The invention proposes an apparatus for transporting a container relative to a filling station, comprising at least one filling station (48) for filling at least one container (36), and also comprising at least one container mount (38) for transporting the container (36) relative to the filling station (48), characterized in that at least one drive surface (13) and at least one mover (20), which can be coupled in particular magnetically to the drive surface (13), are provided, wherein the mover (20) is arranged on the drive surface (13) such that it can be displaced and/or rotated in at least two degrees of freedom, and in that the container mount (38) is connected to the mover (20).

The invention proceeds from an apparatus for transporting a container relative to a filling station.
WO 2011/138448 already discloses a system for transporting containers between various stations, the containers being received in container carriers. The system includes a control unit which controls the transporting of the container carriers, a transporting surface which is divided into part surfaces and on which the container carriers can be movably arranged, and drive means, the drive means being actuated by means of the control unit and a respective drive means being associated with a respective part surface, a respective drive means being realized for the purpose of acting upon an associated container carrier with a drive force. Said system is distinguished by high degree of flexibility, as is required, in particular, for transporting sample containers of a laboratory analysis system.
The object underlying the invention is to optimize a transporting system for a filling station in a further manner.
The advantage of an apparatus according to the invention in contrast is that sequential process steps or fixed process steps are no longer necessarily required. By at least one drive surface and at least one mover which is couplable, in particular magnetically, to the drive surface being provided, and the mover being arranged on the drive surface so as to be displaceable in at least two degrees of freedom and/or rotatable and the container receiving means being connected to the mover, the containers can be supplied to and removed from the filling station in a particularly flexible manner. In addition, by means of said drive principle, the particle emissions or the abrasion produced by relative movements of otherwise required rollers, sliding elements or drive means are able to be reduced, as the mover can now be moved contactlessly relative to the drive surface on account of the magnetic coupling. This is advantageous precisely for pharmaceutical filling lines. In addition, the cleanability of the system is improved by just planar surfaces being necessary without the otherwise usual mechanical connections that are difficult to clean between the drive and the moved container transport. In addition, expenditure precisely on set-up or assembly of the processes to the filling station are reduced by the transport not always having to provide the containers at a fixed position. In addition, the service life is increased by reducing the number of wearing parts. In addition, fixed, unchangeable mechanical routes are avoided. Switching functions are no longer place-bound but can be established at arbitrary places inside the drive surface as a result of corresponding programming. The flexible drive concept with superposition of a rotational movement of the mover can have a direct influence on the sloshing behavior of a filled, but not yet closed container, by the mover, in an expedient further development, generating a rotational movement which counters the sloshing of the filled product. Apart from a targeted superposition of the linear movement of the mover with a rotational movement, no further additional mechanical movement means are necessary in order to reduce the sloshing of the filled product.
In an expedient further development, it is provided that the mover is rotated about a pivot point by an angle in relation to its rest position, wherein the angle depends in particular on a speed and/or the acceleration of the mover. Consequently, the preferred rotation can be determined in a simple manner by means of the known translatory speed or acceleration development.
In an expedient further development, it is provided that an inlet, which includes, in particular, at least one guide wheel and/or one conveying screw, is provided for supplying the containers, wherein the mover moves the container receiving means for taking over the supplied containers at the same speed as the inlet supplies the containers. As a result, the flexible actuation of the movement of the mover can also be applied in a particularly simple manner for receiving in-coming containers without additional mechanical convertors or similar being necessary. The mover is consequently suitable precisely for transporting jobs around the container filling process.
In an expedient further development, it is provided that the inlet is arranged relative to the drive surface such that the inlet is in contact for supplying on one side of a container, whilst on another side of the container the container receiving means of the mover can move into contact with the containers for taking over the container supplied from the inlet. As a result, a simple transfer of the supplied containers to the mover can be achieved. In a particularly expedient manner, several movers are arranged next to one another for taking over the container supplied from the inlet. High speeds for supplying the containers can be transferred in a seamless manner to movers that are standing by. Several movers, which are arranged next to one another, are moved in a particularly expedient manner at the same speed for taking over the container supplied from the inlet for this reason.
In an expedient further development, it is provided that the container receiving means can receive several containers and/or the container receiving means is oriented longitudinally or transversely with respect to the direction of movement of the mover. As a result, the containers to be filled are able to be processed quickly in rows or lines, which increases the production rates of the apparatus.
In an expedient further development, the container receiving means is realized such that at least one container situated in the container receiving means is retained or released by means of a movement, in particular tilting, of the mover. As a result, a functionality of the releasing of a container, as can be necessary for weighing prior to or after the filling process, can be realized in a particularly simple manner just by means of a (rotational) movement without any additional further mechanisms.
In an expedient further development, it is provided that at least one process station such as a closing station and/or at least one weighing device and/or at least one inspection device and/or one inlet and/or one outlet is provided and the drive surface is developed such that the mover moves at least the container receiving means between the filling station and the process station. The process sequences can consequently be developed in a flexible manner by other stations being able to be approached in dependence on the state of the container. In particular in the case of unacceptable weighing results, the container can be moved to the filling station again for topping up, which is easily possible in the case of said drive concept on account of a freely-programmable route.
In an expedient further development, it is provided that the drive surface is realized as a vertical plane. As a result, relative movements that are typical precisely to the filling process, such as transport beneath the filling needles that are, as a rule, oriented vertically, can be realized in a simple manner. In a particularly preferred manner, the container receiving means is moved during the filling process. The filling needles can consequently be fixedly arranged without impairing the filling operation. The fixed arrangement of the filling needles has the effect of reducing particles as friction from the filling hoses or the like that would otherwise occur no longer occurs where the piping is fixed.
In an expedient development, it is provided that several movers, which are movable independently of one another, are provided. As a result, the process sequences can be developed in a flexible manner by other stations being able to be approached depending on the state of the container with high production rates.
Additional expedient further developments are produced from further dependent claims and from the description.

