tool comprises: a first robotic arm configured for transporting the die carrier from the at least one load port to the interface tool, and a second robotic arm configured for transporting the die carrier from the interface tool to the semiconductor processing unit for processing at least one die in the die carrier.

During manufacturing of a semiconductor device, the device is usually processed at many work stations or processing machines. For example, integrated circuits are produced in large batches on a single wafer, which can be cut into many pieces each of which contains one copy of the circuit and is called a die. Multiple dies can be held on a frame, called frame cassette.
The transporting or conveying of a die carrier, e.g. a frame cassette, is an important aspect in the total manufacturing process. While an automated material handling system (AMHS) may be used to automatically transport frame cassettes between various processing machines ("tools"), human operation is conventionally required to load a frame cassette into a processing tool and unload a frame cassette from a processing tool. As such, a huge human resource is needed to transfer frame cassettes in fabrication facility, which often causes injury of human operators. In addition, a production throughput is limited when manual operation causes process interruption during frame cassette transportation.
As such, existing apparatus and methods for handling die carriers are not entirely satisfactory.

Taiwan Semiconductor Manufacturing Co., Ltd.


A race for a rolling-element bearing is characterized in that the race comprises at least one circumferentially-extending region having a reduced stiffness compared with the remainder of the race. The or each circumferentially-extending region may be thinner than the remainder of the race, and may further comprise a hole or a slot. In a particular preferred embodiment there are two such circumferentially-extending regions, each extending around an arc of approximately 60 degrees in the circumferential direction.

A known problem with rolling-element bearings (especially those that operate at high speeds but at low loads) is skidding. The rolling element, instead of rolling on the inner track of the bearing, slides along it. This causes the rolling element to heat up at the contact point. If the sliding element breaks through the lubricant film, damage may be caused to the rolling elements or to the tracks. This phenomenon is known as skidding.
A known way to reduce skidding in lightly-loaded bearings is deliberately to make the outer race non-circular so that an interference exists across the bearing at two or more points. In use, the outer race will then bend due to this interference until a force equilibrium is reached, and a resultant load will be present at two or more positions across the bearing. The magnitude of the force can be controlled (by suitable choice of the magnitude of the non-circularity) to prevent the bearing from skidding.
A disadvantage with such bearings is that they require a squeeze film housing, or some other type of housing with enough clearance to allow the outer race to bend. If it is not possible to incorporate such a housing (for example, because of space or weight restrictions or oil feed issues) then it will be necessary to use a clear housing or a flanged outer race. In high speed applications a clear housing may be prone to fretting and so a flanged outer race is preferable. Another reason that a flanged outer race may be preferred is that such a race allows tighter control of the alignment of the shaft carried by the bearing.
A problem is that a flanged outer race is usually much stiffer than other types of outer race. The solution to the problem of skidding set out above, using a non-circular outer race, relies on the flexibility of the outer race and consequently it is unsatisfactory to use a flanged outer race in this situation.


A degradation compensation unit including a first operation unit receiving downscaled gray data of each pixel for one frame at set or predetermined intervals and calculating a degradation time of each pixel corresponding to the downscaled gray data; an accumulation operation unit receiving the degradation time of each pixel from the first operation unit and calculating an accumulated degradation time of each pixel by accumulating the degradation time of each pixel; a weight calculation unit receiving the accumulated degradation time of each pixel from the accumulation operation unit and calculating a degradation compensation weight for each pixel based on the accumulated degradation time of each pixel; and a second operation unit producing compensated gray data for each pixel corresponding to the degradation compensation weight for each pixel, which is received from the weight calculation unit, and providing the compensated gray data for each pixel to a data driver.

1. Field
The following description relates to a light-emitting apparatus including a degradation compensation unit.
2. Description of the Related Art
Active matrix organic light-emitting diode (AMOLED) panels are panels that generate light by providing (flowing) current to an organic light-emitting diode (OLED) which is a self-luminous element. When an OLED continuously emits light for a certain period of time, even if the same current is provided (flowed) to the OLED, the amount of light that the OLED emits tends to decrease over time.
This is because the OLED is degraded over time. A reduction in the amount of light that the OLED emits may lead to the deterioration of image quality of the entire panel. Therefore, there is a need to reduce the degradation of the OLED.

