A method and apparatus are provided for selecting and analyzing a subpopulation of cells or cell objects for a certain parameter such as DNA, estrogen, and then measuring the selected cells. The observer in real time views a field of cells and then gates for selection based on the morphological criteria those cells that have the visual parameter such as colored DNA or colored antigen into a subpopulation that is to be measured. The selected cells are examined by digital image processing and are measured for a parameter such as a true actual measurement of DNA in picograms. A quantitation of the measured parameter is generated and provided.

The present invention is directed to quantitative testing apparatus and methods which may be used for a wide range of diagnostic and prognostic evaluations of various cells, antigens, or other biological materials taken from the human body. However, for purposes of illustration and ease of understanding, the invention will be disclosed in conjunction with its preferred use, which is the quantitative measurement of cellular DNA for the purpose of cancer diagnosis and prognosis. More specifically, the present invention is directed to methods and apparatus for interactive image analysis which are adapted to analyze and quantify the DNA in different classes of specimen cells taken from a human body.
The current state of the art in the pathology laboratory for measuring the DNA content of a cell is by visual observation. A pathologist observes through a microscope primarily the shape and texture of suspected cancer cells and then classifies the cells into a normal category or into one of several abnormal or cancer categories. Such evaluations are very subjective and can not differentiate and precisely quantify small changes in DNA within individual cells or in very small populations of abnormal cells. These small changes may represent an incipient stage of cancer or a change in cell structure due to treatment of the cancer by chemotherapy or radiation. Such small changes are, therefore, important in the diagnosis and prognosis of these diseases.
However, the advantage in diagnosis and/or prognosis of abnormal ploidy distributions that a pathologist viewing a specimen under a microscope has is the discerning expertise of a skilled person in classifying cells as normal or abnormal. There is an innate human ability to make relatively quick infinite gradations of classification, i.e., almost normal, slightly abnormal, etc. On the other hand, the classification and measurement of cell features and parameters manually by a pathologist on a cell-by-cell basis is extremely tedious and time consuming. Statistical analysis of such cell data taken by hand is relatively difficult because each record has to be entered and then processed. For different records, taken at different times, and under varying conditions broad statistical categorizations may be unreliable.
The alternative is automated cell analysis where the pathologist uses specialized equipment to perform the analysis. In automatic cell analysis, such as that accomplished by a flow cytometer, mass tests are performed in gross on a specimen cell population without a researcher being able to exclude or include certain data of the population. The specimen is measured "as is" without really knowing what cells are being measured and how many. Important single cell data or data from relatively small groups of cells are lost in the overall averaging of a specimen. Further, relatively large amounts of a specimen have to be used to provide results from these tests and the sample is consumed.
Although there are commercially available general purpose flow cytometers, they are very expensive and can handle only liquid blood specimens or tissue disaggregations. These cytometers are incapable of working on standard tissue sections or using conventional microscope slides which are the preferred specimen forms of pathology laboratories. Additionally, a flow cytometer does not allow for the analysis of morphological features of cells such texture, size and shape of cell nuclei and alterations in the nuclear-to-cytoplasmic ratios of cells.
The methods and apparatus illustrated in the referenced Bacus applications have solved these and other problems relating to the analysis of various features and parameters of cell objects. Bacus discloses a measurement method and apparatus which can acquire accurate quantitative data concerning a plurality of individual cells very quickly by an interactive process with a pathologist or an operator.
The Bacus apparatus provides means for displaying on a video monitor an image of a group of cells from a field of a microscope slide. The image is further digitized and stored in a memory of the apparatus. From the digitized image, a processor means identifies each possible cell object automatically by a pattern recognition technique. An interactive program allows the operator to point to each object or cell in succession and make morphological decisions for classification and measurements concerning each. For quantitative DNA analysis, the measurement is of the optical density of the cell object and the classification is by a pathologist as to whether the cell appears normal or cancerous. The decisions include whether to accept or reject a particular cell for further measurement and processing. The cell object, if selected, can then also be classified into one of several classifications for later statistical analysis. The apparatus further has means which permit the classification and storing of more than one image.
When the apparatus is used for DNA analysis, tissue and cell specimens are applied to a slide which is then stained with a specific stain that combines proportionately with the DNA and essentially renders invisible the remainder of the cell so that the image analysis apparatus can measure the optical density of the DNA which is concentrated in the nucleus of the cell. The stain associates with the DNA to provide a detailed nuclear structure and pattern which may be visually observed and interpreted by the pathologist using the apparatus for classification. The amount of DNA in the malignant cells is substantially greater than that for normal cells because the malignant cells are usually dividing and replicating rapidly or the malignant cells have abnormal numbers of chromosomes or have defective chromosomes.
The Bacus apparatus can not only detect minute alterations in the nucleus by providing a real and accurate measurement of the DNA mass in picograms but also can measure and quantify the amount of DNA and relate it to stored statistical analyses to aid in diagnosis. More specifically, the invention allows an iterative analysis of specimen population cells and provides a histogram or other statistical display of the population distribution of the cells with respect to their DNA content and with respect to a standard DNA for normal cells so that subtle shifts in population distribution can be readily understood. To this end cell nuclei images are not only acquired and stored but the data therefrom can be integrated with other statistical data to provide multivariable analysis, discrimination of cells, histograms, and scattergrams of cells or cell populations.
While the methods and apparatus described above are extremely advantageous and advance the art of anueploidy analysis by image processing, they are not as sensitive as they could be. With the progress in measuring the quantity and distribution of DNA in a cellular population, there has come the need to further refine and sensitize that analysis and characterization process. One area in which sensitivity of the above described process can be improved is in the operator classification of cell types.
The previous apparatus of Bacus relies mainly on the pathologist or operator to make a subjective judgement concerning the classification of cell types, and whether they are to be classified at all. This is a principal advantage of the apparatus where the expertise of the pathologist in discerning cell types is automated and measurement of specified parameters of the chosen cells is accurately made. However, it has been learned that different cell types which are really quite different structurally appear morphologically similar under the microscope.
This is particularly true when the nuclear DNA has been enhanced by Feulgen staining. Such nuclear staining is for the purpose of enhancing the optical characteristics of the nuclei of the cells which contain the DNA, but that necessarily de-emphasizes the visual characteristics of the cytoplasm in the rest of the cell outside of the nucleus. The result is to allow easier image analysis and precise measurement of the DNA of the nuclear material, but at the same time this enhancement causes the loss of the visual morphological characteristics of the cytoplasm which a pathologist might use to distinguish one type of cell from another. Additionally, there are different cell types, which it is advantageous to classify separately, but which provide no or only faint visual clues as to their differences.
Thus, there is the need to alert a pathologist classifying the cell populations for DNA analysis with the Bacus instrument about the different cell types, whether by optical enhancement or otherwise. A more definitive mechanism would be the use of some demonstrable marker on the cells themselves by which the pathologist can objectively separate the various cell types. There are known in the art many optical enhancement or marking techniques for cell populations, including those described in the above referenced Bacus applications. For example, since the advent of monoclonal antibody production, numerous antibodies have been developed which are specific for cellular components, either in the cytoplasm, nucleus or on the cell membrane. Some have already been used to type cells in pathology to assist in the definition of the cell of origin of a number of tumors where subjective morphology is equivocal.
Among the most notable of these antibodies are antibodies to Leukocyte Common Antigens, which identify inflammatory cells, and antibodies to a family of cytoplasmic structural proteins called cytokeratins which identify cells arising from epithelial structures. Other antibodies to cytoplasmic components such as intermediate filaments can be utilized to identify cells which provide structural support, the so called stromal cells. In addition, numerous antibodies exist which are more specifically related to individual tumor types.
However, further optical enhancement of the cytoplasm for different types of cells is problematic in view of the current DNA staining technique. There are many difficulties, the least of which is that an optical enhancement factor for the cytoplasm should be compatible with the present imaging techniques using computer analysis of optical density and be required to provide such compatibility without impairing the sensitivity of the imaging techniques for the present nuclear staining. Chemical compatibility with the present Feulgen staining technique also presents a major hurdle. Optical enhancement of the cytoplasm after Feulgen staining of the DNA is substantially unavailable because the Feulgen process is destructive of the cell cytoplasm and changes the way it appears normally. However, prior optical enhancement of the cytoplasm is equally as difficult because the Feulgen staining process is caustic with the use of highly acidic reagents which can easily destroy other optical enhancement factors. Moreover, if done prior to Feulgen staining, the optical enhancement process of the cytoplasm cannot affect the nuclear material in a manner such that the result of the subsequent Feulgen staining will be changed.

Methods and apparatus for immunoploidy analysis


Systems and methods provide automated generation of neighbor frequency lists for configuration of frequency objects for wireless stations. A computing device selects a target sector carrier of a wireless station of multiple wireless stations in a radio access network and identifies, based on distances from the wireless station, neighboring sector carriers of the target sector carrier. The computing device filters the neighboring sector carriers based on an azimuth of the target sector carrier to form a filtered set of neighboring sector carriers. The computing device calculates a probability of neighboring frequencies for the target sector carrier based on locations of the filtered set of neighboring sector carriers and generates, based on the calculating, a neighbor frequency list for the target sector carrier. The neighbor frequency list is used to configure frequency objects, for the target sector carrier, that ensure seamless handovers within the radio access network.

Providers of wireless communication services continue to improve and expand available wireless networks. One aspect of such improvements includes the development of wireless access networks as well as options to utilize such wireless access networks. A wireless access network may manage a large number of devices. For example, a base station (also referred to as a wireless station) may service a large number of mobile devices, connecting these devices to a core network. The mobile devices may move within the wireless access network, using different base stations to maintain a connection with the core network. During an execution of a handover procedure between wireless stations, various signaling may take place between a source wireless station and a new wireless station, as well as signaling with a mobile device. The success or failure of the handover procedure can impact the quality of service provided to the mobile device.