Apparatus for transporting a container relative to a filling station


A polyester copolymer having an aromatic amine incorporated in the main chain, which is excelent in thermal stability as well as dynamic property, and a process for the production of the polyester copolymer, whereby the existing installation of the prior art can be used as it is, thus resulting in lowering of the production cost, are provided. The polyester copolymer comprises an aromatic dicarboxylic acid, diol and at least one compound selected from the group consisting of aromatic compounds having amino group, represented by the following general formula (I), EQU H.sub.2 N--X--COOR (I). wherein X is an aromatic ring-containing group and R is a hydrogen atom or a hydrocarbon group selected from the group consisting of alkyl groups and cycloalkyl groups.

1. Field of the Invention
This invention relates to a novel polyester copolymer and a process for the production of the same.
2. Description of the Prior Art
Polyesters, in particular, polyethylene terephthalate (hereinafter referred to as PET) has a high initial modulus of elasticity as well as excellent thermal dimension stability of widely available polymers and application thereof to tire codes has rapidly been increasing as an industrial material having severer requirements. However, a higher initial modulus of elasticity, more excellent thermal dimension stability and lower heat shrinkage are strongly required than at the present time because of providing a product with high quality, high function and high additional value and accordingly, even when using PET having excellent properties as described above, a large improvement is still required.
A number of proposals have hitherto been made concerning improvement of various properties. Of these proposals, methods of improving polyesters can be classified into the following groups:
1) Improvement on the molecular level as is found in utilization of a copolymerization reaction. PA1 2) Improvement in the molecular weight and in the core-sheath structure with a polymerized product. PA1 3) Change of conditions such as melt spinning, solution spinning, stretching, heat treatment, etc. and improvement of each of the apparatus used therefor. PA1 4) Improvement of after-working for each of the products.
Above all, the improving method 1) comprising adding an aimed improvement material in the polymerization step of the polyester will be useful for the practice on a commercial scale.
The polyester is ordinarily produced by direct esterification of an aromatic dicarboxylic acid and a diol compound by stirring and heating the mixture under some or normal pressure, or by subjecting an alkyl ester of dicarboxylic acid and a diol compound to transesterification to obtain an ester compound and low polymer and then subjecting it to polycondensation by stirring and heating the mixture in a high vacuum.
In addition to these ordinary methods, a number of proposals have hitherto been made as to improvement in the molecular level as appeared in the utilization of the above described copolymerization reaction, for example, a method comprising acetylation of the amino group of p-amino benzoic acid and then effecting the polymerization [Journal of Applied Polymer Science, Vol. 25, 1685-1694 (1980)], a method comprising adding, at the initial period of melt polycondensation of a polyester, an aromatic diamine and aromatic dicarboxylic acid or substituted derivatives and effecting the polycondensation (Japanese Patent Laid-Open Publication No. 67009/1980), and a method comprising adding, at the initial period of melt polycondensation of a polyester, an aminocarboxylic acid compound having an aromatic ring and effecting the polycondensation (Japanese Patent Laid-Open Publication No. 137217/1980). In any method, a substituted derivative of a compound having amino group is utilized from the initial period of the reaction or a compound having amino group is added at the initial period of melt polycondensation of a polyester.
In the utilization of a copolymerization reaction for the improvement on molecular level, a segment for the improvement can be incorporated in a host molecular chain and it is thus possible to choose the variety of an additive and the copolymerization proportion according to the object of the improvement, for example, the thermal dimension stability, heat shrinkage, initial modulus of elasticity, elongation, toughness, etc. of a molded article of the copolymer.
The means for incorporating an aromatic compound having an amino group into a polyester molecular chain according to the present invention is based on this consideration relating to designing on a molecular level.
Since the aimed-improvement can be accomplished by designing on a molecular level according to this means, as described above, a number of proposals have hitherto been made, but there arise problems in these proposals that in the case of a copolymerization reaction of an aromatic compound having an amino group with a polyester-forming compound, having been proposed up to the present time, a substituted derivative is once formed, for example, by acetylation before the copolymerization reaction and then subjected to the copolymerization reaction, thus resulting in increase of the costs for raw materials and for installation of reaction vessels before the existing polyester reaction process. In addition, in the case of adding an aromatic compound having amino group at the initial period of melt polycondensation, there arises a problem that the existing polyester reaction process must be improved, for example, by installing a conduit for introducing an aromatic compound having an amino group at the late period of the esterification reaction or transesterification reaction or by installing a conduit provided with a means for preventing vacuum leakage, in particular, in the case of adding an aromatic compound having an amino group at the initial period of a polycondensation when the reaction proceeds in vacuum. Anyway, it is essential to install a new introduction conduit in the existing process.