Degradation compensation unit, light-emitting apparatus including the same, and method of compensating for degradation of light-emitting apparatus


A flexible circuit connector includes a housing defining an interior space for receiving a flexible circuit. Conductive contacts are retained in the housing, each having a concave portion extending into the interior space for electrically engaging the flexible circuit. An actuator pivotally attached to the housing for being moveable between an open position where an opening is formed between the actuator and the housing for insertion of the flexible circuit into the housing and a closed position where the actuator engages and thus securely retains the circuit board in the housing. The contacts are arranged to have the concave portions thereof substantially aligned with a rotational axis of the actuator for reducing coupling force required for moving the actuator from the open position to the closed position. At least one inspection window is defined in the housing in communication with the interior space for visual inspection of the flexible circuit received in the housing. The actuator has two spaced arms each forming a pivot pin received in a hole defined in the housing. A slot is defined in the housing extending from the hole for guiding the pivot pin into the hole. A retainer is mounted to the housing and engages the pivot pin for retaining the pivot pin in the hole. A soldering tab extends from the retainer for being soldered to a circuit board to fix the connector to the circuit board.

1. Field of the Invention
The present invention generally relates to a flexible circuit connector, and in particular to a flexible circuit connector having a low to zero coupling force (moment).
2. The Prior Art
A flexible circuit connector connects a flexible circuit board to a rigid circuit board. The flexible circuit connector comprises an insulative housing mounted to the rigid circuit board. A plurality of slots is defined in the housing for receiving and retaining conductive contacts electrically connected to the rigid circuit board. An opening is defined in the housing in communication with the slots for receiving an end portion of a flexible circuit whereby conductive traces printed on the flexible circuit board electrically engage the contacts. An actuator is attached to the housing for securing the flexible circuit to the connector. The actuator may be detachable from the connector or movably mounted to the housing to render the actuator movable between an open position where a space is present between the actuator and the housing for the insertion of the flexible circuit and a closed position where the actuator engages and applies a force on the flexible circuit to secure the flexible circuit between the actuator and the housing and ensure proper electrical engagement between the flexible circuit and the contacts. Examples of conventional flexible circuit connectors are those disclosed in U.S. Pat. Nos. 3,989,336, 4,334,728, 4,449,773, 4,477,137, 4,647,131, 4,718,859, 4,778,403, 4,936,792, 5,639,260, 5,458,506, 5,580,272, 5,695,359, 5,695,360, 5,741,154, 5,753,709, 5,785,549, 5,824,883, 5,839,917, 5,895,287, and 5,904,586.
Some of the conventional flexible circuit connectors have a sophisticated structure which complicates the manufacturing process thereof and increases costs. Another disadvantage of the conventional flexible circuit connectors is that they require a large coupling force (moment) in securing a flexible circuit thereto. Furthermore, in certain cases, the conventional flexible circuit may not be effective in securing the flexible circuit.
It is thus desired to provide a flexible circuit connector, which overcomes the problems, discussed above.


Methods and compositions comprising 1,25-dihydroxyvitamin D2 are disclosed. A method for lowering or maintaining lowered serum parathyroid hormone in human patients including administering to said patients an effective amount of 1,25-dihydroxyvitamin D2 to lower or maintain lowered serum parathyroid hormone levels is disclosed. Dosage forms and dosing regimens are also disclosed.

