A highly purified and heat stable cross-linked nonpolymeric tetrameric hemoglobin suitable for use in mammals without causing renal injury and vasoconstriction is provided. A high temperature and short time (HTST) heat processing step is performed to remove undesired dimeric form of hemoglobin, uncross-linked tetrameric hemoglobin, and plasma protein impurities effectively. Addition of N-acetyl cysteine after heat treatment and optionally before heat treatment maintains a low level of met-hemoglobin. The heat stable cross-linked tetrameric hemoglobin can improve and prolong oxygenation in normal and hypoxic tissue. In another aspect, the product is used in the treatment of various types of cancer such as leukemia, colorectal cancer, lung cancer, breast cancer, liver cancer, nasopharyngeal carcinoma and esophageal cancer. The inventive hemoglobin can also be used to prevent tumor metastasis and recurrence following surgical tumor excision. Further the inventive tetrameric hemoglobin can be administered to patients prior to chemotherapy and radiation treatment.

Hemoglobin plays an important role in most vertebrates for gaseous exchange between the vascular system and tissue. It is responsible for carrying oxygen from the respiratory system to the body cells via blood circulation and also carrying the metabolic waste product carbon dioxide away from body cells to the respiratory system, where the carbon dioxide is exhaled. Since hemoglobin has this oxygen transport feature, it can be used as a potent oxygen supplier if it can be stabilized ex vivo and used in vivo.
Naturally-occurring hemoglobin is a tetramer which is generally stable when present within red blood cells. However, when naturally-occurring hemoglobin is removed from red blood cells, it becomes unstable in plasma and splits into two α-β dimers. Each of these dimers is approximately 32 kDa in molecular weight. These dimers may cause substantial renal injury when filtered through the kidneys and excreted. The breakdown of the tetramer linkage also negatively impacts the sustainability of the functional hemoglobin in circulation.
In order to solve the problem, recent developments in hemoglobin processing have incorporated various cross-linking techniques to create intramolecular bonds within the tetramer as well as intermolecular bonds between the tetramers to form polymeric hemoglobin. The prior art teaches that polymeric hemoglobin is the preferred form in order to increase circulatory half-life of the hemoglobin. However, as determined by the present inventors, polymeric hemoglobin more readily converts to met-hemoglobin in blood circulation. Met-hemoglobin cannot bind oxygen and therefore cannot oxygenate tissue. Therefore, the cross-linking taught by the prior art that causes the formation of polymeric hemoglobin is a problem. There is a need in the art for a technique that permits intramolecular crosslinking to create stable tetramers without the simultaneous formation of polymeric hemoglobin.
Further problems with the prior art attempts to stabilize hemoglobin include production of tetrameric hemoglobin that includes an unacceptably high percentage of dimer units; the presence of dimers makes the hemoglobin composition unsatisfactory for administration to mammals. The dimeric form of the hemoglobin can cause severe renal injury in a mammalian body; this renal injury can be severe enough to cause death. Therefore, there is a need in the art to create stable tetrameric hemoglobin with undetectable dimeric form in the final product.
Another problem with prior art hemoglobin products is a sudden increase in blood pressure following administration. In the past, vasoconstriction events have been recorded from older generation of hemoglobin based oxygen carriers. For instance, the Hemopure® product (Biopure Co., USA) resulted in higher mean arterial pressure (124±9 mmHg) or 30% higher when compared to the baseline (96±10 mmHg) as disclosed by Katz et al., 2010. Prior attempts to solve this problem have relied on sulfhydryl reagents to react with hemoglobin sulfhydryl groups, allegedly to prevent endothelium-derived relaxing factor from binding to the sulfhydryl groups. However, the use of sulfhydryl treatment adds processing steps, resulting in added cost and impurities which must be later removed from the hemoglobin composition. Thus there is a need in the art for a process to prepare hemoglobin which will not cause vasoconstriction and high blood pressure when applied to a mammal.
Further problems with prior art attempts to create stable hemoglobin include the presence of protein impurities such as immunoglobin G that can cause allergic effects in mammals. Therefore, there is a need in the art for a process which can produce stable tetrameric hemoglobin without protein impurities.
In addition to the above problems, there is a need in the art for a stabilized tetrameric hemoglobin that is dimer free, phospholipid free and capable of production on an industrial scale.

Treatment methods using a heat stable oxygen carrier-containing pharmaceutical composition


The present disclosure provides a driving mechanism configured to drive a target object to perform a linear motion, wherein the target object includes at least one of a plurality of leaves of a multi-leaf collimator. The driving mechanism may include an output component including an output member. The driving mechanism may also include a transmission component configured to operably connect the output component and the target object. The transmission component may include an output end and an input end. The input end may be operably connected with the output member. The output end may be operably connected with the target object. A linear velocity of the output end may be larger than a linear velocity of the input end.

Multi-leaf collimators are important mechanical components in linear acceleration collimation systems of modern medical radiotherapy equipment, and mainly used for conformation and intensity modulation of target areas (e.g., including lesions). The multi-leaf collimator includes a plurality of leaves. Each of the plurality of leaves is operably connected to a corresponding driving mechanism, so as to be moved to a corresponding position based on a position command sent by a control system, thereby making the plurality of leaves constitute a shape in equal proportion to a lesion tissue to realize conformation with the target area. The driving mechanism may affect the efficiency of adjusting the multi-leaf collimator to a specific shape. Therefore, it is desirable to provide a driving mechanism having an improved driving efficiency.

SHANGHAI UNITED IMAGING HEALTHCARE CO., LTD.


A motor vehicle seat slideway has an unlocking lever pivotally mounted on the moving rail of the slideway and urged towards a rest position, a cable connecting said lever to the seat back to unlock the slideway when the seat back is tilted down forwards, and a trigger pivotally mounted on the moving rail to pivot between a blocking position in which it holds the lever in its actuated position and a retracted position enabling the lever to return to its rest position. The trigger is urged resiliently towards its blocking position, and it also includes an actuator finger which, on coming into contact with an abutment secured to the stationary rail of the slideway, moves the trigger towards its retracted position.

Document FR-A-2 682 332 describes such a slideway for a vehicle seat which includes a seat back mounted on the seat proper, which back is suitable for tilting down forwards, that slideway comprising:
a "stationary" first rail designed to be secured to the vehicle; PA1 a "moving" second rail designed to support the seat proper, said moving rail being disposed parallel to the stationary rail and being mounted to slide along said stationary rail in a "longitudinal" direction; PA1 a latch mounted on the moving rail, said latch being movable between firstly a locked position in which it co-operates with the stationary rail to prevent the two rails moving relative to each other, and secondly an unlocked position in which it co-operates with the stationary rail and enables the moving rail to slide relative to the stationary rail; PA1 a latch spring urging the latch towards its locked position; PA1 means for manually displacing the latch from its locked position to its unlocked position; PA1 an unlocking lever pivotally mounted on the moving rail to move between two angular positions, firstly an active position in which said unlocking lever acts on the latch holding it in its unlocked position, and secondly a rest position in which said unlocking lever does not act on the latch; PA1 means for moving the unlocking lever from its rest position to its active position, said means being designed to be actuated by the seat back being tilted down forwards; PA1 a lever spring for urging the unlocking lever towards its rest position; and PA1 at least one first abutment member secured in permanent manner to the stationary rail and causing the unlocking lever to return to its rest position when the moving rail is in a predetermined position relative to the stationary rail and when the means for moving the lever are not actuated. The slideway unlocking lever disclosed in that document has a neutral angular position between its active position and its rest position, such that the lever is urged by the lever spring either towards its active position when it lies in an angular position between its neutral and active positions, or else towards its rest position when it is in an angular position between its neutral and rest positions. Thus, when the seat is moved backwards with the unlocking lever in the active position, after the seat has been moved as far forwards as possible, the unlocking lever comes into contact with the first abutment member, thereby causing said lever to pivot progressively from its active position to just beyond its neutral position, while the moving rail continues to move backwards a little. PA1 for the stroke of the latch between its locked position and its unlocked position; PA1 for the shape of the unlocking lever; and PA1 more generally, for the position given to the latch so long as the unlocking lever is between its active position and its neutral position. PA1 the unlocking lever and the trigger are pivotally mounted about two respective horizontal axes perpendicular to the longitudinal direction, the trigger comprising a vertical rigid plate having a top edge extending away from the pivot axis of said trigger to a substantially vertical stop edge, the unlocking lever having a bearing member which, when said unlocking lever goes from its rest position to its active position, presses on the top edge of said plate, moving the trigger from its blocking position towards its retracted position, and then goes past the stop edge of the plate, thus enabling the trigger to return towards its blocking position, said stop edge then co-operating with the bearing member to prevent the unlocking lever from returning towards its rest position; PA1 the stationary rail has a web designed to face downwards, the first abutment member being fixed to the underside of said web; and PA1 the moving rail is longitudinally displaceable relative to the stationary rail between a front abutment position and a back abutment position, the slideway including, in addition to the first abutment member, a second abutment member which is disposed to come into contact with the actuator finger of the trigger when the moving rail is in its back abutment position, then moving said trigger towards its retracted position by a camming effect. PA1 the means for moving the unlocking lever from its rest position to its active position comprise a cable connecting the unlocking lever to the seat back, said cable being mounted to be subjected to traction when the seat back is tilted down forwards, then holding the lever in its active position so long as the seat back is tilted down; PA1 a second slideway extends parallel to the first slideway and has a stationary rail substantially identical to the stationary rail of the first slideway, a moving rail substantially identical to the moving rail of the second slideway, and a latch substantially identical to the latch of the first slideway, the latches of the first and second slideways being mounted to pivot vertically on their respective moving rails between their locked and unlocked positions, each of the latches being disposed on one side of the corresponding slideway in an intermediate space situated between the two slideways, and the two latches being connected to each other by a transverse rigid link bar which is itself secured to an actuator handle and which constrains both latches to occupy identical angular positions; and PA1 the link bar is substantially rectilinear.
When the unlocking lever has gone past its neutral position, it is driven immediately into its rest position by the lever spring, such that the latch can then return to its locked position, thus preventing the seat proper from moving.
The slideway described in the above-mentioned document gives complete satisfaction.
Nevertheless, it requires design decisions that can be awkward and difficult to make:
In that known slideway, those parameters must necessarily be selected so that the latch does not co-operate with the stationary rail of the slideway so long as the unlocking lever is situated in an angular position lying between its active position and its neutral position, otherwise the slideway will jam without locking completely.