Polyester copolymer and a process for the production of the same


Thermoplastic articles molded from polycarbonate resin blends which comprise a polycarbonate resin encapped with a monovalent moiety of the formula: ##STR1## wherein R.sub.1 is selected from hydrogen and hydrocarbyl and each R.sub.2 is selected from hydrocarbyl and hydrocarbyloxy exhibit improved color when irradiated with ionizing radiation.

1. Field of The Invention
The invention relates to irradiated articles molded from thermoplastic molding compositions and more particularly relates to articles molded from compositions of irradiation resistant aromatic polycarbonate resins and sterilized by ionizing radiation.
2. Brief Description of The Prior Art
Synthetic polymeric resins have been used increasingly to mold articles useful in medicine and surgery. Examples of such articles include containers, packaging, instruments, prosthetics, tubing, and working components of treatment apparatus. The selection of a particular polymeric resin will depend on the physical properties required in the molded article.
One property necessary to many medical and surgical articles molded from thermoplastic polymeric resins, is their receptivity to sterilization procedures. A commonly preferred sterilization technique is exposure to ionizing radiation. Unfortunately, ionizing radiation may adversely impact some polymeric resins in ways unacceptable to some uses.
For example, polycarbonate resins have many properties which are advantageous to their use in many medical and surgical devices or articles. However, upon exposure to ionizing radiation they generally change from a normally desired transparency and clarity to a yellowed coloration. In addition, this yellow color continuously changes with increasing time after gamma ray exposure. Aesthetically, the yellowed coloration and the continuously changing color are not always acceptable.
A number of compounds have been used as additives to polycarbonate resins, to inhibit the yellowing of articles molded from polycarbonates and subjected to ionizing radiation. Representative of these additives are those described in the U.S. Pat. Nos. 4,624,972 (Nace); 4,657,949 (Nace); 4,757,104 (Nace); 4,804,692 (Lundy et al.) and 4,880,850 (Nelson et al). However, the presence of any additive in a polycarbonate resin molding composition generally has an effect on other desirable physical properties.
Another strategy for reducing the yellowing of a polycarbonate resin upon exposure to ionizing radiation is described in the U.S. Pat. No. 4,778,656 (Allen et al, 1988). The method entails blending the polymer with another polymer, which has the effect of improving ionizing radiation resistance of the polycarbonate. Examples of the additive polymers are polyester, polysulfone-carbonates and certain copolyesters. Like the previously described yellowing inhibitors, these additive polymers also affect physical properties in articles molded from blends of the mixed polymers.
The U.S. Pat. No. 4,933,424 recently issued to one of us (Rosenquist) describes a class of hydroxy-terminated polycarbonate resins, among which we have found a group of resins which exhibit improved color after sterilization with ionizing radiation.