This patent is subject to a terminal disclaimer.

System and method for frequency object enablement in self-organizing networks


This rubber composition comprises a rubber wet master batch which uses a rubber latex solution and a carbon black (A)-containing slurry as raw materials, rubber, and carbon black (B), wherein the amount of the carbon black (A) in the rubber wet master batch is 1 to 35 parts by weight with respect to 100 parts by weight of the rubber component in the rubber wet master batch, and the total amount of the carbon black (A) and (B) in the rubber composition is 50 parts by weight or more with respect to 100 parts by weight of the total rubber component in the rubber composition. Accordingly, the present invention can provide: a rubber composition from which vulcanized rubber having excellent low heat generating properties and wear resistance can be obtained; and a method for producing the rubber composition.

It has been hitherto known in the rubber industry that when a rubber composition containing carbon black is produced, a wet rubber masterbatch is used to improve the workability of the composition and the dispersibility of carbon black therein. This technique is a technique of mixing carbon black and a dispersing solvent beforehand with each other at a predetermined ratio, dispersing carbon black into the dispersing solvent by a mechanical force, mixing the resultant carbon-black-containing slurry solution with a rubber latex solution in a liquid phase, adding a solidifier such as an acid, after the mixing, to the mixture to solidify the mixture, collecting the solidified mixture, and then drying the mixture.
It is known that the use of a wet rubber masterbatch gives a rubber composition better in rubber physical properties, such as abrasion resistance and low exothermicity, than the use of a dry rubber masterbatch yielded by mixing carbon black and rubber with each other in a solid phase since in the case of the former use, carbon black is excellent in dispersibility (Patent Documents 1 to 4).

Rubber composition and method for producing same


A community access or cable television (CATV) entry adapter interfaces a CATV network to subscriber devices at a subscriber premises. The CATV entry adapter is remotely disabled or enabled through the CATV network to prevent or allow downstream CATV signals from reaching subscriber devices connected to the adapter. The CATV entry adapter is also adapted to function as a hub in a MoCA network independently of whether the CATV entry adapter is disabled or enabled.

CATV networks use an infrastructure of interconnected coaxial cables, signal splitters and combiners, repeating amplifiers, filters, trunk lines, cable taps, drop lines and other signal-conducting devices to supply and distribute high frequency "downstream" signals from a main signal distribution facility, known as a "headend," to the premises (homes and offices) of subscribers to the CATV services. The downstream signals enter the subscriber premises and cause the operation of certain subscriber devices, such as television sets, telephone sets and computers. In addition, most CATV networks also transmit "upstream" signals from the subscriber devices back through the CATV network infrastructure to a headend of the CATV network. For example, the subscriber uses a set top box to select programs for display on the television set. As another example, two-way communication is essential when using a personal computer connected through the CATV infrastructure to the public Internet. As a further example, voice over Internet protocol (VoIP) telephone sets use the CATV infrastructure and the public Internet as the communication medium for transmitting two-way telephone conversations.
The downstream signals are delivered from the CATV network infrastructure through a CATV entry adapter to the subscriber premises, and upstream signals originating at the subscriber premises are delivered through the CATV entry adapter to the CATV network infrastructure. The CATV entry adapter is also commonly referred to as an entry device, terminal adapter or a drop amplifier. The CATV entry adapter is a multi-port device which connects at an entry port to the CATV drop cable from the CATV network infrastructure. The multiplicity of other signal distribution ports of the entry adapter are connected to in-home or in-premises coaxial cables which extend throughout the subscriber premises to separate cable outlets. Each cable outlet is connected to, or is available to be connected to, a subscriber device. Typically, most homes have coaxial cables extending to cable outlets in almost every room, because different types of subscriber devices may be used in different rooms. For example, television sets, computers and telephone sets are commonly used in many different rooms of a home or office. The multiple signal distribution ports of the entry adapter deliver the downstream signals from the entry port to each cable outlet and conduct the upstream signals from the distribution ports to the entry port and the drop cable of the CATV infrastructure.
Subscribers pay for CATV services, which are delivered by permitting the subscriber to receive CATV signals supplied by the CATV service provider over the CATV network infrastructure to the subscriber premises. To deliver CATV signals only to those CATV subscribers which have paid for the CATV service, the CATV service provider dispatches a technician to the subscriber premises to connect the drop coaxial cable from the cable tap of the CATV network infrastructure to a CATV entry adapter which is located at the subscriber premises. In this manner, downstream CATV signals are delivered from the CATV network infrastructure to the subscriber, and upstream signals from subscriber devices in the subscriber premises are delivered to the CATV network infrastructure and the CATV service provider.
So long as the subscriber pays for the CATV service, the physical connection between the entry adapter at the subscriber premises and the CATV network infrastructure external to the subscriber is maintained. Should the subscriber fail to pay for the CATV service, the CATV service provider sends a technician to the subscriber premises where the drop cable from the CATV network infrastructure cable tap is disconnected from the entry adapter. Once disconnected in this manner, the subscriber no longer receives CATV signals from the CATV network infrastructure.
Dispatching CATV technicians to enable and disable CATV service at each subscriber premises involves a significant cost to the CATV service provider. For example, each dispatch of a service technician, sometimes referred to as a "truck roll," in a major metropolitan area or a remote rural area may cost as much as $125. Since the typical monthly subscription fee for CATV services is less than $125, the service provider loses a significant amount of income due to the necessity for truck rolls to control the connection and disconnection of the entry adapters at each subscriber premises to and from the CATV network infrastructure. In addition, in those situations where the subscriber must provide entry for the technician to access the CATV entry adapter at the subscriber premises, the costs of truck rolls can be substantially increased due to failed attempts to coordinate schedules and meetings between the subscriber and the technician. A truck roll which is executed to a subscriber premises when the subscriber is not present unnecessarily increases the cost of enabling and disabling CATV service to the subscriber.
Furthermore, CATV service providers terminate CATV service to subscribers in response to the non-payment for CATV services. The termination of the CATV service sometimes motivates the subscriber to pay the CATV bill, resulting in the need to subsequently re-enable the CATV service. Such disabling and re-enabling requires more truck rolls, which further diminishes the profit due to cost of the truck rolls. In actuality, the cost of such truck rolls may discourage the CATV service provider from discontinuing service to many subscribers who have failed to pay, or the discontinuance of service may be delayed for a substantial amount of time during which the non-paying subscriber may continue to enjoy the CATV services provided. All of these factors diminish the profit of the CATV service provider.
Past attempts have been made by CATV service providers to remotely enable and disable a subscriber's CATV service. Such past attempts have involved the use of remotely controllable cable taps that were part of the CATV network infrastructure at a location separated from the subscriber premises. The remotely controllable cable tap and had multiple ports for connection of multiple drop cables, with each drop cable connecting to a different subscriber premises. An out of CATV frequency band downstream control signal was sent by the CATV service provider to each of the controllable cable taps, and the control signal was intended to be interpreted by the controllable cable tap to enable or disable the conduction of CATV signals to each of its connection ports separate from each of the other connection ports. When enabled, a connection port of the controllable cable tap was intended to conduct downstream CATV signals to the subscriber premises connected to that connection port, as well as to conduct upstream CATV signals from the subscriber premises to the CATV network infrastructure.
In actual use, remotely controllable cable taps never functioned on a consistent and reliable basis, and therefore never gained significant acceptance. A malfunction or discrepancy in functionality typically had the effect of adversely affecting many of the connection ports and consequently many of the multiple subscribers connected to that particular controllable cable tap. Thus, an attempt to disable the service to one particular subscriber may have had the effect of terminating the service to other subscribers for whom the CATV service was intended to be continued. Sometimes, the wrong connection port was disabled, thereby terminating the service to an acceptable subscriber while failing to terminate the service to an unacceptable subscriber. Similar problems were encountered in attempts to enable CATV service. In a significant number of circumstances, service could not be re-enabled. Thus even in these circumstances truck rolls were required to manually achieve the connectivity that was intended to be achieved remotely. Because of the potential for adversely impacting the CATV service to multiple subscribers arising from a malfunction or erroneous function within such remotely controllable cable taps, the costs associated with truck rolls and CATV technician service calls under such circumstances outweighed any benefits, and as a consequence there was no significant profit benefit to CATV service providers in using remotely controllable cable taps. Furthermore, remotely controllable cable taps provided no capability to permit some level of service to the subscriber while preventing other levels of service, since the remotely controllable cable tap either entirely permitted or entirely discontinued CATV service of all levels and types.

CATV entry adapter and method for remotely enabling and disabling CATV service at a subscriber's premises


Selective electrolytic deposition is provided on a body having a conductive surface comprised of two different conductive materials in which one of the conductive materials forms a surface layer upon exposure to a particular ambient environment and wherein that surface layer prevents electroplating on that material in the particular electroplating environment utilized for the electroplating of the desired pattern on the other conductive material.