Slideway for a vehicle seat, and a seat including such a slideway


An accelerometer or seismometer has a pair of flat spirals of optical fiber and has one or more elastic disks bearing a mass and supported for flexure. Each spiral is fixedly attached to a corresponding disk side so that disk flexure lengthens a spiral on one disk side and shortens a spiral on an oppositely facing disk side, the spirals being connected as legs of a fiber optic interferometer so that the interferometer provides an output corresponding to the flexure. A pair of the disks may be mounted oppositely of a sealed body with a pair of the spirals arranged to minimize the effect of pressure changes on the sensor, and a pair of the spirals may be mounted oppositely of a thermally conducting disk to minimize temperature differences between the spirals. The mass may be centrally mounted on a disk with the disk peripherally supported, or the mass may be distributed around the disk periphery with the disk centrally supported for isolation from mounting strain. Several of the disks may be coaxially mounted to provide increased sensitivity.

1. Field of the Invention
This invention relates to measuring acceleration and vibration using optical measurement by light interference.
2. Description of the Prior Art
The flexure or strain of an elastic disk is a well-known basis for measurements including acceleration and pressure, acceleration typically being measured by such flexure resulting from momentum forces acting on such a disk in a direction along its axis. The amount of flexure may be determined interferometrically, mechanically, piezoelectrically, or by changes in capacitance or resistance of elements associated with the disk. However, all strain measuring devices have various deficiencies such as limited sensitivity, high cost, limited maximum deflection, and errors due to operating conditions. Some errors due to operating conditions may be fundamental, such as the flexure of a disk due to acceleration being indistinguishable from flexure due to pressure differential. Other operating condition errors are caused by changes in dimensions, modulus of elasticity, index of refraction, and the like caused by temperature and pressure.
Interferometric measurements of strain can provide great resolution and, when carried out with an optical fiber, provide a simple and rugged sensor which requires low power, is immune to electromagnetic interference, and is adapted to remote sensing and to high data rates. Although optical fiber interferometric measurements of acceleration and pressure may be carried out directly with fibers of suitable construction, optical fibers themselves are relatively insensitive per unit length when used directly and are subject to errors due to ambient pressure, tension from acceleration, and the like. Interferometers having a single optical fiber sensing leg are particularly subject to error due to temperature caused variations of the leg length. It is evident that increasing leg length to provide greater sensitivity may proportionately increase errors due to operating conditions.
It is known to minimize operating condition errors by a "push-pull" arrangement of a pair of interferometer optical fiber legs such that a change in a measured variable shortens one leg and lengthens the other leg while both legs change length together with undesired variations due to temperature, pressure, or acceleration. However to be effective, interferometric rejection of such common mode errors requires that both legs be subject to exactly the same conditions.
It is also known to increase the sensitivity of fiber optic acceleration and pressure measurements by using the fibers indirectly, as by arranging an optical fiber wound element for strain due to the displacement or deformation of a primary force measuring element. For example, U.S. Pat. No. 4,893,930 discloses a mass supported between pairs of resilient, cylindrical mandrels each wound with an optical fiber which is one leg of an interferometer. In this arrangement, displacement of the mass causes lateral expansion of one mandrel of a pair and contraction of the other thereof so that the fibers of the pair function in the above-described push-pull manner. Such fiber optic arrangements are effective, but may be somewhat limited in sensitivity and have the push-pull optical fiber legs separated spatially and thermally.
High sensitivity and minimal spatial and thermal separation of push-pull fiber optic legs are provided in hydrophones disclosed in U.S. Pat. No. 4,959,539. In these hydrophones, each side of an elastic and circumferentially supported disk is wound with a flat spiral of optical fiber fixedly attached to the disk side. As a result of this construction, flexure of the disk shortens such a spiral on one side of the disk and lengthens such a spiral on an oppositely facing side. Such a disk may be mounted on a body so that an acoustic pressure differential to be measured exists across the disk, the spirals then being connected for push-pull operation as two legs of a fiber optic interferometer to provide an output corresponding to the flexure while substantially canceling errors due to pressure and temperature effects common to the legs. In one such hydrophone, a pair of the circumferentially supported disks and associated optical fiber spirals are mounted on opposite ends of such a body with the outer spirals connected as one interferometer leg and the inner spirals as another leg so that differences in the lengths of the legs due to acceleration induced flexure of the disks are canceled. This double disk arrangement also has twice the sensitivity of the single disk arrangement. Even greater sensitivity would be desirable if the cancellation of common mode errors is not decreased.


This disclosure relates to methods for differentiating between mammals having active and latent Tuberculosis disease, by determining the percentage of polyfunctional CD4+ T-cells expressing TNF-alpha, IFN-gamma, and IL-2, or by determining expression of IL-17.

Cellular immunity and particularly CD4 T-cells have a central role in the control of Mycobacterium tuberculosis (Mtb) infection IFN-γ and TNF-α are thought to be crucial for protection against Mtb. Diagnosis of Mtb infection remains complex and requires several clinical, radiological, histo-pathological, bacteriological and molecular parameters. IFN-γ-release assays (IGRAs), i.e. Quantiferon and ELISpot, measure responses to antigens (e.g., ESAT-6 or CFP-10) that are mainly limited to Mtb, and discriminate infection from immunity induced by vaccination with Bacille Calmette-Guérin (BCG). IGRAs however do not discriminate between active disease and latent infection. While IFN-γ production alone showed no correlation with disease activity in chronic virus infection, polyfunctional (IFN-γ+IL-2+TNF-α) profiles of pathogen-specific T-cell responses have been correlated with disease activity. A definite correlation between active and latent Mtb infection, suitable for incorporation into an assay for differentiating between the two conditions, has not yet been described. Previous work has described a rough correlation between active disease and the presence of >50% of Mtb-reactive CD4 T cells producing TNF-α that do not also produce IFN-γ and IL-2 (e.g., TNF-α monospecific cells). However, this rough correlation was not sufficiently accurate or specific to serve as a true diagnostic tool. As described below, a specific correlation has been identified and an accurate, reproducible assay system for differentiating between active and latent infection by Mtb provided.

Methods for differentiating between disease states


A reference luminescence amount-acquiring unit of a display device obtains reference brightness corresponding to a BL drive value detected by a drive value-detecting unit and a temperature detected by a temperature-detecting unit. A deterioration-detecting unit calculates an initial status value based on a ratio of reference brightness obtained based on a temperature and a BL drive value in an initial status and brightness in the initial status detected by a luminescence amount-detecting unit, and stores the initial status value. The deterioration-detecting unit further calculates a current status value based on a ratio of reference brightness obtained based on a current temperature and a current BL drive value and current brightness detected by the luminescence amount-detecting unit, compares the initial status value with the current status value, and determines whether calibration is required. When calibration is determined to be required, a warning screen display unit causes performance deterioration to be displayed on a display unit.

In display devices for graphic design use or medical use, regular calibration (CAL) is performed to correct display characteristic deterioration.
FIG. 4 is a diagram illustrating a configuration of a display device according to a related art. A display device includes a display unit using a display panel such as a liquid crystal display (LCD) or a projector (PJ). A warning screen-rendering circuit causes a video signal input from a personal computer or a video to be displayed on the display unit without change when calibration is unnecessary. A timer circuit detects an operating time of the display device or the number of days that have elapsed since calibration was previously performed, and outputs a warning output instruction to the warning screen-rendering circuit when the operating time or the number of days that have elapsed exceeds a reference value. When the warning output instruction is input from the timer circuit, the warning screen-rendering circuit determines that display characteristics have deteriorated, and causes a warning screen to be displayed on the display unit. Thus, the display device displays the warning screen, and recommends calibration to a user.
Meanwhile, Patent Document 1 discloses an LCD device that displays a message representing that it is necessary to exchange a lamp to a user when deterioration in brightness of a backlight (hereinafter referred to as a "BL") is detected. Further, Patent Document 2 displays an LCD display device that gives an instruction for exchanging a BL lamp to a user based on a comparison between a BL drive value at the beginning of use and a BL drive value after a certain period of time elapses.