Irradiation resistant functionally encapped polycarbonate


In an optical fiber functional device for processing a light beam between optical fibers, single-mode optical fibers for processing the light beam are concentrically connected at the mutually opposed ends to convergence-type rod lenses each having a prescribed length and made of a graded-index optical fiber.

The present invention relates to an optical fiber functional device and a method of manufacturing the same, and more particularly relates to an optical fiber functional device capable of being used to form a parallel beam converter system in disposing a functional optical element such as an optical isolator in an optical fiber wave-guide for optical communication, and a method of manufacturing the same.
It is known that if a semiconductor laser unit, which is a main light source for optical fiber communications, optical disk input and output or the like, receives reflected light back from the end of an optical fiber connected to the laser unit, the point of connection of optical fibers, or an optical system such as a coupling lens and an optical connector, the oscillation of the unit becomes so unstable that it undergoes a large operational deterioration such as an increase in noise and a fluctuation in output. Therefore, various optical isolators have been developed to prevent the oscillation of the semiconductor laser unit from becoming unstable due to the reception of the reflected light, to make the unit be a stable light source for optical communication.
Although an optical isolator including a Rochon's prism as a polarizer or an analyzer, a Faraday-effect rotator made of a single crystal of YIG (yttrium-iron garnet), bismuth-substituted yttrium-iron garnet or the like, and a holed permanent magnet made of SmCo or the like to magnetize the rotator in the forward direction is widely known, the isolator is only effective for a certain plane of polarization, and has a problem that if light not coincident with the direction of polarization of the isolator enters into it, the light undergoes a large loss in passing through the isolator. For use between optical fibers, an optical isolator with no dependence on polarization has been desired because a light beam, which is transmitted through the optical fibers, has generally the changed plane of polarization.
Thus, various optical isolators, in each of which the separation and/or synthesis of ordinary and extraordinary rays obtained by a flat plate of double refraction crystal such as calcite or an artificial anisotropic medium instead of a Rochon's prism are utilized to eliminate almost all of the loss of light in the forward direction as to all the planes of polarization so as to make the isolator not dependent on polarization, have been proposed.
FIG. 1 shows a conventional optical isolator disclosed in Japanese Patent Publication No. 28561/83 and including a lens 10, two flat plates 11 and 12 of double-refraction rutile crystals, a Faraday-effect rotator 13 which is a magnetooptic member, and an optically rotatory plate 14 of optically rotatory or anisotropic crystal such as quartz.
In the isolator, the direction of polarization of light from an optical fiber 8 as a light passage is changed by an angle of 45 degrees clockwise by each of the rotator 13 and the optically rotatory plate 14. The flat plates 11 and 12 of double-refraction rutile crystals have the same thickness, and are tilted by a prescribed angle to the optical axis of the isolator so that the axes of the plates are parallel with each other to prevent light from proceeding from another optical fiber 9 to the optical fiber 8.
FIG. 2 shows another conventional optical isolator disclosed in the Japanese Patent Publication No. 58809/86 and including lenses (a) and (b), two double-refraction crystal plates 11, and a Faraday-effect rotator 13. Each of the plates 11 is shaped as a wedge. The oblique sides of the plates 11 face each other across the Faraday-effect rotator 13. Shown at 1 and 4 in FIG. 6 are optical fibers as light passages. The isolator functions nearly in the same manner as that shown in FIG. 1.
Since the diameter of each of the lenses provided in the above-mentioned conventional optical isolators in order to cause each of them to function as a fiber collimator to transmit the light from one of the optical fibers to the other is much larger than that of the fiber, the entire size of the isolator is large. This is a problem. Since the distance from the light outlet end of one of the optical fibers to the nearby lens of the optical isolator and that from the other lens thereof to the light inlet end of the other of the fibers need to be optimized while the state of the optical path for the light transmitted through the lens and the intensity of the light are monitored, it takes much time and trouble to assemble the fiber collimator. This is also problematic.
FIG. 3 shows a conventional optical fiber collimator in which spherical lenses 23 and 24 are connected to the mutually opposed ends of optical fibers 21 and 22 so that the rays of light transmitted through one of the fibers are made parallel with each other. FIG. 4 shows another conventional optical fiber collimator in which rod lenses 25 and 26 of the refractive index distribution type are connected to the mutually opposed ends of optical fibers 21 and 22 so that the rays of light transmitted through one of the fibers are made parallel with each other.
However, from standpoints of the efficiency and cost of production, the conventional optical fiber collimators have problems that the locations of the optical fibers and the lenses need to be modulated and fixed with the accuracy of the micron order, and anti-reflection coatings need to be provided on the lenses to prevent the light from being reflected due to the difference between the refractive indices of each components.