1. Field of the Disclosure
The disclosure relates generally to methods and compounds for Vitamin D therapy. More particularly, the disclosure relates to compositions comprising 1,25-dihydroxyvitamin D2 and methods of administration thereof in the treatment and prevention of disease.
2. Brief Description of Related Technology
Secondary hyperparathyroidism is a disorder which develops primarily because of Vitamin D deficiency. It is characterized by abnormally elevated blood levels of parathyroid hormone (PTH) and, in the absence of early detection and treatment, it becomes associated with parathyroid gland hyperplasia and a constellation of metabolic bone diseases. It is a common complication of chronic kidney disease (CKD), with rising incidence as CKD progresses. Secondary hyperparathyroidism can also develop in individuals with healthy kidneys, due to environmental, cultural or dietary factors which prevent adequate Vitamin D supply.
As to secondary hyperparathyroidism and its occurrence in CKD, there is a progressive loss of cells of the proximal nephrons, the primary site for the synthesis of the vitamin D hormones (collectively "1,25-dihydroxyvitamin D") from 25-hydroxyvitamin D3 and 25-hydroxyvitamin D2. In addition, the loss of functioning nephrons leads to retention of excess phosphorus which combined reduces the activity of the renal 25-hydroxyvitamin D-1α-hydroxylase, the enzyme which catalyzes the reaction to produce the D hormones. These two events account for the low serum levels of 1,25-dihydroxyvitamin D commonly found in patients with moderate to severe CKD when vitamin D supply is adequate.
Reduced serum levels of 1,25-dihydroxyvitamin D cause increased, and ultimately excessive, secretion of PTH by direct and indirect mechanisms. The resulting hyperparathyroidism leads to markedly increased bone turnover and its sequela of renal osteodystrophy, which may include a variety of other diseases, such as, osteitis fibrosa cystica, osteomalacia, osteoporosis, extraskeletal calcification and related disorders, e.g., bone pain, periarticular inflammation and Mockerberg's sclerosis. Reduced serum levels of 1,25-dihydroxyvitamin D can also cause muscle weakness and growth retardation with skeletal deformities (most often seen in pediatric patients).
"Vitamin D" is a term that refers broadly to the organic substances named Vitamin D2, Vitamin D3, Vitamin D4, etc., and is sometimes used loosely to refer to their metabolites and hormonal forms that influence calcium and phosphorus homeostasis. "Vitamin D deficiency" is a term that broadly refers to reduced or low blood levels of Vitamin D, as defined immediately above.
The most widely recognized forms of Vitamin D are Vitamin D2 (ergocalciferol) and Vitamin D3 (cholecalciferol). Vitamin D2 is produced in plants from ergosterol during sunlight exposure and is present, to a limited extent, in the human diet. Vitamin D3 is generated from 7-dehydrocholesterol in human skin during exposure to sunlight and also is found, to a greater extent than Vitamin D2, in the human diet, principally in dairy products (milk and butter), certain fish and fish oils, and egg yolk. Vitamin D supplements for human use consist of either Vitamin D2 or Vitamin D3.
Both Vitamin D2 and Vitamin D3 are metabolized into prohormones by one or more enzymes located in the liver. The involved enzymes are mitochondrial and microsomal cytochrome P450 (CYP) isoforms, including CYP27A1, CYP2R1. CYP3A4, CYP2J3 and possibly others. These enzymes metabolize Vitamin D2 into two prohormones known as 25-hydroxyvitamin D2 and 24(S)-hydroxyvitamin D2, and Vitamin D3 into a prohormone known as 25-hydroxyvitamin D3. The two 25-hydroxylated prohormones are more prominent in the blood, and can be collectively referred to as "25-hydroxyvitamin D." Vitamin D2 and Vitamin D3 can be metabolized into their respective prohormones outside of the liver in certain epithelial cells, such as enterocytes, which contain the same (or similar) enzymes, but extrahepatic prohormone production probably contributes little to blood levels of 25-hydroxyvitamin D.
The rates of hepatic and extrahepatic production of the Vitamin D prohormones are not tightly regulated, and they vary mainly with intracellular concentrations of the precursors (Vitamin D2 and Vitamin D3). Higher concentrations of either precursor increase prohormone production, while lower concentrations decrease production. Hepatic production of prohormones is inhibited by high levels of 25-hydroxyvitamin D via a poorly understood mechanism apparently directed to prevention of excessive blood prohormone levels.