Display device for detecting deterioration based on detected temperature and backlight luminescence


Disclosed are devices and methods for scanning sensing systems having an array of light sensing pixels, such as pixels that use single-photon avalanche diodes. Light pulses are emitted into a field of view (FOV) at starts of a sequence of time intervals, and a weighted tabulation of the times-of-flight of the reflected light pulses within each time interval is used to detect an object in the FOV and determine its distance. Each weight is based on the time-of-flight between the emitted pulse and the received reflected light pulse and on the number of the emitted light pulse in the sequence of emitted light pulses. For near objects the weights emphasize times-of-flight from peripheral time intervals of the sequence; for far objects the weights emphasize central time intervals of the sequence.

Scanning light sensors and scanning depth sensor (SDS) systems can be used as stand-alone electronic devices, or as components of other electronic devices, such as digital cameras and 3D imagers. An SDS typically operates by emitting light into a field of view (FOV) and detecting reflections of the emitted light. By measuring the time between emission of the light and reception of its reflection, a distance to an object can be calculated. In some SDSs the light is emitted in one or more narrow beams, such as by lasers. In line scan implementations, an emitted beam is swept or scanned across the FOV and the reflected light beam is received at respective specific locations on an array of light sensing pixels. As the emitted beam is scanned over the FOV, the location of the received reflected beam sweeps across the array. The light detector that detects the reflected light beams in an SDS may be a SPAD detector, in which the array of light sensing pixels uses SPADs for enhanced light detection capabilities.
SPAD detectors are utilized in a variety of applications, such as low-light detection applications, time-of-flight (TOF) applications, and time-correlated single-photon counting applications. A SPAD detector typically includes an array of light sensing pixels, with each pixel including a SPAD. Each SPAD is a photosensitive region that is configured to detect low levels of light (down to a single photon) and to signal the arrival times of the light. An individual SPAD includes a diode reverse biased into its avalanche region. When a photon impinging on a SPAD of a SPAD pixel is part of a reflection from an object of an emitted light pulse, the output signal can be used to estimate the arrival time of the photon at the SPAD after emission of the light pulse. Multiple such arrival times can be used to estimate a distance to the object with greater certainty.
A SPAD typically has a constant sensitivity to photons, regardless of the distance between the SPAD and an object from which a photon has been reflected. In situations in which the object is close to the SPAD detector, the photons in the light reflected from that object impinge on the SPADs of the SPAD detector sooner and often in higher numbers than in situations in which the object is farther from the SPAD detector. Additionally, the photons in light reflected from an object having a higher reflectivity may impinge on the SPADs in higher numbers than photons in light reflected from an object having a lower reflectivity. When one or more photons impinge on a SPAD, the photons may trigger an avalanche event. A triggered SPAD (i.e., a SPAD in which an avalanche event has been triggered) will produce an output pulse signal corresponding to the SPAD's trigger time. Following an avalanche event or trigger, a SPAD will be saturated and have a recharging "dead time" during which the SPAD cannot be used to detect photons. Emitted photons reflected from a closer or more reflective object can saturate a SPAD at an early time and cause the SPAD to be unusable for detecting photons reflected from objects within a desired detection range. This can result in incorrect or unavailable estimates of the distance to an object within an intended detection range.
A TOF is a measurement of the amount of time that elapses between an emitter emitting a light pulse toward an object and the SPAD detector detecting photons in a light pulse that reflects off the object. In general, the light that reflects off an object that is close to the SPAD detector has a shorter TOF. The photons in the reflected light can impinge on the SPAD detector more quickly and in higher numbers than when an object is farther from the SPAD detector. The photons in the light reflected from the closer or more reflective object can saturate the SPADs more quickly, which can result in an incorrect estimate of the TOF.
Conversely, the light that reflects off an object that is farther from the SPAD detector has a longer TOF, and a lower intensity reflected light pulse. During the longer TOF, the amount of ambient light that is measured by the SPAD detector can overwhelm the reflected light pulse that was originally emitted by the emitter. It can be challenging to discern the reflected light pulse from the measured ambient light, which can make it difficult to correctly estimate the TOF.
Methods and devices are presented that, in some embodiments, address the problem of saturating SPADs and/or of poor signal to noise ratio (SNR).

Spatial temporal weighting in a SPAD detector


A floor system with low resistance to impact has loosely connected separate light weight components forming a support frame upon which a plurality of floor panels is disposed. The support frame is comprised of a plurality of support elements which, in turn, are constructed of a plurality of support members each having a maximum dimension of at most a predetermined fixed size. The plurality of floor panels is disposed onto of and supported by the support elements. The floor panels preferably have mating beveled edges, which bevels facilitate the panels in kicking up and over each other upon substantially horizontal impact. The position of the floor panels is relative to the support elements is loosely maintained by cooperating short pins and holes. In one aspect of the invention, the support elements are spaced apart and are not connected to each other for support. In another aspect, the support elements are interconnected and supported by a supporting structure. Given this construction, a floor system can support substantially vertical loads of personnel and equipment but break apart into pieces having a maximum dimension of at most a predetermined, fixed size when subjected to substantially horizontal impact loads.

The Federal Aviation Administration (FAA) of the U.S. Government and other bodies have requested designs for enclosures for various types of antennas to be used at airports. An important requirement for these enclosures is the ability to withstand repeated jet blasts of 150 m.p.h. from aircraft and sustained winds. A jet blast may have a duration of up to one minute, may be from an angle up to 15.degree. from horizontal and may occur up too 500 times per month. However the enclosure must shatter on impact by a colliding light aircraft traveling at about 75 m.p.h. Moreover, only minimum damage upon the aircraft can be inflicted. To this end, upon impact the enclosure must shatter into small pieces e.g., pieces having a maximum span of at most four feet. These criteria result from a plan to construct antenna towers and other structures very close to and along airport runways, such as for use with improved instrument landing systems. The location of these structures necessitates the frangibility of the enclosures. I am currently unaware of any enclosures which are specifically designed to be frangible and to shatter upon impact yet withstand large distributed loads.
A radar antenna in such an enclosure must be accessible by installers and maintenance personnel, thus, a floor system is required therein to allow personnel to work inside the enclosure. Such a floor system needs to support primarily vertical loads of personnel and equipment but also needs to break up easily into separate parts when subjected to impact loads from a collision. These impact loads normally involve large horizontally-directed forces. A typical load of personnel and equipment on a floor which must be supported by the floor system is about 100 pounds per square foot in the vertical direction A substantially horizontal impact load of 700 ft./lbs. per breakage area must also cause failure of the floor system. I am currently unaware of any such frangible floor systems.
Accordingly it is an object of the present invention to provide a floor system for a frangible enclosure such as may be used to house an antenna. The floor system must provide low resistance to localized impact, but have high resistance to distributed loads such as those from wind. More particularly, it is an object of the invention to provide a floor system that will withstand primarily vertical loads of personnel and equipment, but shatter on impact from a colliding light aircraft, with the objective of minimizing damage to the aircraft.
Another object of the present invention is to provide a floor system for a frangible enclosure which upon localized impact separates into pieces having a dimension of at most four feet.
A further object of the present invention is to provide a floor system for a frangible enclosure that is easily fabricated, transported and handled.

Floor system with low resistance to impact


A relay device for multicast communications. The relay device transmitting a multicast user data packet containing a content to base stations. The relay device stores information indicative of a multicast group, information indicative of the base station and information indicative of a zone to which the base station belongs (these items of information forming a set by being associated with each other), and determines, when receiving a LEAVE packet via the base station, whether transmit a query packet about a leave target multicast group by comparing the information indicative of the base station associated with the leave target multicast group and with information indicative of a base station relaying the received LEAVE packet, transmits the user data packet containing the query packet to each of the base stations belonging to the zone on the basis of a result of the determination.