Electrolytic metal deposition is a widely used industrial process having application to a wide variety of products and fields. In electronic applications where a specific metal pattern is required, electrolytic deposition may be used in either of two manners. In the first, a uniform metal layer is formed by electrolytic deposition, the exposed surface of that layer is coated with a photoresist, the photoresist is then exposed in the desired pattern for the final metal structure, the photoresist is developed and the structure is etched to remove the unprotected electroplated material In the second technique, a photoresist pattern is disposed on the conductive surface of a substrate structure, exposed and developed to expose the underlying conductive layer in the desired plating pattern. Thereafter, the structure is electroplated to produce a thick layer on the exposed portion of the underlying conductive layer. Where relatively thick conductive layers are desired, these processes both present problems with respect to the durability of the photoresist in the etching or plating bath because extended time periods in these solutions can cause deterioration of the photoresist. Sufficient deterioration of the photoresist results in plating or etching in undesired locations. Another technique for plating which can be used for a connected structure is to define the conductor to be plated with photoresist and remove the rest of the layer. This process depends on carrying the plating current through the structure being plated itself This tends to result in non-uniform plating with the greater thickness being near the external electrical connections to the structure and successively lesser thicknesses further from the connections. Thus, this is not a preferred method. An additional problem where fine line, thick metallic patterns are desired is the inability of both the plating-followed-by-photoresist-and-etching and the photoresist-followed-by-plating process to provide reliable definition of fine line structures. Another problem with the plating followed by photoresist and etching process is the problem of accurately aligning the photoresist exposure mask with respect to the underlying structure on the substrate beneath a thick metal layer.
There is a need for a process which enables thick, patterned layers of metal to be electrolytically deposited on a conductive substrate in a reliable manner with a minimum of processing steps.

Selective electrolytic desposition on conductive and non-conductive substrates


A cutting unit for a slot-type perforator is mounted in a casing having a specific edge, driven by a piston or plunger. The cutting unit includes cutting tools associated with a first holder immovable relative to the piston, and a second holder, including a recess, cooperating with the casing's edge, immovable relative to the casing. The holders move relative to each other causing extending and retracting the cutting tools in opposite directions, during piston's movements. The cutting unit includes a retractable mechanism to bring its parts into a transportation position and to fix them therein. The retractable mechanism includes a guide groove made in the second holder, and a connecting rod attached to the first holder. The rod moves through the groove ensuring the return of the second holder into the transportation position, wherein it is fixed absent pressure upon the piston, caused by interaction of the edge and recess.

In the prior art are known the cutting units of hydro-mechanical slot perforating machines, which include cutting tools enabling to form simultaneously two perforation slots in the production string, with the mechanism of their extension, for example, disclosed in patents RU 2249678 C2, IPC E21B 43/112, Apr. 10, 2005, RU 2371569 C1, IPC E21B 43/112, Oct. 27, 2009, RU 86654 U1, IPC E21B 43/112, Sep. 10, 2009, RU 2348797 C1, IPC E21B 43/112, Mar. 10, 2009. At that the size of cutting tools used in the mentioned designs of the cutting units approaches the diameter of the perforator's casing that allows creating perforations slots of a considerable depth.
The disadvantage of multiple-cutting units is the use of cutting tools extension mechanisms therein, envisaging the presence of a significant distance between the cutting tools in a working position, which conditions a significant height difference of the perforating slots formed simultaneously.
Known is a cutting unit of hydromechanical slot-type perforator disclosed in the patent for utility model RU 100802 U1, IPC E21B 43/112, Dec. 27, 2010, which eliminates the mentioned disadvantage. It is the closest to the present invention and is further referred to as a 'prototype'.
The cutting unit of hydromechanical slot-type perforator of the prototype includes a retractable blades mounted on the axes of the upper and lower holders, installed inside the perforator's casing by means of the fingers, with that the upper holder is mounted on the plunger and the lower holder is secured to the housing, in addition, holders are made flat and located in the same plane with the possibility of deviations in opposite directions at translational impact of the plunger, in addition, working surfaces of the holders interacting with each other are performed at the ends of the holders, rounded, and the lower holder is additionally provided with a supporting surface with the possibility of exposure to the lower spring anchor through the washer, while the lower spring is located in the glass—the tensioner.
Cutting tools of the device, according to the prototype, are mounted at the holders close enough to each other. Advancing in opposite directions during the opposite movement and interaction of the holders, cutting tools perform back-to-radial displacement, and, taking up the operating position, turn out to be approximately at the same level relative to the vertical axis of the perforator. This ensures that the production casing opening with simultaneous formation of two perforating slots with a minimum height difference between them.
The disadvantage of the cutting unit according to the prototype is lack of an effective mechanism to bring the telescoping parts in the initial (transport) position after perforation as well as lack of restraint and fixing devices. Thus, the prototype does not provide any means for the return of the lower cutting disc in the transport position and for fixing it in such position. The upper cutting disc, which rises in the holder together with the piston under conditions of reducing operating pressure, takes up the initial position under the force of its own weight. However, the prototype does not provide the means for holding the top cutting disc in the perforator's housing during its transportation. Given the design features of the cutting unit according to the prototype, it can lead to spontaneous extension of cutting discs out of the case during transportation of the perforator and when it is lowered into the borehole, as well as to inability to remove the device from the well after perforation. In addition, the spontaneous extension of the cutting disc out of the body can cause damage and injury to personnel working with the device.

Cutting unit of a hydromechanical slot perforator


A modular order fullment system uses a number of inexpensive mobile apparatuses such as containers with horizontally accessible bins that are brought to a stationary frame that supports a pick-to-light system to direct a human or robotic operator to pick from or put to receptacles in the mobile apparatus.

Field of the Invention
The field of art disclosed herein pertains to devices order fulfillment systems that direct operators using a light module for a particular slot, and more particularly to pick walls that incorporate light modules.
Description of the Related Art
Order fulfillment such as for e-commerce or store replenishment for less than a full container of products is often accomplished by having an operator directed to pick a product from a donor container and put the product into an order container. Reading a display or piece of paper with the order is an inefficient approach when the permutations of possible donor containers and order containers increases. To provide for better efficiency and accuracy, many distribution centers and warehouses rely upon a pick-to-light (PTL) system in order to direct an operator to where the pick or put is to occur. The PTL can include alphanumeric and colored information that is located at the particular destination to inform and guide the operator. A warehouse management system (WMS) keeps track of the inventory and the orders to be filled and is integrated with the PTL system to direct the pick or put operation and to receive confirmation of its completion.
While PTL systems frequency achieve a return on investment (ROI) that quickly pays for the infrastructure investment by reducing the amount of labor required, there is still considerable investment involved. Automating delivery and take-away of the containers can require a sizeable investment to satisfy throughput demands, especially during a peak season. A need exists for taking maximum advantage of the PTL systems capacity without necessary installing more automated conveyances.


A dosage unit for treating constipation in a human patient is described. The dosage unit of the invention includes a halogenated prostaglandin analog and a pharmaceutically suitable excipient. The dosage unit relieves constipation without substantial side effects. In particular, the dosage unit includes a prostaglandin (PG) analog represented by Formula (I) and/or its tautomers, and a pharmaceutically suitable excipient, wherein the dosage unit contains the PG analog in an amount of 24 μg+/−10%:

Constipation is generally defined as infrequent and difficult passage of stool. Medical reporting estimates that one of every 50 people in the United States suffers from constipation, making it one of the most common disorders among Americans. Constipation is more likely to affect females than males and more likely to occur in older adults, showing an exponential increase after the age of 65. The actual occurrence of constipation is likely higher than reported, as many individuals suffer at home without seeking professional care.
Although in some instances constipation may be caused by obstruction, most constipation can be associated with factors such as a diet low in soluble and insoluble fibers, inadequate exercise, medication use (in particular, opiate analgesics, anticholinergic antidepressants, antihistamines, and vinca alkaloids), bowel disorders, neuromuscular disorders, metabolic disorders, poor abdominal pressure or
muscular atony.
A precise quantitative definition of constipation has been difficult to establish due to the wide range of perceived "normal" bowel habits, as well as the diverse array of symptoms and signs associated with constipation. The FDA has recognized a need for prescriptive treatment of occasional constipation.
Prostaglandins (hereinafter, referred to as PGs) are members of class of organic carboxylic acids, which are contained in tissues or organs of human or other mammals, and exhibit a wide range of physiological activity. PGs found in nature (primary PGs) generally have a prostanoic acid skeleton as shown in the formula (A):