The Vitamin D prohormones are further metabolized in the kidneys into potent hormones by an enzyme known as CYP27B1 (or 25-hydroxyvitamin D3-1α-hydroxylase) located in the proximal kidney tubule. The prohormones 25-hydroxyvitamin D2 and 24(S)-hydroxyvitamin D2 are metabolized into hormones known as 1α,25-dihydroxyvitamin D2 and 1α,24(S)-dihydroxyvitamin D2. Likewise, 25-hydroxyvitamin D3 is metabolized into a hormone known as 1α,25-dihydroxyvitamin D3 (or calcitriol). These hormones are released by the kidneys into the blood for systemic delivery. The two 1α,25-dihydroxylated hormones, usually far more prominent in the blood than 1α,24(S)-dihydroxyvitamin D2, can be collectively referred to as "1,25-dihydroxyvitamin D." Vitamin D prohormones can be metabolized into hormones outside of the kidneys in keratinocytes, lung epithelial cells, enterocytes, cells of the immune system (e.g., macrophages) and certain other cells containing CYP27B1 or similar enzymes, but such extrarenal hormone production is incapable of sustaining normal blood levels of 1,25-dihydroxyvitamin D in advanced CKD.
Blood levels of 1,25-dihydroxyvitamin D are precisely regulated by a feedback mechanism which involves PTH. The renal 1α-hydroxylase (or CYP27B1) is stimulated by PTH and inhibited by 1,25-dihydroxyvitamin D. When blood levels of 1,25-dihydroxyvitamin D fall, the parathyroid glands sense this change via intracellular Vitamin D receptors (VDR) and secrete PTH. The secreted PTH stimulates expression of renal CYP27B1 and, thereby, increases production of Vitamin D hormones. As blood concentrations of 1,25-dihydroxyvitamin D rise again, the parathyroid glands attenuate further PTH secretion. As blood PTH levels fall, renal production of Vitamin D hormones decreases. Rising blood levels of 1,25-dihydroxyvitamin D also directly inhibit further Vitamin D hormone production by CYP27B1.
PTH secretion can be abnormally suppressed in situations where blood 1,25-dihydroxyvitamin D concentrations become excessively elevated, as can occur in certain disorders such as sarcoidosis or as a result of bolus doses of Vitamin D hormone replacement therapies. Oversuppression of PTH secretion can cause or exacerbate disturbances in calcium homeostasis. The parathyroid glands and the renal CYP27B1 are exquisitely sensitive to changes in blood concentrations of Vitamin D hormones so that serum 1,25-dihydroxyvitamin D is tightly controlled, fluctuating up or down by less than 20% during any 24-hour period. In contrast to renal production of Vitamin D hormones, extrarenal production is not under precise feedback control.
Blood levels of 1,25-dihydroxyvitamin D and substrate 25-hydroxyvitamin D prohormone, and regulation thereof, can also be affected by vitamin D hormone analogs, such as 1α-hydroxyvitamin D2 and 19-nor-1,25 dihydroxyvitamin D2.
The Vitamin D hormones have essential roles in human health which are mediated by the intracellular VDR. In particular, the Vitamin D hormones regulate blood calcium levels by controlling intestinal absorption of dietary calcium and reabsorption of calcium by the kidneys. The Vitamin D hormones also participate in the regulation of cellular differentiation and growth and normal bone formation and metabolism. Further, Vitamin D hormones are required for the normal functioning of the musculoskeletal, immune and renin-angiotensin systems. Numerous other roles for Vitamin D hormones are being postulated and elucidated, based on the documented presence of intracellular VDR in nearly every human tissue. For example, vitamin D has been postulated to play a role in cellular differentiation and cancer, in regulation of the immune system (immune enhancing or immune suppressing effects, depending on the situation), and atherosclerosis. Vitamin D deficiency increases the risk of many common cancers, multiple sclerosis, rheumatoid arthritis, hypertension, cardiovascular heart disease, and type I diabetes.
The actions of Vitamin D hormones on specific tissues depend on the degree to which they bind to (or occupy) the intracellular VDR in those tissues. VDR binding increases as the intracellular concentrations of the hormones rise, and decreases as the intracellular concentrations fall. In all cells, intracellular concentrations of the Vitamin D hormones change in direct proportion to changes in blood hormone concentrations. In cells containing CYP27B1 (or similar enzymes), intracellular concentrations of the Vitamin D hormones also change in direct proportion to changes in blood and/or intracellular prohormone concentrations, as discussed above.