1. Field of the Invention
The present invention relates to a relay device, a wireless communication system and a multicast relay method that realize multicast communications efficient and effective in mobile communications.
2. Description of the Related Art
WiMAX (Worldwide Interoperability for Microwave Access) is defined as a fixed wireless communication technology based on IEEE802.16. Standardization of the WiMAX technology for providing a fast wireless communication service is in progress. The WiMAX Forum® is an industry-led organization established as an organization for promoting the WiMAX technology. Non-Patent document 1 given below is a document issued by the WiMAX Forum® as a technical overview about the WiMAX technology.
Non-Patent document 1 describes a purport of supporting a multi BS (Base Station)-MBS (Multicast Broadcast Service) in the WiMAX technology. Specifically, the wireless communication system using the WiMAX technology is requested to provide, through multicast communications, a variety of contents such as a news program, a sports program, a weather forecast and traffic information.
IGMP (Internet Group Management Protocol) and MLD (Multicast Listener Discovery) are employed as multicast group management protocols in a way that participates in and leaves a multicast group in the multicast communications using an IP (Internet Protocol) protocol. The IGMP is the multicast group management protocol that supports IPv4, and the MLD is the multicast group management protocol that supports IPv6.
The following document is a conventional art related document that discloses a system etc for supporting the multicast communications. Patent document 1 given below discloses a wireless multicast system etc. The wireless multicast system is that a router storing associative information between information representing wireless access point equipment that transmits the packet to the multicast group and information representing the multicast group, specifies the access point equipment that should establish a connection to a wireless terminal by transmitting the associative information to the wireless terminal.
Further, Patent document 2 given below discloses an IP packet multicast method. According to this method, in relay nodes having a hierarchical structure, a high-order node storing low-order node information in response to a participation request given from the low-order node and deletes the information in response to a cancellation request.
The Patent document 1 is a "Japanese Patent Application Laid-Open Publication No. 2004-15435".
The Patent document 2 is a "Japanese Patent Application Laid-Open Publication No. 2002-94562".
The Non-Patent document 1 is a "WiMAX Forum, "A Technical Overview and Performance Evaluation", Mobile WiMAX-Part 1, Feb. 16, 2006".
A wireless multicast system disclosed in Patent document 1 described above is not, however, suited to a system that supports mobile communications because of making the wireless terminal desiring to receive the packet of the predetermined multicast group select the should-be-connected wireless access point equipment.
Further, according to a multicast communication method disclosed in Patent document 2 given above, each of the base station (RNC) manages the information on the participating multicast group regarding each of the connected mobile terminals, and hence such a problem arises that the information managed in each base station increases in quantity and needs synchronizing between the respective base stations, resulting in intricacy of the system architecture.
Further, Non-Patent document 1 does not disclose a specific method of supporting the multi BS-MBS in the WiMAX technology.

Relay device, wireless communication system and multicast relay method


Implementations relate to a spherical wheel drive and mounting. In some implementations, a wheel mechanism includes a spherical wheel, a base, and a rotary bearing coupled to the base and contacting a surface of the spherical wheel, where the rotary bearing configured to allow the spherical wheel to rotate. The wheel mechanism includes an omni wheel coupled to the base and engaged with a surface of the spherical wheel, and an actuator coupled to the base and to the omni wheel, where the actuator configured to rotate the omni wheel to cause rotation of the spherical wheel.

Wheel systems use wheels to contact the ground and support a load, where the wheel systems can be used to move large loads more easily across ground surfaces and to particular physical locations. Some wheel systems are wheel drive systems that can drive the wheels with motors to move the load under motorized and/or user control. In some examples, casters can be provided on the bottom of an object or a cart supporting a load, where the wheels of the caster allow the object to be rolled over the ground and can be driven by motors connected to the wheels.
Some wheel drive systems may use a spherical wheel that can roll in multiple directions. In some of these systems, one motor-driven roller is positioned to contact a surface of a spherical wheel to drive the spherical wheel in a first direction, and another motor-driven roller contacts the spherical wheel at a different location of the spherical wheel to drive the spherical wheel in a different direction, e.g., perpendicular to the first direction. Each of the rollers may be an "omni wheel" having smaller rollers contacting the spherical wheel and allowing the spherical wheel to rotate in directions other than the driven direction of the omni wheel.
Some wheel systems are desired to be highly stable so that the load carried by the wheel system is not allowed to have accidental or unintended motion, e.g., when the load is being moved and/or when the load is stationary after it has been moved into a particular location. One example of such a load is a slave device used in a teleoperated surgical system, which is used to provide teleoperated surgery on a patient. A surgeon typically operates a master controller to remotely control (e.g., telemanipulate) the motion and functions of surgical instruments in the slave device at the surgical site. Teleoperated slave devices that include the surgical instruments can be moved to a location near a patient in an operating room using a wheel system and held stationary at that location during a medical procedure.
Some wheel systems may allow unintended motion of the carried load. For example, casters, spherical wheels, and other wheel systems typically have backlash and play in the components of the wheel mechanisms, which allows the carried load to vibrate, wobble, or otherwise move in small amounts even when the wheel system is held stationary at a location. For example, casters typically can swivel, and the components allowing this motion may allow the carried load to sway or be nudged unintentionally when moved or when stationary. Spherical wheel systems may cause vibration in their loads when moved due to a cogging effect of multiple small rollers of an omni wheel successively contacting the surface of the spherical wheel as the omni wheel rotates. Furthermore, omni wheels typically include backlash and play in the small rollers of the omni wheel, thus causing backlash in the contact path from the omni wheel to the spherical wheel and causing instability in the load during movement or when stationary.
Such unintended motion in the load of a wheel system can be harmful and dangerous, e.g., if the load is a medical device that depends on stability during medical procedures in which contact is made with a patient, such as teleoperated surgical devices. Providing additional stability mechanisms in such wheel systems, such as adding retractable feet at a stationary position, adds to the cost of the wheel systems and devices.


A plate or other utilitarian object for generating conversations is provided comprising a substantially flat central portion for holding on object and a raised side surface positioned coaxially with the substantially flat central portion. A circular perforation is formed coaxially with the substantially flat central portion and the raised side surface and is positioned at a border between the substantially flat central portion and the raised side surface. A plurality of axial perforations are formed in the raised side surface extending along an entire width thereof from the circular perforation to an outer edge of the raised side surface. Each adjacent pair of the plurality of axial perforations and a corresponding portion of the circular perforation defines a selectively removable tab, the selectively removable tab including text material thereon. The text material preferably comprises an open-ended opinion-evoking statement.

The present invention relates generally to a method and apparatus for generating conversation, provoking thought, entertainment and education, and more particularly a method and apparatus for coupling a construction with an article having an alternative utility, the construction including one or more phrases and a delivery system for evoking an opinion type response to the one or more phrases.
During any occasion or event where a group of people who may or may not know each other are brought together, often conversation between them, and particularly the start up of conversation, may be difficult. Also, there are many occasions where an individual is alone and may desire some diversion.
Therefore, it would be beneficial to provide a method and apparatus that overcame these difficulties in the prior art.


The present disclosure relates provides compounds according to Formula I or Formula II as well as compositions including such compounds useful for the prevention of schistosomiasis infection and/or swimmer's itch.

The following description of the background of the present technology is provided simply as an aid in understanding the present technology and is not admitted to describe or constitute prior art to the present technology.
Schistosomiasis is caused by the blood fluke Schistosoma. The life cycle of schistosomes shifts between an intermediate snail host and a mammalian definitive host. Once shed from snails, infectious larvae of the schistosomes, called cercariae, infect humans by swimming in freshwater sources and burrowing under the skin. The cercariae lose their tails while burrowing through the skin of the host, becoming schistosomulae. The schistosomulae migrate through the bloodstream to the hepatic portal vein to mature to adult worms where the females lay eggs, and the cycle repeats. Schistosomiasis is a devastating and widespread disease affecting more than 200 million people worldwide. Current treatment relies on the drug, Praziquantel, for which there is evidence of increasing drug resistance. Recent efforts to develop a vaccine to combat schistosomiasis have proven unsuccessful.

Use of a rotifer-derived compound and its analogs for preventing schistosomiasis


A method of applying a medicinal substance onto an area within a patient's body cavity includes providing an applicator formed by six integral sections. A proximal section is formed with an entry passage. An axial intermediate passage of the applicator extends from the entry passage through a flange section and a passage section. A slot section has a slot delivery passage communicating with the axial intermediate passage, and at least one axially-elongated slot therethrough. A solid section extends from the slot section, and a dome section extends to an end of the applicator. The method further includes locating the slot delivery passage adjacent the area within the cavity, forming a substance mass externally of the cavity, moving the mass into the slot delivery passage, and moving at least a portion of the substance onto the area.

This invention relates to methods of applying a medicinal substance, and particularly relates to methods of applying a medicinal substance onto an area to be treated within a body cavity of a patient.
Various medical conditions, which are located within the vaginal and/or anal openings of the human anatomy, can be treated with medicinal creams and other substances of similar consistency. Frequently, such creams are prescribed by physicians, and are to be applied in measured dosages over a period of time. Because of the necessity for frequent applications of the cream to the affected locations, it is beneficial and economical for the patient to self-administer the measured dosage applications.
However, it is difficult, and in some instances impossible, for the patient to view, or sense, that the proper dosage of the cream is being applied in the vaginal and anal areas. In addition, the act of administering the medicinal cream in such areas, frequently places the patient in awkward physical positions, which require a level of dexterity not inherent in some patients. Under these conditions, imprecise amounts of the cream could be administered undesirably.
In the past, several devices have been developed for storing multiple doses of the medicinal substances within a barrel of a syringe or a cartridge, to facilitate the successive application of time-spaced doses over a period of time. Such devices also include a plunger within the barrel, and a stem for engaging the plunger and urging the cream in successive doses from within the barrel, and through a dispensing means such as an applicator.
Cleanliness of such devices is unpredictable, during dispensing and during storage and transporting thereof. Thus, there is a need for a multiple-dose delivery device which can be easily cleaned while retaining the cream within the barrel, and also during storage and transporting of the device between the time-spaced administering of successive doses of the cream. Also, there is a need for a multiple-dose delivery device which can be dismantled easily for effective cleaning, and for storage and portability.
Other devices developed in the past have included some means for tactile notice to the patient that the appropriate dose has been dispensed. While devices of this type have provided a useful purpose, such devices tend to be complex, costly and, at times, unwieldy. Frequently, the tactile systems of such devices make it difficult, if not impossible, to dismantle the components of the device for cleaning, storage and transporting.
Thus, there is a need for a multiple-dose delivery device which includes an effective tactile system, which is uncomplicated, inexpensive and facilitates the ready dismantling of the components of the device.
Devices developed in the past facilitate the dispensing of the cream generally within the vaginal and/or anal openings, but tend not provide structure which focuses the cream directly onto the critical areas for a most effective treatment.
Thus, there is a need for a multiple-dose delivery device, and an applicator thereof, which focuses the cream directly onto the critical areas to be treated.