PGs are classified into several types according to the structure and substituents on the five-membered ring, for example,
Prostaglandins of the A series (PGAs);
Prostaglandins of the B series (PGBs);
Prostaglandins of the C series (PGCs);
Prostaglandins of the D series (PGDs);
Prostaglandins of the E series (PGEs);
Prostaglandins of the F series (PGFs);
and the like. Further, they are classified into PG1s containing a 13,14-double bond; PG2s containing, 5,6- and 13,14-double bonds; and PG3s containing 5,6-, 13,14- and 17,18-double bonds. PGs are known to have various pharmacological and physiological activities, for example, vasodilatation, inducing of inflammation, platelet aggregation, stimulating uterine muscle, stimulating intestinal muscle, anti-ulcer effect and the like. The major prostaglandins produced in the human gastrointestinal (GI) system are those of the E, I and F series (Sellin, Gastrointestinal and Liver Disease: Pathophysiology, Diagnosis, and Management. (WB Saunders Company, 1998); Robert, Physiology of the Gastrointestinal Tract 1407-1434 (Raven, 1981); Rampton, Prostaglandins: Biology and Chemistry of Prostaglandins and Related Eicosanoids 323-344 (Churchill Livingstone, 1988); Hawkey, et al., Gastroenterology, 89: 1162-1188 (1985); Eberhart, et al., Gastroenterology, 109: 285-301 (1995)).
Under normal physiological conditions, endogenously produced prostaglandins play a major role in maintaining GI function, including regulation of intestinal motility and transit, and regulation of fecal consistency. (Sellin, Gastrointestinal and Liver Disease: Pathophysiology, Diagnosis, and Management. (WB Saunders Company, 1998); Robert, Physiology of the Gastrointestinal Tract 1407-1434 (Raven, 1981); Rampton, Prostaglandins: Biology and Chemistry of Prostaglandins and Related Eicosanoids 323-344 (Churchill Livingstone, 1988); Hawkey, et al., Gastroenterology, 89: 1162-1188 (1985); Eberhart, et al., Gastroenterology, 109: 285-301 (1995); Robert, Adv Prostaglandin Thromboxane Res, 2:507-520 (1976); Main, et al., Postgrad Med J, 64 Suppl 1: 3-6 (1988); Sanders, Am J Physiol, 247: G117 (1984); Pairet, et al., Am J Physiol., 250 (3 pt 1): G302-G308 (1986); Gaginella, Textbook of Secretory Diarrhea 15-30 (Raven Press, 1990)). When administered in pharmacological doses, both PGE2 and PGF2α have been shown to stimulate intestinal transit and to cause diarrhea (Robert, Physiology of the Gastrointestinal Tract 1407-1434 (Raven, 1981); Rampton, Prostaglandins: Biology and Chemistry of Prostaglandins and Related Eicosanoids 323-344 (Churchill Livingstone, 1988); Robert, Adv Prostaglandin Thromboxane Res, 2:507-520 (1976)). Furthermore, the most commonly reported side effect of misoprostol, a PGE1 analogue developed for the treatment of peptic ulcer disease, is diarrhea (Monk, et al., Drugs 33 (1): 1-30 (1997)).
PGE or PGF can stimulate the intestines and cause intestinal contraction, but the enteropooling effect is poor. Accordingly, it is impossible to use PGEs or PGFs as cathartics because of side effects such as stomachache caused by the intestinal contraction.
Multiple mechanisms, including modifying enteric nerve responses, altering smooth muscle contraction, stimulating mucous secretion, stimulating cellular ionic (in particular electrogenic CI− transport) and increasing intestinal fluid volume have been reported to contribute to the GI effects of prostaglandins (Robert, Physiology of the Gastrointestinal Tract 1407-1434 (Raven, 1981); Rampton, Prostaglandins: Biology and Chemistry of Prostaglandins and Related Eicosanoids 323-344 (Churchill Livingstone, 1988); Hawkey, et al., Gastroenterology, 89: 1162-1188 (1985); Eberhart, et al., Gastroenterology, 109: 285-301 (1995); Robert, Adv Prostaglandin Thromboxane Res, 2:507-520 (1976); Main, et al., Postgrad Med J, 64 Suppl 1: 3-6 (1988); Sanders, Am J Physiol, 247: G117 (1984); Pairet, et al., Am J Physiol, 250 (3 pt 1): G302-G308 (1986); Gaginella, Textbook of Secretory Diarrhea 15-30 (Raven Press, 1990); Federal Register Vol. 50, No. 10 (GPO, 1985); Pierce, et al., Gastroenterology 60 (1): 22-32 (1971); Beubler, et al., Gastroenterology, 90: 1972 (1986); Clarke, et al., Am J Physiol 259: G62 (1990); Hunt, et al., J Vet Pharmacol Ther, 8 (2): 165-173 (1985); Dajani, et al., Eur J Pharmacol, 34(1): 105-113 (1975); Sellin, Gastrointestinal and Liver Disease: Pathophysiology, Diagnosis, and Management 1451-1471 (WB Saunders Company, 1998)). Prostaglandins have additionally been shown to have cytoprotective effects (Sellin, Gastrointestinal and Liver Disease: Pathophysiology, Diagnosis, and Management. (WB Saunders Company, 1998); Robert, Physiology of the Gastrointestinal Tract 1407-1434 (Raven, 1981); Robert, Adv Prostaglandin Thromboxane Res 2:507-520 (1976); Wallace, et al., Aiiment Pharmacol Ther 9: 227-235 (1995)).
U.S. Pat. No. 5,317,032 to Ueno et al. describes prostaglandin analog cathartics, including the existence of bicyclic tautomers and U.S. Pat. No. 6,414,016 to Ueno describes the bicyclic tautomers as having pronounced activity as anti-constipation agents. The bicyclic tautomers, substituted by one or more halogen atoms can be employed in small doses for relieving constipation. At the C-16 position, especially, fluorine atoms, can be employed in small doses for relieving constipation. The doses, however, by which these prostaglandin analogs are optimally effective is not known. Moreover, the range at which the PG analogs are safe, while yet exerting therapeutic effects, needs to be determined. Clinical dose-ranging studies will be necessary to evaluate the safety and tolerance of PG analogs.

Dosage unit comprising a prostaglandin analog for treating constipation


This disclosure relates to systems and methods that identify, predict, and rank immunogenic T-cell epitopes. In particular, this disclosure identifies epitopes that arose from disease-associated mutations, wherein the epitopes are predicted to elicit immune response from T cells. Specifically, this disclosure simultaneously considers peptide-level information, including MHC Class I and II presentation, helper and cytotoxic T cell response and sample-level information, including mutation clonality and MHC allele dosage. In some embodiment, the systems and methods are used for personalized treatment of cancers.

Stimulating immune response against tumor cells by employing tumor-specific antigens has led to prominence in fighting cancer. These antigens have been determined as the link between tumor genomics and clinical benefit in immunotherapy. Briefly, genes harboring cancer mutations give rise to peptides carrying the mutation. These peptides subsequently bind to the major histocompatibility complexes (MHCs) Class I and II, and are presented onto the tumor cell surface as antigens. The immune system, particularly cytotoxic T cells and helper T cells, may recognize these antigens as non-self and trigger immune responses. Many of these antigens are exclusive to the tumor and are previously unseen by the immune system. Therefore, they serve as a suitable target for immunotherapy, where the treatment would home in on the tumor cells without damaging normal cells.
Eliciting T-cell response using tumor-specific antigens has met with variable results. Utilizing these antigens faced two obstacles: first, immune cells must recognize these antigens as non-self and elicit immune responses without attacking normal cells; second, even if the T cells recognize the antigens as non-self, cells in our body, including mutated tumor cells, possess safe checks known as immune checkpoints, which prevents T cells from long-term, high amplitude attacks. These immune checkpoints need to be made dysfunctional for successful immunotherapy. The second obstacle has come under the spotlight in recent years. Inhibitors to these immune checkpoints, such as anti-PD1, anti-PDL1, and anti-CTLA4 antibodies, were developed, followed by a growing number of drugs, clinical trials, and target cancer types. Nevertheless, there is still substantial room for improvements, as the response rate of the immune checkpoint inhibitor treatment is approximately 20% or lower. It is thus ideal to select patients who would be sensitive to immunotherapy prior to treatment. Possession of high quantity or high qualitied tumor-specific antigens have been suggested to be highly relevant to treatment response and survival rate. An accurate identification of these antigens is in high demand to facilitate patient selection in administering immune checkpoint inhibitors.
In contrast, progresses that directly exploits the selection of antigens for T-cell recognition remains relatively stagnant. T cells elicit attacks after recognizing antigens foreign. However, effective approaches for T-cell recognition of tumor-specific antigens is currently lacking. Therapeutic approaches could be collectively grouped into cancer vaccination and adoptive cell transfer. Therapeutic cancer vaccination aims at delaying tumor progression and promoting tumor regression by enlarging the T cells from a naïve repertoire and reactivating existing T cells. The vaccine is composed of the said tumor-specific antigens, where these antigens are selected for their ability to stimulate immune responses. However, advancement of vaccines has been hindered by suboptimal selection of immunogenic antigens, leaving the vaccines ineffective. Adoptive cell transfer directly focuses on training the immune cells to attack tumor cells. The immune cells, typically T cells or dendritic cells, are collected from the patient and trained in a laboratory. The T cells that successfully eliminate tumor cells through recognizing tumor-specific antigens are reinfused back to the patient, where the T cells would attack tumor cells in the patient. However, this approach is also plagued by ineffective antigen selection, leading to a low success rate. As shown in both approaches, optimal selection of immunogenic tumor-specific antigens is necessary for achieving clinical benefit in immunotherapy.
A reliable method to accurately identify immunogenic tumor-specific antigens would be widely applicable and crucially beneficial to the various immunotherapy strategies. Current identification of tumor-specific antigens generally consists of identifying a mutation and predicting binding affinity of MHC to epitopes, the antigenic determinant portion of the antigen. Multiple epitope prediction tools exist with inconsistent results, and subsequent experiments only validated approximately 55% of the predicted epitopes (Rajasagi M et al., Blood. 2014 Jul. 17; 124(3):453-62.) Typical methods are based on the peptide sequences, without simultaneous consideration of both classes of MHCs and their corresponding immune cells. Furthermore, each patient or sample has specific characteristics that impact predictions, and these sample-specific characteristics have not been incorporated in current neoantigen ranking methods. These characteristics can be collectively named dosage of alleles. A high dosage in the mutated alleles and the MHC alleles lead to discernably higher chances of tumor-specific antigens being recognized by the immune system, and hence affects the epitope predictions. This disclosure describes systems and methods that accurately identify, predict, and rank immunogenic epitopes using both peptide-level information and sample-level information. Peptide-level information simultaneously integrates MHC Class I and II presentation, CD4 activation and CD8 activation, while sample-level information includes dosage of alleles, namely clonality of mutated alleles and number of MHC alleles. Moreover, the systems and methods incorporate a comprehensive list of factors, each based on crucial components in the cellular processes, tumor-specific characteristics, antigen presentation processes, and immune activation processes. Optimal selection of epitopes with weights on each factor is disclosed. The disclosure also describes epitope ranking methods for further development in personalized treatment such as using cancer vaccine, adoptive cell transfer, or immune checkpoint inhibitors.