Vitamin D2, Vitamin D3 and their prohormonal forms have affinities for the VDR which are estimated to be at least 100-fold lower than those of the Vitamin D hormones and do not effectively activate the receptor. As a consequence, physiological concentrations of these hormone precursors exert little, if any, biological actions without prior metabolism to Vitamin D hormones. However, supraphysiological levels of these hormone precursors, especially the prohormones, in the range of 10 to 1,000 fold higher than normal, can sufficiently occupy the VDR and exert actions like the Vitamin D hormones.
Blood levels of Vitamin D2 and Vitamin D3 are normally present at stable concentrations in human blood, given a sustained, adequate supply of Vitamin D from sunlight exposure and an unsupplemented diet. Slight, if any, increases in blood Vitamin D levels occur after meals since unsupplemented diets have low Vitamin D content, even those containing foods fortified with Vitamin D. The Vitamin D content of the human diet is so low that the National Institutes of Health (NIH) cautions "it can be difficult to obtain enough Vitamin D from natural food sources" [NIH, Office of Dietary Supplements, Dietary Supplement Fact Sheet: Vitamin D (2005)]. Almost all human Vitamin D supply comes from fortified foods, exposure to sunlight or from dietary supplements, with the last source becoming increasingly important. Blood Vitamin D levels rise only gradually, if at all, after sunlight exposure since cutaneous 7-dehydrocholesterol is modified by UV radiation to pre-Vitamin D3 which undergoes thermal conversion in the skin to Vitamin D3 over a period of several days before circulating in the blood.
Blood Vitamin D hormone concentrations also remain generally constant through the day in healthy individuals, but can vary significantly over longer periods of time in response to seasonal changes in sunlight exposure or sustained alterations in Vitamin D intake. Marked differences in normal Vitamin D hormone levels are commonly observed between healthy individuals, with some individuals having stable concentrations as low as approximately 20 pg/mL and others as high as approximately 70 pg/mL. Due to this wide normal range, medical professionals have difficulty interpreting isolated laboratory determinations of serum total 1,25-dihydroxyvitamin D; a value of 25 pg/mL may represent a normal value for one individual or a relative deficiency in another.
Transiently low blood levels of 1,25-dihydroxyvitamin D stimulate the parathyroid glands to secrete PTH for brief periods ending when normal blood Vitamin D hormone levels are restored. In contrast, chronically low blood levels of 1,25-dihydroxyvitamin D continuously stimulate the parathyroid glands to secrete PTH, resulting in a disorder known as secondary hyperparathyroidism. Chronically low hormone levels also decrease intestinal calcium absorption, leading to reduced blood calcium concentrations (hypocalcemia) which further stimulate PTH secretion. Continuously stimulated parathyroid glands become increasingly hyperplastic and eventually develop resistance to regulation by vitamin D hormones. Without early detection and treatment, secondary hyperparathyroidism progressively increases in severity, causing debilitating metabolic bone diseases, including osteoporosis and renal osteodystrophy.
Chronically low blood levels of 1,25-dihydroxyvitamin D develop when there is insufficient renal CYP27B1 to produce the required supply of Vitamin D hormones, a situation which commonly arises in CKD. The activity of renal CYP27B1 declines as the Glomerular Filtration Rate (GFR) falls below approximately 60 ml/min/1.73 m2 due to the loss of functioning nephrons. In end-stage renal disease (ESRD), when the kidneys fail completely and hemodialysis is required for survival, renal CYP27B1 often becomes altogether absent. Any remaining CYP27B1 is greatly inhibited by elevated serum phosphorous (hyperphosphatemia) caused by inadequate renal excretion of dietary phosphorous.