This patent is subject to a terminal disclaimer.

Methods of applying a medicinal substance


Gas focusing flow cytometers are fabricatable employing simple and inexpensive manufacturing techniques. When such cytometers or conventional cytometers are combined with fiber optical light paths and laser diode and semiconductor photodetectors, light weight and handheld, optionally disposable devices which maintain high performance are possible.

1. Field of the Invention
The present invention is directed to flow cytometers.
2. Description of the Related Art
Flow cytometers are useful in the detection of particulates in liquid systems, in particular for the detection and/or identification of microbes, including pathogens. Flow cytometry per se is a mature technology. Flow cytometers concentrate a particulate-containing inlet stream to a relatively small diameter "observation" stream in which the particles pass "single file" past a detector located in an observation channel. Focusing of the liquid sample is achieved by injecting a liquid as a sheath surrounding the stream of sample. The necessity for a rather large volume of liquid relative to the volume of sample contributes to the overall size of the device, and with biological samples suspected of containing pathogens, contributes to waste disposal problems. Reducing complexity by eliminating liquid focusing has been attempted, J. Crosland-Taylor, NATURE 171, 37-38 (1953), but has not been regarded as successful, due to deficiencies such as channel clogging and slow velocity of sample flow which reduces the optical detection rate. Thus, current flow cytometers employ liquid focusing.
Typical flow cytometers are bench scale devices comprising a flow cytometer cell, a laser light source, and a photomultiplier detector. In order to produce an acceptable signal to noise ratio, the detection system also includes a dichroic beam splitter, focusing optics, and a combination of photodiode and photomultiplier. A typical flow cytometer is represented schematically in FIG. 1. The most compact commercial instruments occupy more than 2 ft3 (ca. 0.07 m3) of space, and are quite expensive. Typical flow cells are constructed of quartz, and alone cost ca. U.S. $3500 (2002) and thus are clearly not disposable. The optical components of the detection system are major contributors to the overall cost, as are the laser and photomultiplier.
Flow cytometers have gained widespread use in a variety of medical, scientific, and engineering fields such as disease diagnosis and monitoring, D. S. Stein et al., J. INFECT. Dis. 165 (2), 352-63 (1992); D. Fenili et al. CLIN. CHEM. LAB. MED., 36 (12), 909-17 (1998), cell biology C. L. Harding, et al., BIOTECHNOL. PROG. 16 (5), 800-02 (2000), toxicology, K. A. Criswell, et al., CYTOMETRY 32 (1), 18-27 (1998), and environmental monitoring, G. B. J. Dubelaar, SCIENTIA MARINA 64 (2), 255-65 (2000). Flow cytometers have been used in monitoring of white blood cells for HIV infection, and for monitoring of dialysis fluids and the like. Use of flow cytometers is also being increasingly investigated in view of threats of biological contamination, not only due to terrorist activities, but also due to increased contamination of water supplies caused by steadily increasing population density.
It would be desirable to provide flow cytometers which occupy less physical space, to the extent, for example, of providing hand held devices. It would further be desirable to provide flow cytometers which do not rely on liquids as the focusing fluid, and which utilize less expensive, and less bulky detection devices. It would be desirable to provide flow cytometer cells which are disposable as a practical matter.

Flow cytometers and detection system of lesser size

The Regents of the University of Michigan


The present invention provides a method of treating and preventing the common cold and associated secondary illnesses in a human subject, when the common cold is caused by viruses. The method comprises applying to the nasal passages of the human subject at ambient temperature, an effective amount of a pharmaceutical preparation comprising povidone-iodine (PVP-I) at a concentration of greater than 0.10% w/v and less than 2.5% in which at least 50% of the PVP-I is not associated with liposomes or other particulate carriers.