Ranking system for immunogenic cancer-specific epitopes


The sensitivity of a MEMS microphone is substantially increased by using a portion of the package that holds the MEMS microphone as the diaphragm or a part of the diaphragm. As a result, the diaphragm of the present invention is substantially larger, and thus more sensitive, than the diaphragm in a comparably-sized MEMS microphone die.

1. Field of the Invention
The present invention relates to a MEMS and, more particularly, to a MEMS microphone.
2. Description of the Related Art
A micro-electromechanical system (MEMS) is a microscopic machine that is fabricated using the same types of steps (e.g., the deposition of layers of material and the selective removal of the layers of material) that are used to fabricate conventional analog and digital CMOS circuits.
For example, one type of MEMS is a microphone. Microphones commonly use a micro-machined diaphragm (a thin layer of material suspended across an opening) that vibrates in response to pressure changes (e.g., sound waves). Microphones convert the pressure changes into electrical signals by measuring changes in the deformation of the diaphragm. The deformation of the diaphragm, in turn, can be detected by changes in the capacitance, piezoresistance, or piezoelectric effect of the diaphragm.
FIG. 1 shows a view that illustrates a prior-art, piezoelectric microphone 100. As shown in FIG. 1, microphone 100 includes a rigid U-shaped back plate 110, a diaphragm 112 that is formed across the opening in back plate 110, and a piezocrystal 114 that is connected between back plate 110 and diaphragm 112.
In operation, changes in air pressure (e.g., sound waves) cause diaphragm 112 to vibrate which, in turn, causes the end of piezocrystal 114 to be pushed and pulled. The pushing and pulling on the end of piezocrystal 114 oppositely charges the two sides of piezocrystal 114. The charges are proportional to the amount of pushing and pulling, and thus can be used to convert pressure waves into electrical signals which can then be amplified.
When a microphone is reduced in size to that of a MEMS, one concern that arises is sensitivity. This is because the size of the diaphragm of a MEMS microphone is so relatively small (e.g., less than a millimeter across), due to being formed across a cavity or a back side opening in a relatively-small semiconductor die.


A display device is provided that includes a display panel and a backlight panel. The backlight panel includes a plurality of self-calibrating illumination modules configured to provide backlighting for the display panel. Each self-calibrating illumination module includes at least one light source configured to emit light toward the display panel, at least one light sensor configured to detect light emitted from the at least one light source that is internally reflected within the display device, and a controller configured to control a current supplied to the at least one light source based at least on an intensity of light detected by the at least one light sensor.

Multi-segment dimming backlight panel technology for liquid crystal displays (LCD) provides enhanced color and light contrast in the video content being played. The enhanced contrast in color and light intensity provides a better view experience of high dynamic range (HDR) content. By using multi-segment dimming backlight panels, sections of the display showing a sunny sky may be visually contrasted with sections of the display showing a shaded portion of the ground.

Self-calibrating illumination modules for display backlight


First humidified gas is supplied from a first supply port to a sheet to be conveyed to increase the moisture content of the sheet. Second humidified gas is supplied to a space where nozzles of the inkjet recording head are exposed, from a second supply port provided at a position closer to the inkjet recording head than the first supply port to increase the atmosphere humidity of the space. The part of the sheet of which the moisture content has been increased is made to enter the space where the atmosphere humidity has been increased, and recording is performed. When a conveyance operation stops, the quantity of flow or humidity of the first humidified gas is reduced. In resupplying a temporarily returned sheet, the amount of moisture to be provided by the first humidified gas is set in accordance with regions of the sheet.

1. Field of the Invention
The present invention relates to a recording method and recording apparatus capable of reducing drying out of ink of an inkjet recording head.
2. Description of the Related Art
Japanese Patent Laid-Open No. 2000-255053 discloses a technique of, in a printer that includes a plurality of inkjet recording heads arranged in a direction in which a sheet is conveyed, reducing drying out of ink by improving the moisture retention of the recording heads by supplying humidified gas from the upstream to adjacent areas of the nozzles of the recording heads.

Recording method and recording apparatus


The disclosed embodiments disclose techniques for facilitating access to a target device. During operation, a target device presents a unique code to a user device that is located in proximity to the target device. The user device presents this unique code to a management server that is associated with the target device to gain access to the target device, with the management server linking the two devices. The target device receives notification that the user device has been linked and displays a set of received user account information on a display. Subsequently, the target device receives notification from the management server that the linked user device has applied a credit to the target device, and initiates an operation that is associated with consuming the credit.

Field of the Invention
This disclosure generally relates to techniques for managing access behavior to target devices. More specifically, this disclosure relates to techniques for tracking, accessing, and applying credit and prize balance information for redemption-style games.
Related Art
Redemption games are provided in many family entertainment centers and other establishments. These games are typically arcade games of skill (such as skee-ball) that reward a player proportionally to their score in the game. Such games typically accept cash as input, and provide rewards that most often comes in the form of physical tickets (with more tickets being awarded for higher scores), which can then be redeemed at a central location for prizes.
Saving and redeeming large numbers of tickets can be unwieldy, and thus some games are configured to support credit-card style cards that track both the remaining available credits as well as the number of tickets that have been won. However, credit-card style cards do not provide users with a ubiquitous way to determine how many credits remain available nor how many tickets they have acquired. Typically such cards can be swiped at specific stations at the host location to determine this information, but such locations are limited and not useful to anyone attempting to determine their balances when they are off the premises of the establishment.
Hence, what is needed are techniques and systems for accessing and applying credit and reward balances without the above-described problems of existing techniques.


A reusable or confectionery drinking straw includes a second end portion mouthpiece having a single aperture or multiple apertures, the sensation of the liquid flowing through the aperture(s) capable of being modified by the user. The mouthpiece of the straw device is integral to the straw or it may be removably attached to the straw. The drinking straw device may be edible, partially edible, or inedible. The drinking straw device may be in the form of a bracelet, which may be edible, partially edible, or inedible.