Chronically low blood levels of 1,25-dihydroxyvitamin D also develop because of a deficiency of Vitamin D prohormones, since renal hormone production cannot proceed without the required precursors. Prohormone production declines markedly when cholecalciferol and ergocalciferol are in short supply, a condition often described by terms such as "Vitamin D insufficiency," "Vitamin D deficiency," or "hypovitaminosis D." Therefore, measurement of 25-hydroxyvitamin D levels in blood has become the accepted method among healthcare professionals to monitor Vitamin D status. Recent studies have documented that the great majority of CKD patients have low blood levels of 25-hydroxyvitamin D, and that the prevalence of Vitamin D insufficiency and deficiency increases as CKD progresses.
It follows that individuals most vulnerable to developing chronically low blood levels of 1,25-dihydroxyvitamin D are those with CKD. Most CKD patients typically have decreased levels of renal CYP27B1 and a shortage of 25-hydroxyvitamin D prohormones. Not surprisingly, most CKD patients develop secondary hyperparathyroidism. Unfortunately, early detection and treatment of secondary hyperparathyroidism in CKD is rare, let alone prevention.
The National Kidney Foundation (NKF) has recently focused the medical community's attention on the need for early detection and treatment of secondary hyperparathyroidism by publishing Kidney Disease Outcomes Quality Initiative (K/DOQI) Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease [Am. J. Kidney Dis. 42:S1-S202, 2003)]. The K/DOQI Guidelines identified the primary etiology of secondary hyperparathyroidism as chronically low blood levels of 1,25-dihydroxyvitamin and recommended regular screening in CKD Stages 3 through 5 for elevated blood PTH levels relative to Stage-specific PTH target ranges. CKD Stage 3 was defined as moderately decreased kidney function (GFR of 30-59 mL/min/1.73 m2) with an intact PTH (iPTH) target range of 35-70 pg/mL; Stage 4 was defined as severely decreased kidney function (GFR of 15-29 mL/min/1.73 m2), with an iPTH target range of 70-110 pg/mL; and Stage 5 was defined as kidney failure (GFR of <15 mL/min/1.73 m2 or dialysis) with an iPTH target range of 150-300 pg/mL. In the event that screening revealed an iPTH value to be above the ranges targeted for CKD Stages 3 and 4, the Guidelines recommended a follow-up evaluation of serum total 25-hydroxyvitamin D to detect possible Vitamin D insufficiency or deficiency. If 25-hydroxyvitamin D below 30 ng/mL was observed, the recommended intervention was Vitamin D repletion therapy using orally administered ergocalciferol. If 25-hydroxyvitamin D above 30 ng/mL was observed, the recommended intervention was Vitamin D hormone replacement therapy using known oral or intravenous Vitamin D hormones or analogs. The Guidelines did not recommend the concurrent application of Vitamin D repletion and Vitamin D hormone replacement therapies, consistent with warnings mandated by the Food and Drug Administration in package inserts for Vitamin D hormone replacement products.
The NKF K/DOQI Guidelines defined Vitamin D sufficiency as serum 25-hydroxyvitamin D levels ≧30 ng/mL. Recommended Vitamin D repletion therapy for patients with "Vitamin D insufficiency," defined as serum 25-hydroxyvitamin D of 16-30 ng/mL, was 50,000 IU per month of oral Vitamin D2 for 6 months, given either in single monthly doses or in divided doses of approximately 1,600 IU per day. Recommended repletion therapy for patients with "Vitamin D deficiency" was more aggressive: for "mild" deficiency, defined as serum 25-hydroxyvitamin D of 5-15 ng/mL, the Guidelines recommended 50,000 IU per week of oral Vitamin D2 for 4 weeks, followed by 50,000 IU per month for another 5 months; for "severe" deficiency, defined as serum 25-hydroxyvitamin D below 5 ng/mL, the Guidelines recommended 50,000 IU/week of oral Vitamin D2 for 12 weeks, followed by 50,000 IU/month for another 3 months. Doses of 50,000 IU per week are approximately equivalent to 7,000 IU per day.
Most concepts of vitamin D metabolism and function have been developed with the rat and/or chick as experimental models. Studying vitamin D metabolism is hampered by the paucity of data on the normal circulating levels of vitamin D metabolites in mammals under normal conditions. Most recent research has focused on the analysis of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D as indicators of vitamin D status or aberrant physiological states.