Infective respiratory diseases are often broadly classified into upper respiratory tract infections (URI) and lower respiratory tract infections (LRI). The upper respiratory tract includes the oral cavity, nasal cavity, sinuses, middle ear, pharynx and larynx. The lower respiratory tract includes the trachea, bronchi, bronchioles and alveoli in the lungs. Each site can be the locus of a specific clinical condition that may have discrete presentation, causation and therapeutic challenges. For this reason, it is not appropriate to talk about "upper respiratory infections" or "lower respiratory tract infections" as single, continuous or homogeneous conditions or therapeutic targets, because each term embraces a multiplicity of clinically discrete sites, causations, clinical conditions and treatment challenges. Further, it would not be assumed in the art that any treatment disclosed as useful for a specific site or condition would necessarily indicate its utility in another site or condition in the upper or lower respiratory tract.
The common cold is a widely-recognised URI, usually but not exclusively due to a viral infection of the nasal mucosa. Other common URI include tonsillitis, sinusitis and otitis media. Acute tonsillitis is an infection of the palatine tonsils in the pharynx that is typically caused by bacteria belonging to the group A streptococcus genus, and is commonly treated with penicillin. Sinusitis is an inflammatory condition of the sinuses that can be due to infection, allergy or auto-immune causes; where a bacterial cause is suspected, it is generally treated with an antibiotic. Otitis media is an infection of the middle ear often caused by bacteria and typically treated with antibiotics. Unlike these three cited conditions, currently, there is no effective treatment for the common cold, which is generally caused by viruses.
While normally mild and self-limiting, the common cold, or simply the "cold" as it is generally known, has a very high incidence and prevalence and causes high morbidity, medical costs and productivity losses, as well as contributing to an unduly high burden on the health care system. In the United States, adults experience an average of 2 to 3 colds per year, while school children can have more than 10 a year, in total contributing to an estimated 1 billion colds each year, resulting in up to 100 million doctor visits per year that cost the community an estimated $8 billion and add considerably to the burden on the medical system, which in most advanced economies is already over-stretched. In addition, up to 200 million school days are missed annually and 150 million workdays are lost due to employees having colds, and up to another 150 million workdays lost due to parents staying home to care for their sick children with colds. The total economic impact of cold-related productivity losses has been estimated to potentially exceed $20 billion per year in the United States alone, with losses of comparable scale in other industrialized countries. Additionally, billions of dollars in the United States are spent each year on over-the-counter (OTC) medicines, supplements and other remedies that mostly have little or no proven benefit, other some modest symptomatic relief.
In addition, there is the indirect cost of antibiotic resistance caused in part by over-prescribing of antibiotics for colds by primary care physicians, despite the fact that most colds are viral in origin and antibiotics only target bacteria. This is becoming an extremely serious medical problem because of the rise of drug-resistant pathogenic bacteria.
A further problem is that colds may predispose or precipitate other conditions, notably otitis media, sinusitis and bronchitis, resulting in additional morbidity, medical cost, productivity losses and antibiotic use.
In addition, for certain "at-risk" individuals, colds can lead to serious lower respiratory infections such as pneumonia, due to enhanced susceptibility of the individuals or as a result of exacerbation of an underlying respiratory disease. These at-risk individuals include people undergoing cancer chemotherapy or who are otherwise immune-compromised, and people with underlying respiratory disease including asthma, Chronic Obstructive Pulmonary Disease (COPD), cystic fibrosis and emphysema. In such at-risk individuals, a cold can represent a serious threat that could lead to hospitalisation and potentially be life-threatening.
Despite all these important medical, economic and societal needs for an effective treatment or preventative for the common cold and despite decades of medical research in the field, there is no effective treatment available for colds and no vaccine exists to prevent colds. The reasons for this and the ongoing challenges are discussed below.
The common cold is a symptom complex initiated by an infection of the nasal mucosal cells inside the nasal cavity. For the purposes of the present invention, the term "nasal passages" will be used to include all those sites within the nasal cavity and oropharynx that are the typical site of the infection that causes the common cold symptom complex. While a cold can cause or predispose other URI or LRI notably sinusitis, otitis media and bronchitis, these are regarded in the art and defined herein as secondary complications or sequelae of a cold and not part of the common cold condition itself.
Overwhelmingly, viruses are the cause of the infection of the nasal passages leading to the condition known as the common cold. Indeed, identified and characterised viruses are known to cause at least 70% of all colds, while a further approximately 25% of colds are non-specific with respect to cause, but are believed to be viral, although in such cases the specific viral cause has not been identified or characterised. Of the viruses known to cause colds, the most common is the human rhinovirus (HRV), which is believed to account for at least half of all colds and therefore the majority of viral colds. However, there are more than 100 serotypes of HRV. In addition, there are many other viruses that can cause colds including coronaviruses, influenza viruses, parainfluenza viruses and respiratory syncytial virus (RSV). In many cases, there are numerous strains or serotypes of each. Overall, an estimated 200 species, strains or serotypes of viruses can cause the infection of the nasal passages that leads to the common cold.
Despite the range of potential infective causes, the symptoms of the clinical condition that results from the infection are generally similar. Symptoms may include sneezing, rhinorrhoea (runny nose), nasal congestion, sore throat, coughing, headache, malaise, chills and myalgia (body aches and pains). It is the constellation of these symptoms or the "symptom complex" that defines the condition generally known as the common cold rather than the infection per se. Indeed, some infected individuals will present with no symptoms, i.e. have no cold, even when they can be shown microbiologically to have an infection of the nasal passages. One reason for the idiosyncrasy is that the symptom complex is the result of the body's reaction to the infection rather than the infection itself.
The common cold starts as an infection of the cells lining the nasal passages. Because most of the research in the field has focused on HRV, the clinical pathology of HRV colds has been much better characterized than other viral colds, although it is generally assumed that the pathology would be similar for most viral colds. For HRV colds, once a cell is infected, the viruses multiply rapidly inside the cells and after 8-10 hours cause the cell to burst and release large numbers of infectious progeny viruses into the nasal passages that can infect other cells to propagate the infection.
The cell damage caused by the infection triggers local cellular defence mechanisms, including the release of the chemical bradykinin that is believed to directly cause sneezing, rhinorrhoea, congestion, sore throat and cough. These are known as the "local symptoms" of the common cold.
In addition to these non-specific cellular defences, certain immune cells present in the nasal passages, particularly monocytes and granulocytes, become engaged. Monocytes detect the presence of viral antigens or nucleic acid, typically RNA, and release cytokines, which are pro-inflammatory chemicals that recruit other immune cells, notably granulocytes, to the site of the infection or foreign material. Granulocytes, especially neutrophils in the case of colds, ingest and destroy foreign material including invading microorganisms. They also secrete more cytokines to attract even more neutrophils to the site to accelerate virus removal. However, as a side effect, the cytokines cause a low grade fever, drowsiness, malaise, myalgia and headache. These are known as the "systemic symptoms" of a cold, but are not unique to colds and can occur to some extent whenever the immune system reacts to foreign proteins or nucleic acid, for example following a vaccination or as a result of a bacterial or viral infection anywhere in the body.
The constellation of these local and systemic symptoms represents a "symptom complex" that is characteristic of and defines the clinical condition known as a cold. The composition, severity and timing of the common cold symptom complex may vary from one individual to another, depending on their underlying health status and pre-existing conditions, such as immunodeficiency or asthma. It may also vary from one infecting virus to another. The diverse range of viral causes and the range of impacts, from the comparatively mild through to serious and in some instances fatal consequences of such infections, have presented major challenges for antiviral drug development in the field.
Once a subject is infected, cold symptoms start to appear 24-36 hours after the initial infection in the nasal passages and typically last 8-9 days from the time of onset. During the first 4-5 days of the cold, large numbers of the infectious virus are produced and can be detected in the nasal mucous, which is thought to be the principal vehicle for transmission of the disease. Transmission occurs either through aerosolisation during coughing and sneezing or by nose-blowing with other people then breathing in the virus-laden aerosol particles or touching contaminated hands or surfaces. The substantial amount of nasal mucous produced during the first few days of the cold amplifies viral shedding from infected individuals and thereby the efficiency of the transmission process. Further, research has shown that even after all symptoms have disappeared, viral shedding from a cold may continue at a low level for a further 2-3 weeks.
Unlike many viral diseases, there is no vaccine for the common cold. Viral vaccines rely on the long-term immune memory of a particular virus, so that when that virus re-presents, antibodies already exist to immediately target the virus for destruction by various immune processes before it can cause an infection. However, the immunity derived from an infection by one cold virus may be relatively short lived and restricted to only one particular virus or serotype, whereas colds can be caused by up to 200 different viruses that are constantly evolving and thereby evading the antibody-mediated immune system. Thus, antibody-mediated immunity plays little practical or effective role in preventing the common cold in the population.
The alternative to prevention with a vaccine is treatment subsequent to the infection, but there are several substantial challenges to treating a cold. One of these is that there are many microorganisms that can cause a cold. In contrast, other infectious diseases typically have a single microbial cause and an uncomplicated cause-symptom pathway. Examples are human immunodeficiency virus (HIV) that causes AIDS and herpes simplex virus (HSV) that causes cold sores. In each case, specific antiviral treatments are available that suppress or destroy the virus responsible and thereby treat the symptoms of the disease. The common cold is different to these diseases, because it can be the result of an infection by any one of at least 200 different microorganisms.
Numerous attempts over many years have been made to develop antiviral agents as possible treatments for the common cold, but none has succeeded in reaching the market. Human rhinovirus (HRV) is the primary causative agent of the common cold and has been the focus of almost all antiviral drug development in the field. It is now known that there are three HRV species, A, B and C, which fall within the genus Enterovirus (EV) and the family Picornaviridae. HRV species are further divided into over a hundred distinct serotypes. Virtually all modern drug discovery and development aimed at the common cold took place between the 1980s and the early 2000s and with few exceptions was aimed at developing drugs that targeted HRV specifically. At one time or other during this period, most of the major pharmaceutical companies attempted to develop antiviral drugs targeting HRV, but by 2000 most programs had been mothballed or abandoned. One exception was the drug pleconaril, which was still under development at the US company, Viropharma, during the early 2000s. Pleconaril belongs to the capsid binder class of antiviral agents and binds to the coat or capsid of the virus to interfere with uncoating, which is an early, essential stage in the infectious cycle. Other capsid binders have been reported to interfere with the binding of HRV to the ICAM-1 receptor on cells, also preventing entry of the virus into cells. Viropharma's 2002 New Drug Application (NDA) received a unanimous vote against approval by the FDA Advisory Committee because Phase III data indicated only a one-day reduction in cold duration while presenting a risk of cytochrome P450 induction leading to possible undesirable side effects. Viropharma abandoned pleconaril and no other antiviral drug for HRV has since progressed to a Phase III trial.
Apart from side effects, another limitation of HRV-specific antiviral agents is that they only target around half of all colds, at best. This narrow spectrum problem for antiviral drugs is a particular concern because it may not be possible for physicians to distinguish the causative organism based on the symptom complex presentation alone. Another limitation is that because they target specific receptor or protein binding mechanisms, viruses can mutate and become resistant to the agent, rendering the agent ineffective.
In addition to these HRV-specific approaches, a small number of non-specific approaches have been tested clinically, including interferon (a chemical produced naturally by cells to defend against virus infection), acidic buffers (because some viruses, especially HRV, are acid labile), and carrageenan (a seaweed extract). Interferon was shown to be ineffective and acidic buffers reduced viral shedding but had little impact on symptoms. Only carrageenan has been developed commercially and introduced in a small number of countries, but it is not approved in other countries including the US. The putative mechanism by which it works is to coat viruses and nasal surfaces with a polysaccharide that prevents attachment of the virus. Clinical studies with carrageenan have shown mixed results, but it appears that if used continuously during the symptomatic period of a cold it may slightly reduce the duration of a cold, but may have little effect on the severity of the symptoms.
Another challenge for any treatment for the common cold is that the intervention window is very narrow. Once symptoms are observed, the infection may have been in progress for 24-36 hours and thereafter, by day 3 or 4 after first symptoms, the viral load in the nasal mucous is already reduced to relatively low levels. This means that any therapeutic intervention targeting the virus would have a limited window of time in which to exert its effect and achieve significant symptomatic benefits or effect in terms of reduction of cold duration. This presents a practical problem for any drug that is available on prescription, because of the additional delay in obtaining access to the drug once symptoms are observed.
Further as already noted, the symptom complex is a product of the body's reaction to the infection, rather than the infection per se. Once primed by the infection, the cellular defence mechanisms and immune response can remain engaged and are known to cause ongoing symptoms for several days even after the amount of virus in the nasal passages starts to decline. This limits the capacity of an antiviral agent to treat cold symptoms based on its antiviral action alone.
In summary, there are formidable technical challenges to discovering and developing an effective treatment and as a result, and despite decades of research into possible treatments, no effective treatment has emerged despite a very substantial medical, economic and social need to find, develop and commercialise an effective treatment for the common cold.
An effective treatment for the cold is generally considered in the art to be one that demonstrates a significant reduction in (1) the severity of symptoms, and/or (2) the duration of a cold. For the purposes of evaluating symptom severity effects, those in the art commonly employ a measure referred to as the total symptom score (TSS), which is a measure of the severity of the overall symptom complex based on an un-weighted composite of selected symptoms, typically calculated as a daily mean score. The TSS is commonly comprised of five local and three systemic symptoms, each assessed on an ordinal severity scale. The duration of a cold is another important measure for clinical evaluations. One measure considered to be valid in the art is the time to alleviation of illness (TAI) which is determined as the time from initiation of treatment to the time when rhinorrhoea is absent and no other individual symptom is rated above 'mild' in severity.