1. Technical Field
The present device relates generally to a reusable or confectionery drinking straw whose novelty involves the sensory effects created by the number, size, shape, or placement of apertures, and the user's ability to modify the effects by manipulation of the device.
2. Background Information
There have been many attempts to develop novel ways to imbibe liquids with a drinking straw. Drinking straws have in the past been sold separately from the container, or they are attached to, and purchased with, a beverage container.
In their simplest configuration, drinking straws are freestanding, simple vertical tubes. Over the years, there have been many modifications to the simple vertical tube. In two such modifications found in prior art, Katsukawa (U.S. Pat No.6,585,170 B2) and Mandell (U.S. Pat. No.5,160,087), use a visual element, a heart-shaped design, to illustrate their inventive concept. Taylor (US 2006/0169791 A1) proposes a drinking straw device that is a tube that is partially edible. This prior art discloses a method of manufacture to combine an outer layer of liquid resistant paper wrapper with an inner layer of edible material, such as flavored food, medicine, or candy. The first and second end mouthpieces of Taylor are identical. That is, the inventive concept of the manufacture of the device is tubular from beginning to end to allow "a small number of components which can be manufactured economically in volume resulting in a relatively low unit cost" Taylor. Another such example is the invention of Lee (U.S. Pat. No. 6,360,912). Lee modifies the freestanding, simple vertical tube by creating a device that actually prevents the flow of liquid to the mouth of the user. Lee uses a valve for opening and closing the straw. He creates a device having a totally internal valve that is capable "of adjusting the flow rate of the beverage being spouted through the straw while keeping the taste and aroma of the beverage, preventing foreign matters from being introduced into the container, and preventing the beverage from being unintentionally spouted from the container due to an impact applied to the container." While these inventions serve their respective purposes for mass production and low cost, none creates a reusable or confectionery device that allows the user to create a personalized stream of liquid to enter the mouth in a manner that is particularized to the sensory desires of the user through the use of a regulator that modifies the location or the sensation of the flow of the liquid thatpasses through the mouthpiece. Nor is there an objective in Katsukawa, Lee, Mandell, or Taylor of using the mouthpiece of the drinking straw in combination with other elements of the drinking straw, such as the size, number, shape, and placement of mouthpiece apertures, and the shape of the mouthpiece, the straw cap, or the bore In more complex configurations, drinking straws are freestanding, ornamental straws that spiral, loop, or bend in ways that draw the user's attention to the flow of the contents through the straw as the beverage is sipped. The ornamental configurations of drinking straws currently available, such as the heart shape of Katsukawa, may be seen as attempts to improve the passive entertainment value of the straw to the user, while creating a method of manufacturing. However, the prior art of Mandrell represents a novel approach to the entertainment value of drinking straws. The device's inventive concept is to foster teamwork, and therefore, requires at least two persons to operate the device. Mandell does not work, then, with use by one person since individualism is not the objective. Therefore, there remains a need for a drinking straw that is freestanding (or capable of use independently) with a more active entertainment value, and where a single user has variable control over the sensual (i.e., visual, tactile, taste, and smell) drinking experience as he or she uses the straw.
In other configurations, a straw with a movable extension, usually made of plastic, is built into the cap of a beverage container. The user pulls up the movable extension of the straw from its horizontal position on the cap of the container, and extracts the contents. The straw is stored by replacing the movable extension of the straw back into its horizontal position on the cap of the container.
In yet other configurations, the drinking straw is purchased with the container, but is removable from the container The container is designed to allow the straw to fit through a hole in the lid of the container This straw remains in a near vertical position when in use or in storage. In some of these configurations, the straw has a removable cap molded around a base of the straw that can fit over the straw. The removable cap for the straw is designed to snap onto the straw when the straw is not in use, so as to keep the straw clean. There is a need, however, to improve the functionality of the removable cap, i.e., for a removable cap that also functions as a supplemental straw appurtenance. By "supplemental straw appurtenance," it is meant that the removable cap is a physical extension of the drinking straw in functionality, in that the cap, by user preference, is a part of the device to extract the contents from a container in a novel and unique stream of liquid to the mouth of the user.
As with all drinking straws, the drinking straw device of the current invention can be used to imbibe the contents of a beverage container from either end of the straw. While all drinking straws can be used to imbibe the contents of a beverage container from either end of the straw, not all inventive concepts of drinking straws allow the contents to be sent to the mouth from either end of the straw. The prior art of del Fabro (U.S. Pat. No. 4,379,511) is illustrative of an inventive concept that allows the liquid contents in the drinking straw to be sent to the mouth from either end of the straw. Del Fabro creates a drinking straw with a floatation element sandwiched between two open tubes, allowing the device to "extend upwardly . . . a distance sufficient to permit normal usage." Either end of the device may be used as the mouthpiece without compromising the inventive concept. On the other hand, the straw device of Efremkin (U.S. Pat. No. 8,025,242 B2) is a drinking straw device that takes in liquid from a container only from a pre-determined depth (5-15 mm) from the top of the liquid, so as to have minimal negative biological effects. The inventive concept of Efremkin, then, allows the use of only one end of the device as a mouthpiece, rather than the use of both ends as mouthpieces. The distal end of the Efremkin device comprises multiple apertures. But to achieve Efremkin's inventive concept, the multiple apertures must remain submerged in the liquid when in use, and the liquid must remain undisturbed to ensure that intake is from a predetermined depth from the top of the liquid. Unlike the Efremkin device, however, the current invention allows either end of the drinking straw device to be used. The end of the straw with multiple apertures can be used to deliver a novel stream of liquid to the mouth of the user when the apertures are placed in the mouth. Alternatively, when an end of the drinking straw device of the current invention with multiple apertures or with an enlarged end is placed in the beverage, the straw also can be an excellent mechanism for creating added turbulence for better stirring of the beverage—a functionality that is not available with Efremkin's inventive concept.
The drinking straw device of the current invention is designed for a sustainable environment. Currently, the majority of commercially available drinking straws are ubiquitous, mass produced straight tubes that are marketed for limited or one time use., and are discarded at the end of their use. There is a need for a drinking straw concept that will encourage multiple reuse through an improvement in functionality, i.e., through improvements in the active entertainment value of the device that can be altered at the whim or desire of the user over multiple uses. That is, the current invention is constructed for multiple uses (reusable), and is manufactured of a reusable material such as flexible tubing, hard or soft plastic, or other resins, stainless steel, composite material, sterling silver, or any other suitable renewable composite or natural material. It is anticipated that the device will be cleaned by the purchaser or consumer in a dishwasher or by hand. Furthermore, it's price point for manufacture would allow it to be personalized to the sensory preference of the user. In other words, the current invention requires a somewhat higher price point than most commercialized straws on the market which are produced for mass consumption without regard for, or the capability for, modifying the drinking experience to the desires of the user while the drinking straw is in use. The current inventive concept advances environmental sustainability in that it ensures that each drinking straw in use has greater longevity in reuse, and advances the use of the drinking straw as a fourth piece of cutlery, thereby joining the ranks of the knife, fork, and spoon.
It is known that the intensity of the flow of liquid to the mouth of the user is dependent upon several factors, among which are the thickness of the beverage, the number, size, shape, placement, or angle of the aperture or apertures, and the strength of the suction applied by the user. The object of this invention is to provide a drinking straw that can provide a novel drinking experience that uses the number, size, shape, or placement of the aperture to deliver a unique sensation to the user's palate. In other words, where the strength of the suction applied by the user and the thickness of the beverage are held constant, the drinking experience from the novelty drinking straw of the current invention is predicated upon the sensation created by the number, size, shape, angle, or placement of the aperture or apertures on the mouthpiece of the drinking straw, and their manipulation by the user according to the user's preference. Unlike the device of Lee, the current invention allows the user to manipulate the sensation of the liquid flow. With Lee, the user is not allowed to manipulate the sensation of the liquid flow, but is allowed either to open or to close the device so that liquid either flows or does not flow through the straw. The liquid that passes through an end portion of the straw device of the current invention flows in a unique spray or stream of liquid to the mouth of the user. The mouthpiece of the current device may be at either end or at both ends of the straw.
By "mouthpiece" is meant the generally accepted definition of an object that in normal use is placed in the mouth, or the piece or part of an object to which the mouth is applied or that is held in the mouth. The mouthpiece of the current invention is in direct fluid communication with the mouthpiece at the opposite end of the device. The end of the straw mouthpiece of the current invention may consist of a single aperture, or may consist of multiple apertures. The multiple apertures of the current invention may be of the same shape or different shapes; the same size, or different sizes. Furthermore, the multiple apertures on the mouthpiece of this invention may be constructed at any angle, or in any position, shape, or size, and may be in any combination of shapes, position, and/or sizes. The shape of the aperture, also, may be simple or complex, for example, having a kaleidoscope-type visual effect through light refraction or through other variation in visual effect.
The current device, in its totality, may be simple or complex, i.e., shaped in a geometric form, or in the shape of a plant (vegetable, fruit, flower, tree, etc.), bird, fowl, fish, or other mammal, mineral, cartoon character, or any other object. (See FIG. 1A vs. FIG. 4A.) Since the drinking straw device can be made of any reusable material, such as plastic, silver, stainless steel, or a suitable form of paper, the exterior form of the device may be molded, brazed or welded, as appropriate, onto the exterior shaft of the straw. The material contemplated for more formal and informal, novelty table or bar straws would be manufactured of stainless steel or other hard material suitable for dining or bar use, where the material can be cleaned and sanitized for reuse in a manner similar to other cutlery or flatware. The drinking straw device alternatively can be made of a suitable candy material. The entire device may be completely edible or it may be partly edible. For example, the second end portion mouthpiece may be edible, and the first end portion mouthpiece may be edible or not. Where the second end portion mouthpiece is made of a candy material, the suctioned flow of the stream of candy-flavored liquid up and through the single aperture of the first end portion mouthpiece, through the shaft, to the aperture(s) of the second end portion mouthpiece, forms a stream or streams of the candy-flavored liquid that passes out of the second end portion aperture(s), creating a novel burst of liquid stream(s) to the palate of the user. In a more complex configuration or embodiment, the visual and olfactory sensation (as enhanced by the shape, color, taste, feel, or smell of the device) could be made to correspond with, enhance, or complement the oral sensation, as for example with FIG. 1B.
Previous efforts at developing straws were for passive entertainment or visual value alone, or they used modifications that targeted only the ends of the straw, mostly by using a rounded configuration for the mouthpiece or its aperture(s). Almost all use a rounded configuration for the internal construction of the bore, which is the cavity within the shaft of the straw. However, it is well known that shapes and images create pleasurable perceptions through their association with past experiences or known connotations. It is, therefore, another objective of the current invention to provide a sensory experience that carries through from the visual component of the drinking straw. Consequently, in addition to modifications of the external shape of the device, the drinking straw of the current device applies a modification to the internal shape of the bore. Specifically, the shape of the bore is carried through to the end portions of the straw, creating a visual experience that directly influences the intensity of the sensory perception or excitement in the drinking experience because of its association with pleasurable images. The internal shape of the bore that is carried through to the mouthpiece aperture directly influences the sensation from the drinking experience, just as the external shape of the mouthpiece and the mouthpiece aperture influence the sensation of the drinking experience. See, for example, FIGS. 1A, 1B, 4A, and 4B.