Shortly after the discovery of vitamin D2 it seemed apparent that Vitamins D2 and D3 had similar biological activities in most mammals. More recent research, fostered by the discovery of sensitive analytical techniques and the availability of high specific activity 3H-labeled vitamin D species, indicated that differences in the metabolism of Vitamins D2 and D3 in mammals are perhaps widespread. Most notable were the apparent discrimination against Vitamin D2 by pigs [Biochem J. 204:185-189], cows [J Nutr 113:2595-2600], and humans [Gene Regulation, Structure-Function Analysis and Clinical Application, Walter de Gruyter. Berlin, pp. 765-766] and the apparent preference of Vitamin D2 by rats [Biochem J 204:185-189, J Bone Miner Res 5(Supplement 2):S265].
Vitamin D and its metabolites are transported in the blood of vertebrates attached to Vitamin D binding protein (DBP). Baird et al [Recent Prog Horm Res. 25:611-664] have shown that protein binding increases the solubility of steroids and that the metabolic clearance rate of steroids is in part dependent on their binding to specific plasma proteins.
Hay and Watson [Comp Biochem Physiol 56B:375-380] studied the affinities of DBP for 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3 in 63 vertebrate species. They found that many of the studied species discriminated against 25-hydroxyvitamin D2 in favor of 25-hydroxyvitamin D3 [Biochem J 204:185-189]. However, in rats the discrimination is against Vitamin D3 in favor of Vitamin D2. The rat DBP is known to have equal affinity for 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3, but a lower affinity for Vitamin D2 relative to Vitamin D3 [Steroids 37:581-592]. Reddy et al., [Calci Tissue Int 36:524] suggested that the lower affinity for Vitamin D2 resulted in its enhanced availability for liver 25-hydroxylation. Hence, in the presence of DBP, more 25-hydroxyvitamin D2 was made relative to 25-hydroxyvitamin D3 when equal amounts of Vitamin D2 or Vitamin D3 substrate were perfused into rat livers. In the experiments conducted by Reddy et al., if binding protein was eliminated from the perfusion media, equal amounts of 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3 were synthesized. Collectively, these data suggest that discrimination against the different forms of Vitamin D could likely result from variations in the affinity of DBP for the parent compound and/or one or more of their metabolites. Regardless of the mechanism for discrimination, it appears that these differences are present to afford the species the most efficient utilization of the most abundant Vitamin D metabolites available in their environment.
Critical questions remain unanswered regarding complete elucidation of the Vitamin D2 metabolic pathway, and species differences between Vitamin D2 and D3 metabolism are still virtually unexplored. The introduction of Vitamin D as a pharmacological intervention has resulted in a totally different set of issues regarding their metabolism, tissue kinetics, mechanism of action, and potential therapeutic uses.
Vitamin D receptors are present throughout the human body in a wide variety of cells, and there have been reports that vitamin D hormone has diverse "non-classical" biologic effects on cellular proliferation, the immune system and the cardiovascular system, beyond its "classical" effects on the PTH system. It has also been reported that 25-hydroxyvitamin D2 has direct effects on parathyroid cells in suppressing PTH [Kidney International, 70(4):654-659, August 2006]. There has been one report that Vitamin D2 was less than one-third as potent as Vitamin D3 and exhibited a shorter duration of action relative to Vitamin D3; administration of 50,000 IU of ergocalciferol or cholecalciferol to healthy male humans produced similar rises in serum concentration of the administered vitamin, indicating equivalent absorption, but 25-hydroxyvitamin D3 levels peaked at 14 days whereas 25-hydroxyvitamin D2 levels fell early and were not different from baseline at 14 days [J. Clin. Endocrinol. Metab., 89(11):5387-5391 (2004)].
Thus, the relative contribution of 25-hydroxyvitamin D compounds and 1,25-dihydroxyvitamin D compounds to PTH suppression, the relative potency of 1,25-dihydroxyvitamin D2 and 1,25-dihydroxyvitamin D3 in vivo, and the spectrum of non-classical biological effects of each of these hormones has not clearly been elucidated. There remains a need for alternative vitamin D hormone therapies that ideally provide beneficial effects on PTH levels, immune status and/or cardiovascular health, with reduced toxicity.