In addition to these symptom-related measures, in studies where subjects are deliberately infected with a cold virus, typically HRV, it is possible to measure the viral load present at various times after infection as another important measure of the effectiveness of any intervention in the common cold. This is commonly done by sampling the mucous in the nasal passages, using swabs or nasal washings, and detecting the amount or concentration of virus present using techniques such as cell culture or quantitative polymerase chain reaction (qPCR).
Other potentially important clinical endpoints in the evaluation of any cold therapy include the extent to which it (1) reduces the incidence or severity of secondary illnesses such as otitis media, sinusitis and bronchitis, (2) reduces the incidence or severity of serious LRI and disease exacerbations in at-risk individuals, and (3) prevents a cold occurring when a subject is exposed to others with colds.
Topical treatment of colds by applying broad-spectrum chemical disinfectant-type agents to the nasal passages has not been attempted in the field of respiratory diseases management. Such an approach may seem to have potential superficially, because of the ability of the disinfectant to eradicate the virus directly from the nasal passages. However, in most cases there are serious limitations with such agents including local burning, irritation, cellular toxicity, systemic toxicity and unpleasant odour. One chemical disinfectant that has reduced toxic potential and recently has been shown to be safe to use in the nose is povidone-iodine, commonly referred to as PVP-I.
Povidone-iodine (PVP-I) is a broad-spectrum topical microbicide that is known to rapidly inactivate viruses, principally through the potent oxidative effects of free iodine on microbial proteins and nucleic acids. It is known in the art that the instantaneous potency of any PVP-I solution is related to the concentration of free iodine released from the polymer carrier, where free iodine is typically less than 30 ppm in PVP-I solutions, ensuring adequate potency for antimicrobial action while avoiding the iodine-related stinging, burning and other toxicities of traditional iodine solutions such as Lugol's solution, which is a solution of free iodine in potassium iodide. With a PVP-I solution, the majority of the iodine remains within or bound to the complex and is only released as the exogenous free iodine is depleted, for instance as a result of its oxidative interaction with microbial protein. In this way a relatively stable low level of free iodine is maintained while a reservoir of inactive complex-bound iodine remains close to the site of action and ready for use as needed.
Because the oxidative effect of free iodine is potent and not protein or target specific, PVP-I has shown no susceptibility to viral resistance development despite more than 30 years of extensive usage as a topical antiseptic. In addition, it has found some therapeutic utility as a topical agent to treat certain infective skin conditions, including acne and cold sores, which are caused by certain bacteria and herpes simplex virus respectively. In some markets, including Australia and Japan, it is widely used as a throat gargle to treat sore throats, many of which may be associated with the common cold. However, as shown in one randomised, controlled study by Satomura et al ("Prevention of upper respiratory tract infections by gargling: a randomized trial." American Journal of Preventive Medicine 29.4 (2005): 302-307) while such gargling practices may have a slight effect on the sore throat or pharyngeal symptoms of colds, they have no significant effect on nasal cold symptoms or bronchial complications, and no benefit in terms of reducing the incidence of the common cold.
The intranasal use of PVP-I has been extremely limited. PVP-I has been proposed as an intranasal solution or cream for eradication of antibiotic resistant bacteria, which can be inadvertently carried in the nasal passages and contribute to outbreaks of infection in the hospital setting. Hill and Casewell ("The in-vitro activity of povidone-iodine cream against Staphylococcus aureus and its bioavailability in nasal secretions." Journal of Hospital Infection 45.3 (2000): 198-205) tested a 5% PVP-I cream and concluded it may have a role in the prevention of colonization and infection caused by MRSA. Hollander et al ("Asymptomatic carriage of Klebsiella pneumoniae producing extended-spectrum b-lactamase by patients in a neurological early rehabilitation unit: Management of an outbreak." Journal of Hospital Infection 48.3 (2001): 207-213) used a 1.25% PVP-I solution as a nasal spray to eradicate drug-resistant Klebsiella pneumonia from the nasal passages of patients in a neurological rehabilitation unit. Kramer et al ("New aspects of the tolerance of the antiseptic povidone-iodine in different ex vivo models." Dermatology 204.Suppl. 1 (2002): 86-91) confirmed that PVP-I solutions were also effective against MRSA and showed that a PVP-I concentration of 1.25% or lower was suitable for use in the nose. In none of these cases was it suggested that PVP-I solutions might have utility in treating or preventing the common cold as caused by a virus.
Despite its broad-spectrum, lack of resistance potential, utility in certain therapeutic applications and potential safety and utility in the nasal passages for eradication of drug-resistant bacteria, PVP-I has significant known limitations that would lead one skilled in the art to conclude that PVP-I would not be suitable, safe or effective as an agent to treat the common cold as caused by a virus.
One perceived limitation is that PVP-I is a topical agent that does not enter nasal cells, while the replication of cold viruses occurs exclusively inside nasal cells. Those skilled in the art would conclude that any topical intervention such as PVP-I might temporarily degrade the viral load in the nasal mucous but would have no direct impact on the ongoing infection inside the cells, and the latter would continue to drive bradykinin and cytokine production and thereby the symptom complex. In any case, as infected cells burst and released more virus, the viral load in the nasal mucous would be replenished, counteracting any depletive effects of PVP-I. This contrasts with the known useful application of PVP-I to the nasal passages for eradication of bacteria such as MRSA, where the bacteria reside and replicate on the surface of the nasal cells and are not engaged in any active infection.
The process of mucociliary clearance also needs to be considered in the intranasal use of a topical agent, including PVP-I. Mucociliary clearance is a natural cleaning process in the nasal passages whereby the sweeping effect of the hairlike follicles on nasal cells, called cilia, direct mucous towards the throat allowing the mucous to exit the nasal passages and ultimately be swallowed. This process is designed to constantly clean the nasal passages by removal of contaminants including microorganisms in nasal mucous. Gluck et al ("A clinical study on the tolerability of a liposomal povidone-iodine nasal spray: implications for further development." ORL 69.2 (2006): 92-99) showed that the mucociliary clearance time was approximately 15 minutes in healthy noses and that the application of a PVP-I preparation did not significantly alter the clearance time. This would indicate that the maximum time available for a topical intranasal preparation to have any antiviral or other local effect is approximately 15 minutes.
In addition, during a cold, any topical agent is further rapidly cleared by rhinorrhoea or runny nose, which according to Winther ("Rhinovirus infections in the upper airway." Proceedings of the American Thoracic Society 8.1 (2011): 79-89) is the most common early symptom of the common cold in adults. Rhinorrhoea is due to watery fluid secretions from nasal glands and goblet cells in the nasal passages that are principally designed to expel pathogens and other noxious materials from the nose. The volume of the fluids produced over the first several days of a cold is substantial and according to Turner et al ("Efficacy of tremacamra, a soluble intercellular adhesion molecule 1, for experimental rhinovirus infection: a randomized clinical trial." JAMA 281.19 (1999): 1797-1804) the amount of expelled fluids from the anterior nares is approximately 33 g over 7 days for an adult cold. In addition to these fluids secreted from the nostrils, a significant volume of secreted fluids may be swallowed. Overall, during a cold, the high volume of secreted fluids would lead to dilution of any topical agent and its accelerated clearance, causing a significant reduction in the effective exposure time and effect in the nasal passages. Accordingly, one could reasonably conclude that the effective exposure time for any topical agent such as PVP-I during a cold might be no more than one or two minutes.
Another perceived limitation is that free iodine, the only active antimicrobial moiety in PVP-I solutions, is rapidly consumed by nasal mucous because of the presence of mucins, glycoproteins present in nasal mucous secretions that contain a high concentration of cysteine, which reacts readily with free iodine thereby inactivating it and making it unavailable for microbicidal action. Hill and Casewell (2000), previously referenced herein, demonstrated that nasal secretions reduced the microbicidal activity of 5% PVP-I cream and calculated that 1.0 mL of nasal secretions inactivated the equivalent of 22.5 mg of PVP-I. Given the volume of a solution that can be applied into the nasal passages and the likely concentration of PVP-I in such a solution, one would conclude that most if not all of the free iodine available for release from a PVP-I intranasal application could be inactivated by the nasal secretions. This problem is amplified during the common cold when the volume of secretions and the level of mucins are greatly elevated due to rhinorrhoea as discussed above. This is much less of a problem when PVP-I might be applied to the nasal passages for eradication of MRSA or other resident bacteria, where mucous is limited and rhinorrhoea is not typical.
Another long-standing perceived limitation is that PVP-I has significant toxicity for human cells. Kramer et al (2002), previously referenced herein, showed that a PVP-I concentration of 2.5% or greater was toxic to the nasal cilia and therefore generally unsuitable for use in the nose. A concentration of 1.25% or lower did not cause ciliotoxicity. However, even at or below 1.25%, PVP-I has significant toxicity for human immune cells particularly relevant to the treatment of the common cold. Van den Broek et al ("Interaction of povidone-iodine compounds, phagocytic cells, and microorganisms." Antimicrobial Agents and Chemotherapy 22.4 (1982): 593-597) showed that PVP-I significantly reduced the viability of granulocytes at concentrations above 0.05%, with virtually all granulocytes destroyed above 0.1%. Because granulocytes play a central role in the cellular immune processes that eliminate viruses during a cold, such toxicity generally would be considered undesirable for a cold treatment agent. Monocytes, which have an important immune signalling role in a cold and act in concert with granulocytes to eliminate viruses, showed slightly more resilience to PVP-I, but were substantially degraded by PVP-I concentrations above 0.1%. Because the toxicity of PVP-I to immune cells has been known in the art since 1982, it has presented a long-standing perceived barrier to the development of PVP-I for many therapeutic applications. Again and in contrast, this is much less of a problem when PVP-I is applied to the nasal passages for eradication of resident bacteria, where immune cells are not actively engaged in fighting an infection.
In an effort to combat the cellular toxicity problem of aqueous PVP-I preparations and expand the utility of PVP-I, researchers recently have sought to develop liposomal formulations of PVP-I wherein the majority of the PVP-I is encapsulated in liposomes. Such liposomal PVP-I preparations have significantly reduced toxicity to human cells, potentially making them more suitable for certain intranasal applications, but not the common cold. While trapping the majority of the PVP-I within liposomes reduces toxicity, it also slows the rate and/or extent of free iodine release, which also reduces its potency such that, and as further described herein, renders it unsuitable for an application such as the common cold and such liposomal PVP-I formulations have never been proposed for the treatment or prevention of the common cold.
A further perceived limitation on the intranasal use of PVP-I is that iodine absorption could lead to systemic toxicity due to its well-known effects on thyroid function. It is well known in the art that the nasal passages represent a highly efficient portal for drugs and other agents to enter the systemic circulation. Therefore, when using any iodine-based product in the nasal passages, one needs to be extremely wary of the potential for excessive iodine absorption. In the United States, the National Institutes of Health guidelines state that the safe upper limit for total iodine ingestion by adults is 1,100 micrograms of iodine per day. This easily could be exceeded by intranasal applications of a PVP-I preparation in the nose depending on the volume, concentration and frequency of application of the preparation.
A final and crucial perceived limitation of PVP-I is that it is has limited activity against HRV, the virus responsible for the majority of colds. It is well known in the art that enveloped viruses are highly susceptible to inactivation by various agents including PVP-I, whereas non-enveloped or 'naked' viruses and particularly HRV, are resistant to inactivation by most chemical agents. A study by Reimer et al ("Antimicrobial effectiveness of povidone-iodine and consequences for new application areas." Dermatology 204.Suppl. 1 (2002): 114-120) showed that against the enveloped virus, human influenza virus, PVP-I at very low concentrations achieved a 4 log10 reduction in viable virus count, which is generally considered a microbicidal effect, within a 30 second exposure. This contrasts with human rhinovirus, a naked virus, where PVP-I at any concentration barely achieved a 1 log reduction after 30 seconds exposure and required 30 minutes exposure for a 4 log reduction. This further compares with another naked virus, adenovirus, where a 4 log reduction required only 5 minutes exposure, reinforcing the fact that rhinovirus is one of the most resilient naked viruses and further that activity of any agent against adenovirus or other naked viruses may not be representative of the agent's activity against HRV. Further, and in any case, adenovirus is not a common or recognised cause of the common cold and therefore not relevant for comparison in the context of the common cold.
The relatively weak activity of PVP-I against HRV has been corroborated by other studies. For example, Wutzler et al ("Virucidal activity and cytotoxicity of the liposomal formulation of povidone-iodine." Antiviral research 54.2 (2002): 89-97) showed that PVP-I produced a 1.1 log reduction in HRV after 30 seconds exposure and required 30 minutes for a microbicidal effect (4 log reduction), compared with a microbicidal effect after only 5 minutes for adenovirus and after only 30 seconds for the enveloped herpes simplex virus (HSV). Like adenovirus, HSV is not a common or recognised cause of colds.
Kawana et al ("Inactivation of human viruses by povidone-iodine in comparison with other antiseptics." Dermatology 195.Suppl. 2 (1997): 29-35) tested the activity of PVP-I against multiple viruses and confirmed the rapid microbicidal effect against enveloped viruses. However, PVP-I failed to produce a microbicidal effect against HRV within the maximum exposure period tested, which was 10 minutes. Given that these various studies were conducted under ideal in vitro conditions, one skilled in the art would assume that the performance of PVP-I against HRV in vivo, especially in the face of inactivation and clearance processes, would be clinically negligible. For all the above reasons, it would not be obvious that the intranasal application of PVP-I would be effective as a treatment for the common cold. Further, PVP-I has never been developed or commercialised as an intranasal treatment for the common cold and based on published information, has never been even assessed in a clinical study to determine its effectiveness as a prospective treatment for the common cold. If it were assessed in a controlled clinical study, those skilled in the art would assume that it would not meet the criteria for an effective treatment, namely that it would not cause a significant reduction in the severity of symptoms or the duration of a cold.
Despite all these limitations, the present inventors have surprisingly found that when used as an intranasal preparation according to the methods of the present invention, PVP-I is effective in reducing both the severity of symptoms of a cold and the duration of a cold. Further, it has additional benefits with respect to reducing the viral load and viral shedding in the nasal passages during a cold, reducing secondary illnesses, and reducing the risk or severity of serious LRI and exacerbations in at-risk individuals. Finally, methods are disclosed that have utility in prevention of colds.