It also is an objective of this invention to create a reusable straw device that provides a more active source of entertainment. The current invention provides, then, a novel flow of liquid to the user's mouth by enhancing the variation in the intensity or sensation of the beverage flow through the use of an integral beverage flow regulator (hereafter called a regulator or flow regulator) that modifies the location or the sensation of the flow of the liquid that passes through an end portion of the straw device to the mouth of the user. Where the drinking straw device is manufactured in a plastic material that is pliable, the user simply could use his or her fingers to squeeze the device to modify or manipulate the sensation created by the device's aperture(s), creating an even more intense sensation than ordinarily would be available. However, there also is the need for a device that can alter the sensation when the material used for construction is not so pliable. In this instance, the user could use the integral flow regulator of the current invention. With the integral regulator, the user can further modify the direction of the liquid flow or modify the liquid sensation to his or her mouth by manipulating or rotating the external component of the flow regulator. At the operator's choice, the flow regulator is configured to control the number, size, shape, or angle of apertures through which the fluid flows, and thereby, the direction of the liquid flow. The valve, then, allows a change in the direction, location, or sensation of the flow of liquid without the necessity of removing and replacing the mouthpiece. Consequently, in addition to the variation in liquid flow created by the number, size, shape, angle, or placement of the apertures, then, this invention allows the user, by using a regulator, to further vary the intensity or sensation of the flow of liquid to suit the user's own preference, and/or for the region of the mouth to be targeted for the desired or selected sensation. FIG. 9C is an example of a flow regulator (valve) configured to change the desired sensation through manipulation of the device. A change in the number, size, shape, angle, or combination of apertures open or closed creates a change in the direction, intensity or sensation of the liquid in the mouth of the user. The device of the current invention with its regulator may be of one-piece or two-piece construction, and in its simplest form may be removably attached to the drinking straw, as in FIG. 5D. The regulator may be fully external, as in FIGS. 1B, 5D, and 7B, or partially internal (consist of an internal and an external component), such as with FIG. 1A, 1B, and 2C. The flow regulator is integrally constructed preferably of the same material as the straw device, and may be manufactured for placement on either or both ends of the straw device, or at any point along the straw's shaft. The introduction of a flow regulator would permit more sophisticated sensations such as a spray mist or oscillating liquid sensations. Finally, either the regulator, or a stationary protuberance constructed in the fashion of the fully external regulator, is a convenient way to demarcate the location on the straw device where the lips would rest on and encircle the mouthpiece securely. This is important since with the more complex shapes and embodiments of the device of the current invention, the location of the mouthpiece may not be readily apparent, such as with FIG. 4B.
The regulator of the current invention is, in effect, a valve that is capable of being opened and closed by the user in increments to suit the user's preference, by the user's manipulation of the external component of the regulator. A variety of valves may be utilized, including but not limited to screw-activated, diaphragm, and pinch valves. Where the regulator comprises an exterior component only, any of the clamp-type valve devices currently available in the marketplace to selectively adjust or regulate the amount of flow of liquids through flexible tubing would suffice. Where the regulator comprises an interior and an exterior component, the interior component connects, through an opening in the wall of the straw device, to the exterior component. The external component of the valve may be in the form of a dial or disk, a lever, a push-pull (tab) mechanism, or any other method for manipulation commonly found in the marketplace. The user, for example, through the use of a rotating disk on an exterior wall of the straw device, modifies the intensity or sensation of the flow of the liquid through the straw device's aperture or apertures, as the case may be. As with a conventional valve, the user modifies the liquid flow by manipulating an exterior component. Unless the regulator is manufactured specifically to use air passage to stop the flow of liquid from the bore to the mouthpiece, it is important that the external portion of the regulator or valve be constructed so that air does not enter the device at its point of attachment to the drinking straw device. The integral, adjustable beverage flow regulator may be constructed with an internally rotating disk or an internally sliding plate so as to selectively adjust, modify, or regulate the flow of liquid. The internally sliding plate may have different apertures or an aperture to enhance or complement the apertures through which the liquid normally flows to the user from the bore of the shaft to the mouthpiece of the straw device. For example, with a sliding plate, the user can open or close off the flow of liquid to the device's selected mouthpiece aperture(s). In its open or unlocked position, liquid flows unimpeded to and through the bore through the selected mouthpiece aperture(s). In its closed or locked position, no liquid flows through the mouthpiece aperture(s).
Alternatively, and for a drinking straw device with a single mouthpiece aperture, the regulator could have an external disk component and an internally rotating (adjustable) disk component with a potential for a kaleidoscope of apertures, as FIGS. 4A and 4B. The internally rotating disk component may have apertures of a single size (FIG. 2D) or of different sizes (FIG. 2B), or of the same shape (FIG. 2D) or of different shapes (FIG. 2B), with different angles, or in random (FIGS. 4C, 6A) or non-random placement, or in any combination of the foregoing attributes. As with the regulator described in, this embodiment of the regulator is constructed so that the user manipulates an external component, such as a disk, tab, clamp, screw, or lever. However, in one embodiment the component of the regulator that is constructed on an exterior wall of the device connects internally to the regulator's internally rotating disk with multiple apertures. Using the external component of the regulator, the user creates variations in sensation or intensity by modifying the types or number of apertures engaged.
In yet another embodiment of the regulator, the drinking straw device of the current invention could have a rotating arm constructed along an interior wall of the chosen mouthpiece of the device, as in FIG. 7A. The rotating arm moves along an interior wall of the mouthpiece and is capable of limiting the flow of liquid to a single aperture or to multiple apertures. In its full open position, the rotating arm would allow unimpeded flow of liquid to and through the aperture(s). The rotating arm may be constructed to close off the flow of liquid from a single aperture or from multiple apertures, depending upon the user's preference. The internally constructed rotating arm is manipulated externally by the user through any number of commercially available mechanisms, such as a lever or a screw-like appurtenance or attachment, that connect the rotating arm to the external component of the straw device.
To assist in keeping the straw sanitary when not in use, the drinking straw device may have a rigid or flexible drinking straw cover or cap, preferably made of the same material as the straw device, such as plastic or metal that fits over the external portion of the mouthpiece through a snap or screw mechanism. The drinking straw cap of the current invention, however, is a drinking straw cap regulator; it is removably attached to the straw device, and is removable at the user's whim. The cap regulator has an improved functionality. That is, the cap regulator has multiple apertures, thereby being capable of further altering the flow of liquid from the selected end of the straw or of the selected mouthpiece that it covers, as in FIG. 1B. In this embodiment, the cap becomes an alternative or supplemental mouthpiece, the straw device preferably being of two-piece construction.
As the user sips from the straw device of the current invention, the rush of liquid from the first end portion of the straw device to the palate through strategically- or randomly-placed aperture or apertures in the chosen mouthpiece provides a new experience for the user, who receives a novel drinking sensation through a burst (meaning a single stream of liquid breaks apart to become a multiple stream) of liquid that is exciting, yet sensually pleasing to the palate and desires of the user.
The drinking straw of the current invention can be made from any suitable fibrous on non-fibrous material, such as metal, hard or flexible tubing, plastic, resin, and a suitable, reusable paper product. The present invention can be manufactured for use separately, or can be manufactured for use as an integral part of a novelty container.
Furthermore, the invention may be manufactured so that the selected mouthpiece of the device is either fixed or movable. Whether the selected mouthpiece of the current invention is fixed or movable, when in use both ends of the straw device are in direct fluid communication with each other. In one embodiment of its movable form, the mouthpiece of the straw device is retractable, capable of being extended and retracted at the desire of the user, such as in FIGS. 4B and 5A. This feature of the current invention allows a greater variety of novelty straws to be manufactured, since the shape of the mouthpiece of the more complex-shaped device may be uncomfortable to place entirely in one's mouth without an extendable/retractable feature. The user simply holds the straw with the fingers of one hand, and using the fingers of the second hand, manipulates the straw device such that, in effect, the straw device lengthens. The user, then, positions the smaller component of the mouthpiece (hereinafter called a supplemental mouthpiece) for more convenient use. In another embodiment of the device, the movable mouthpiece may be rotated for the purpose of opening or closing the aperture(s), as described above. In all of the embodiments above, however, the user places his or her mouth around the second end portion mouthpiece, sips the liquid which flows through the aperture of the first end portion mouthpiece. Where the second end portion mouthpiece consists of multiple apertures, the liquid continues to move up and through the shaft to the second end portion mouthpiece, and out through the second end portion mouthpiece apertures, sending multiple streams of liquid to the mouth of the user, and creating a novel sensation as the single stream of liquid passes through the multiple apertures as separate streams of liquid.
In another effort to improve the comfort of utilizing the straw of the current invention which may take any number of forms, the device has a new feature called a lip rest. The lip rest is a circular protuberance, preferably, made of the same material as the drinking straw device, and has a circumference that is slightly less than the circumference of the second end portion mouthpiece at its widest point. The lip rest encircles and is attached to the exterior wall of the shaft. The lip rest, in essence, is a ledge upon and above which the lip of the user comfortably rests to form a tight seal with the shaft, when the user's mouth is placed around the second end portion mouthpiece. In some embodiments of the current invention, the external portion of the regulator may function as a lip rest, as well.
Any portion of the current invention may be enlarged (bulbous), in the shape of a geometric figure, plant, animal, mineral, cartoon character, or of any other object. The drinking straw device of the current invention may be substantially straight or may be bent into any other suitable shape that still allows fluid to pass through the bore. The bore may have a consistent inside diameter/perimeter, or the inside diameter/perimeter of the bore may taper off at either end. The inside diameter/perimeter of the bore may be equal to, greater than, or less than the inside diameter/perimeter of the aperture at either end of the device. The outside dimensions of the drinking straw device may vary, and the location of the bore within the shaft of the device may be centered or not.
One challenge of the current invention is to create a novel drinking straw device of different outside features, dimensions, shapes and/or sizes without sacrificing the draw (suctioning capability) of the device. For example, the internal area of the selected mouthpiece where it connects with the upper end of the bore must remain in direct fluid communication with the opposite mouthpiece, and not be so large as to dissipate the liquid's flow more than desired. To prevent this, the straw device may be integrally formed by molding, brazing, or welding the desired shape around the exterior of the straw's shaft in order to maintain the desired flow of liquid to the mouthpiece. This would remove the likelihood that the draw or sensation would be dissipated unintentionally by the shape of the device.
As a separately purchased straw device, the present invention can become a standard piece of cutlery or flatware used in formal or informal indoor and outdoor dining settings, depending upon the material used for manufacturing the device. Sterling silver, stainless steel, or other metals are the preferable material for use in formal and informal indoor and outdoor dining settings. One advantage of the current invention is that in its simplest and most elegant configuration, it can be cleaned and sanitized for reuse in a fashion similar to other cutlery. Another objective of the current invention is to provide a straw device that would be suitable as the fourth piece of cutlery (or flatware as it may be called), along with the knife, fork, and spoon. Furthermore, the current invention could be used as chopsticks are used, but with the added functionality of a device where both liquid and solid contents may be enjoyed using one standard utensil, as with FIGS. 6A and 6B.
The straw of the current invention is also suitable for use as a novelty confection. Lollipops are solid, hard candy or they contain "treats" that have been stored within the body cavity of the candy. With the current invention, the straw device is made of lollipop confection of any flavor. The instant confectionery straw can itself flavor a beverage through which the user sips the liquid.
In the confectionery form of the current invention, the drinking straw can be entirely edible, or only partially edible, depending upon the composition of the materials used to support the confection. The normally jaded lollipop user will have a novel confection that also can be used in a new and different way—to increase their pleasurable drinking experience as the device dissolves into, and blends with, their favorite beverage. For example, where the second end portion mouthpiece of the current invention is a confection, stirring it in the beverage imparts some of it to the surrounding fluid, particularly where the beverage is hot or warm in temperature. When the confectionery second end portion mouthpiece is in the mouth, however, the user's saliva will more efficiently dissolve the confection into the user's mouth, so the user receives both the taste of the beverage and the taste of the confection on his or her taste buds. More specifically, when in use as a confectionery device, the second end portion mouthpiece is in direct fluid communication with the aperture of the first end portion mouthpiece, so that a suctioned flow of the stream of liquid up and through the aperture of the first end portion mouthpiece, through the bore, through the plurality of apertures of the second end portion mouthpiece, forms separate streams of the flavored liquid that passes out of the second end apertures, creating a novel burst of multiple liquid flavored streams to the palate of the user. With the current invention, then, the liquid mixes with the candy flavor of the second end portion mouthpiece prior to entering the mouth of the user. Before this invention, the flavor of the candy mixed with the liquid after the liquid entered the mouth of the user, rather than before the liquid entered the mouth of the user. Alternatively, with the current invention the user may chose to suck on the candy second end portion even without using it to imbibe a beverage.
The drinking straw of the current invention would be suitable for adults as a singular, novelty gift item, as a bar straw, or as souvenirs, favors, or commemoratives, for example, at wedding receptions. Children also will be delighted to carry their own private drinking straws of the present invention, which are shaped in the form of a bracelet. The drinking straw bracelet is preferably made of a pliable material, such as plastic, that can be flexed to form a circular configuration (FIGS. 1A, 1B) on a drinking container (not pictured), or around the child's arm (not pictured). The drinking straw is preferably in a novelty shape, such as an land animal (FIG. 2B), aquatic animal (FIG. 2C), plant (FIGS. 5A-D), or a cartoon character (FIG. 8). In any of these and other embodiments such as a Christmas tree, or a carrot or celery stick, the straw can be made from single or multiple colors for carrying and use, for example, at amusement parks. or for children as a party favor, for example, at a child's birthday party.