Methods and compounds for vitamin D therapy


Polymer electrolyte membranes (PEMs), methods and use thereof in fuel cells and methods of preparing thereof are disclosed. A PEM may include at least one porous support film and a polysiloxane polymer bonded to the at least one porous support film, wherein the polysiloxane polymer includes at least one polysiloxane grafted to a heterocycle.

Fuel cells, by the use of electrochemical reactions, serve as an energy source for mobile or stationary applications. They may offer lower emissions, higher energy and lower levels of noise and vibration as compared to alternative energy sources. A fuel cell may typically include a negative electrode (e.g., anode), a positive electrode (e.g., cathode) and a membrane between the anode and cathode.
While various membranes may be employed in the development of fuel cells, polymer electrolyte membranes or proton exchange membranes (PEMs) are currently important components of fuel cells. For example, high temperature (HT) PEMs which are operational at temperatures above 120° C. with no or low humidification, may exhibit beneficial properties such as anode tolerance to significant quantities of carbon monoxide poisoning, enhanced electrode kinetics, reduced cathode flooding, and efficient thermal management.
There are limitations, however, to the existing membranes used in fuel cells and their methods of production. For example, polymer proton conductors including perfluorosulfonic polymers such as Nafion®, which are widely used as a standard materials in low temperature PEM (e.g., perfluorosulfonic acid (PFSA) membrane, sulfonated PEM) fuel stacks due to their proton conductivity and stability, may be difficult to synthesize. The capital costs thus associated with producing some low temperature PEMs still remain high. Also, sulfonated PEMs may depend strongly on the amount of water the membranes contain and the temperature of exposure. Furthermore, membranes having free phosphoric acid (H3PO4) may exhibit acid leaching, thus resulting in decreased proton conductivity.
Therefore, a need exists to develop mechanically and thermally stable polymer electrolyte membranes exhibiting low acid leaching and high proton conductivity at high temperatures and low relative humidity.

Proton exchange membranes based on heterocycles and acids through an organic-inorganic hybrid process


An apparatus is for withdrawing the desired one of a plurality of magnetic disc packs accommodated in a pack holder and for transporting the pack to a specified signal recording-reproduction assembly, or for returning the pack from the assembly into the holder. The pack is guided, for reciprocating movement, along a straight path extending from a first rest position within the holder to a second rest position for recording or reproduction. A pack transport assembly, for reciprocatingly driving the pack, has projecting pack pushing levers for pushing the pack from the first rest position toward the second rest position.

The so-called still video floppy disc system is known as an apparatus for recording and reproducing still pictures (see "Nikkei Electronics," July 2, 1984, pp. 80-85, published by Nikkei McGraw-Hill).
FIG. 17 shows a magnetic disc pack 1 for the still video floppy disc system. The pack comprises a flat rigid jacket 11, and a magnetic disc 12 rotatably housed in the jacket 11. The magnetic disc is usable for recording 50 still pictures (in the case of field recording).
Such magnetic disc: packs are usable to provide an image filing system. For example, a multiplicity of still pictures can be filed if it is possible to provide an apparatus comprising a boxlike pack holder 2 for holding magnetic disc packs 1 therein as seen in FIG. 5, and an automatic mechanism for withdrawing the desired pack 1 from the holder, transporting the pack to a specified signal recording-reproduction position and returning the pack to the holder after recording or reproduction. If the apparatus is adapted for automatic pack changing, for example, for 10 magnetic disc packs, a filing system can be realized for recording or reproducing 500 images.
Unexamined Japanese Patent Publication SHO 61-267966 discloses an automatic magnetic disc: pack changing apparatus which is usable for such a filing system. FIG. 19 shows the disclosed apparatus. After a pack holder 2 is loaded into the apparatus with magnetic disc packs 1 accommodated therein, the pack holder 2 is moved in the direction of arrow A to bring the pack 1 to be used for recording or reproduction to a position opposed to a bucket 9 in a standby position. The pack 1 is then transported in the direction of arrow B and loaded into the bucket 9 by the pack transport mechanism to be described below. The bucket 9 is thereafter moved in the direction of arrow C along with the pack 1 to mount the pack 1 on a rotary drive shaft 91. The magnetic disc in the pack 1 is then driven by the shaft to record or reproduce signals. When to be changed for another pack, the pack is transported reversely.
With reference to FIG. 20, the pack transport mechanism comprises a pawl 92 engageable in a recess 17 formed in the jacket of the pack, and reciprocating means 93 connected to the pawl.
With the above automatic pack changing apparatus, the magnetic disc: pack 1 must be transported first in the direction of arrow B and then in the direction of arrow C perpendicular to the direction B as seen in FIG. 19. Accordingly the transport of the pack requires a complex mechanism, while the change of the pack requires a period of time since the pack needs to be transported a large distance with a change of its course. Moreover, changing the course of transport renders the pack very prone to damage.
Additionally, the transport mechanism is in direct engagement with the disc pack 1 as shown in FIG. 20, so that the accuracy with which the pack is positioned in place is dependent on the accuracy of positioning the transport mechanism. Since the pack transport mechanism is complex as stated above, it is difficult to set the pack in the specified recording reproduction position accurately.

Recording-reproduction apparatus for magnetic disc packs with an automatic pack changing mechanism