Treatment and prevention of the common cold using povidone-iodine


A method is disclosed for synthesizing borosilicate TON-framework type molecular sieves in a hydroxide media using a 1,3-dimethylimidazolium cation or a 1,4-bis(N-methylimidazolium)butane dication as a structure directing agent.

Molecular sieves are a commercially important class of crystalline materials. They have distinct crystal structures with ordered pore structures which are demonstrated by distinct X-ray diffraction patterns. The crystal structure defines cavities and pores which are characteristic of the different species.
Molecular sieves are classified by the Structure Commission of the International Zeolite Association according to the rules of the IUPAC Commission on Zeolite Nomenclature. According to this classification, framework type zeolites and other crystalline microporous molecular sieves, for which a structure has been established, are assigned a three letter code and are described in the "Atlas of Zeolite Framework Types," Sixth Revised Edition, Elsevier (2007).
One known molecular sieve for which a structure has been established is the material designated as TON, which is a crystalline material having one-dimensional 10-membered ring channels. Examples of TON-framework type molecular sieves include ISI-1, KZ-2, NU-10, Theta-1 and ZSM-22. TON-framework type materials are of significant commercial interest because of their activity as catalysts in dewaxing of paraffinic hydrocarbons.
Borosilicate molecular sieves can be of interest when a molecular sieve of reduced acidity is desired. A borosilicate molecular sieve having the TON-framework type is reported to have been hydrothermally synthesized using a 1,3-dimethylimidazolium cation as the structure directing agent, but the synthesis requires the presence of concentrated hydrofluoric acid. See R. H. Archer et al., Micropor. Mesopor. Mater. 2010, 130, 255-265. An amorphous material was produced from a borosilicate hydroxide-mediated reaction gel when a 1,3-dimethylimidazolium cation was used as the structure directing agent.
The use of fluoride in molecular sieve reaction gels is undesirable on a large scale because of the potential hazards involved. There thus remains a need for a method of synthesizing borosilicate TON-framework type molecular sieves that eliminates the need for a source of fluoride.

Synthesis of borosilicate ton-framework type molecular sieves


There are provided systems and methods for remote monitoring of tagged physical objects in an emergency. A user may set up a series of beacons at a facility of the user, such as an office or hospital. The beacons may connect to tag devices as the devices enter a coverage area for the wireless beacons or upon request by a service provider server in an emergency situation. The beacons communicate distance information regarding the tag devices and associated physical objects to a service provider server. The service provider server may determine the location of a physical object and provides the location to the user or to emergency personnel. In an emergency, the service provider server may provide a notification to a specific subset of users, in which the notification includes the location of a physical object of interest to the subset of users because of the emergency condition.

In an emergency situation, finding and monitoring certain physical objects becomes increasingly important. For example, in an earthquake people may be injured increasing the need to find a first aid kit or other piece of emergency equipment. However, the very conditions brought on by the emergency, e.g. dust, debris, smoke, etc., can make finding such objects more difficult. The ability of quickly locating such emergency equipment for use by those present in the emergency, whether by emergency responders, bystanders, or victims of the emergency, may be a matter of life and death.
Additionally, situations may arise in which certain key items, such as a computer containing highly sensitive information or a prototype device under development in a costly research and development program, should be monitored in the event of an emergency. For example, if a fire breaks out in part of a building, there may be time to ensure that irreplaceable items are safely removed from the building.
However, many surveillance and tracking systems can cost tens of thousands or hundreds of thousands of dollars to deploy and maintain on a large scale. Accordingly, current systems for locating and monitoring physical objects within a facility are not satisfactory in all respects.
Embodiments of the present disclosure and their advantages are best understood by reference to the following detailed description. It should be appreciated that like reference numerals are used to identify like elements illustrated in one or more of the figures. However, such repetition of reference numerals to identify similar elements is for ease of explanation and should not be construed as limiting the present disclosure.