Novelty drinking straw with flow regulator


A method for preparing antimicrobial formulations of 2-(alkylthio)ethanamines hydrohalides is disclosed. The formulations are prepared directly from the hydrolysis product of 2-(alkylthio)ethyl propionamides, thereby eliminating both waste streams and isolation procedures.

2-(Alkylthio)ethanamines in which the alkylthio group contains 8 to 12 carbon atoms are known to possess antimicrobial properties: see, for example, U.S. Pat. No. 3,291,683 and European Patent Application Publication No. 266,828. A process for the preparation of 2-(alkylthio)ethanamines from alkyl mercaptans and 2-oxazolines in the presence of a Lewis acid catalyst is taught in U.S. Pat. No. 4,086,273. In that process, for example, 2-ethyl-2-oxazoline (I) and the alkyl mercaptan (II) react in the presence of a Lewis acid catalyst to form a 2-(alkylthio)ethyl propionamide (III) which is subsequently hydrolyzed with an aqueous hydrohalic acid to the 2-(alkylthio)ethanamine hydrohalide (IV) and propionic acid. ##STR1##
The resulting solution is very acidic and is therefore corrosive to metals and human tissue. Furthermore, since the 2-(alkylthio)ethanamine hydrohalide (IV) is a quaternary amine, it is not surprising that the product behaves as a surfactant. As a result, neutralization of the reaction mixture often leads to emulsions. Formulations of such materials are often unstable with respect to phase separation, particularly when subjected to one or more freeze-thaw cycles. It would be desirable to have a stable antimicrobial formulation of 2-(alkylthio)ethanamine hydrohalides that is non-corrosive and non-settling. Moreover, it would be highly desirable to be able to form such an antimicrobial formulation directly from the reaction mixture that results from the hydrolysis of the 2-(alkylthio)ethyl propionamide (III) without any undue unit operations or waste streams.

Process for the preparation of antimicrobial formulations of 2-(alkylthio)ethanamine hydrohalides


The present sprocket wheel invention enhances the efficiency of the sprockets made of two materials, e.g., a lighter material at central portion of the sprocket and a hard material at peripheral portion of the sprocket comprising teeth, by drilling half holes on the outer edge of the central portion and half holes on the inner edge of the peripheral portion of the sprocket. In the preferred embodiment, half of the thickness of the sprocket is the entire hole on the peripheral portion of the sprocket with harder materials, and the other half of the thickness of the sprocket is designed to have said half holes for rivets to attach the central portion and the peripheral portion of the sprocket.

Power transmissions by chains are widely used in various vehicles, e.g., bicycles and motorcycle. The sprockets in these chain-transmissions transmit the torque from the axels to the chain by the sprocket teeth. For high performance sprockets, two requirements are important. (i) The sprockets must sustain high torque. (ii) The sprockets must be lightweight, for the weight in vehicle would increase the burden on other part of the vehicle, e.g., the engine and the sprocket teeth.
It is not a new idea to use two different materials for the central portion and the peripheral portion of the sprockets, so that lightweight but relatively soft materials can be used at the central portion of the sprockets and harder but heavier materials can be used at the peripheral portion comprising teeth. U.S. Pat. No. 969,237, which was patented in 1910, is one of the examples.
The basic design, which is composed of a central portion and a peripheral portion comprising teeth is widely used. See also U.S. Publication No.: US 2005/0272546.
In certain applications of the two-material design, e.g., U.S. Pat. No. 7,481,729, as well as U.S. Pat. No. 969,237, the peripheral portion's perforated inward extensions, i.e., the toothed portion, that overlap with the central portion with corresponding recesses and holes, act as connection between the central portion and the peripheral portion of the sprocket. That design creates (i) the weak point in the design, i.e., the necks of the extensions, and (ii) the compromise between the strength of the connection and the weight, i.e., the increased number of extensions increases the connective strength but also increases the weight of the sprocket, while the decreased number of extensions increases the force on each extension and thereby increases the metal fatigue at the necks of the extensions.
As the weight of the material increases proportional to the square of the diameter, the thickness of the peripheral portion, i.e., the portion of the diameter that is occupied by the peripheral portion, which is at the outer limit of the sprocket, is critically related to the weight of the overall sprocket. A slight increase in the thickness of the peripheral portion would increase the weight of the entire sprocket significantly.

Sprockets made of two materials with half holes on the edge of central portion


A stirring device of a plug-flow fermentation device includes a shaft rotatable about an axis of rotation which defines an axial direction. The stirring device further includes a boundary stirring element that defines the axial extent of a stirring volume covered by the stirring device. A nearest neighbor of the boundary stirring element in the axial direction has an axial maximum width which is smaller than an axial maximum width of the boundary stirring element and which is larger than an axial maximum width of a next-nearest neighbor of the boundary stirring element.

EP 2837421 A1 relates to a stirring device comprising a mounting structure for a stirring element and a method of mounting a stirring element. According to an embodiment, the stirring device comprises a plurality of stirring elements attached to a shaft, the plurality of stirring elements being configured differently in different axial positions of the shaft. At least one stirring element in an output region of the biogas fermenter may have larger axial and/or radial extent compared to the other stirring elements of the plurality of stirring elements.

Stirring device with improved stirring element configuration


An image-forming apparatus includes: an apparatus main body; a unit part that includes an electronic component and that can be installed in the apparatus main body by being guided in a first predetermined direction; a unit-side electrode that is provided to the unit part to be connected electrically with the electronic component; a main body-side electrode that is provided to the apparatus main body and is connected electrically with the unit-side electrode when the unit part is installed in the apparatus main body; and a ground electrode that is provided to the apparatus main body and is connected electrically with a ground, the ground electrode being disposed at a position upstream of the main body-side electrode with respect to the first predetermined direction.

1. Technical Field
The present invention relates to an image-forming apparatus.
2. Related Art
Generally in the art, image-forming apparatuses are formed of a main body having removable unit parts. Such unit parts may include, for example, a toner cartridge, a processing cartridge, and the like; and may contain electronic components, such as a memory for storing information indicating a state of use of a unit part.


The present invention provides methods for increasing arterial compliance. The methods generally involve administering to an individual in need thereof an effective amount of relaxin. The present invention further provides methods of increasing arterial compliance in individuals who have Type 1 or Type 2 diabetes. The present invention further provides methods of increasing arterial compliance in perimenopausal, menopausal, and post-menopausal women. The present invention further provides methods of increasing arterial compliance in individuals who have or who are at risk of developing age-associated arterial stiffness.

Arterial compliance declines with age even in healthy individuals with no overt cardiovascular disease. With age, a decrease is seen in the ability of the large and small arteries to distend in response to an increase in pressure. The age-associated reduction in arterial compliance is an independent risk factor for the development of cardiovascular disease, and is associated with a number of other pathological conditions. For example, reduced arterial compliance is also associated with both Type 1 diabetes mellitus and Type 2 diabetes mellitus. It has been reported that diabetic arteries appear to age at an accelerated rate compared to arteries of nondiabetic individuals. See, e.g., Arnett et al. (1994) Am J Epidemiol. 140:669-682; Rowe (1987) Am J Cardid. 60:68 G-71 G; Cameron et al. (2003) Diabetes Car-26(7):2133-8; Kass et al. (2001) Circulation 104; 1464-1470; Avolio of al. (1983) Circulation 68; 50-58; U.S. Pat. Nos. 6,251,863; 6,211,147.
There is a need in the art for methods of increasing arterial compliance, and for treating disorders associated with or resulting from reduced arterial compliance. The present invention addresses these needs.

Use of relaxin to increase arterial compliance

University of Pittsburgh—Of the Commonwealth System of Higher Education