Optical fiber rod lens device and method of making same


The inventive device comprises a housing (1) which is configured in the shape of a flat strip comprising an enclosure (6) on one side which projects outwards and contains a material (7) that changes its state or viscosity at a predetermined temperature. Said enclosure (6) opens onto the space inside the housing through a hole (8) which can be plugged with a tongue (9), this space inside the housing containing a strip (11) consisting of a porous material that is visible form the outside through holes made on the top surface (5) of the housing.

The present invention concerns a device for detecting and quantitatively measuring the exposure of an object to a temperature at least equal to a predetermined temperature with account being taken of the duration of said exposure.
It applies especially, but not exclusively, to the checking of the integrity of the cold chain necessary for preserving certain objects or products, for example perishable foodstuffs, or even products for medical use, such as blood, vaccines or even temperature-sensitive medicines.
By way of example, it is known that a concentrate of red corpuscles can be preserved in a blood bank for forty-two days at a temperature of between +40° C. and +8° C. Once distributed by the blood transfusion service, this concentrate must be used very quickly if the ambient temperature exceeds +10° C. It is therefore important to know the moment when this temperature is exceeded and to measure for how long in order to know whether the concentrate is still usable.
A similar problem arises in the case of frozen products which must be preserved at a temperature of −30° C. and which, after de-frosting, must be consumed quickly.
Here again, it is important to detect whenever the preservation temperature is exceeded and, if necessary, the period for which it is exceeded, and the result of these two detections should be irreversible in character so that it can be ascertained long afterwards that the temperature has been exceeded as stated.
In an attempt to arrive at these results, electronic devices have already been proposed, employing a temperature measuring probe and a micro-controller making it possible both to detect when the temperature is exceeded and for how long. However, such a device proves too expensive to be used systematically on all the objects for which it is wished to monitor the temperature.
Attempts were also made to use temperature indicators employing fusible bodies changing state when a predetermined temperature is exceeded. These indicators, however, frequently inaccurate, do not take into account either by how much or for how long the temperature is exceeded, so that nothing makes it possible to indicate whether the object or the product remains usable or not.
The aim of the invention is therefore more particularly to eliminate these drawbacks by means of a device which detects the instances when the temperature is exceeded and which integrates into the time the amount by which the temperature is exceeded.

Device for detecting and quantitatively measuring the exposure of an object to a predetermined temperature for a predetermined duration


A large scale LED exposure array and system for printers, and unique methods of inputting data to and operating such an array, are disclosed. The array can be loaded and refreshed with data information at rates compatible with high speed printing, and forms part of an electronic image forming and handling system which can load an refresh an exposure array at variable speeds of at least 100 to 300 ft./min. The system includes compensation for differences in illuminating capability of individual LEDs in a large array, by introducing modifications in LED on-time which are centered with respect to the incremental area of the photoreceptor on which a pixel is to be formed, and to compensate for changes in pixel exposure time with increase in speed of the photoreceptor. Also disclosed are an LED configuration which can emit high energy in a controlled pattern to give a desired pixel spot on a photoreceptor, and an arrangement for mounting the array to maintain each light emitting spot in focus on the photoreceptor surface, although a wide array is employed.

This invention relates to an imaging array and system, and a method of operating the same, in which a large number of closely spaced imaging devices, preferably light emitting diodes (LEDs) optically coupled to a common lens system and electronically coupled into an organized driving system, are capable of high speed exposures of incremental areas of a photoreceptor. An image or images can thus be formed of a large number of small pixels, at resolutions in the order of three hundred lines per inch, on copy material of various types, and at speeds in the order of 100 to 300 ft./min.
The combination of such resolution and speed has been heretofore unattainable as a practical matter. Relatively sophisticated copy machines have been developed, using powder toner, and while a few of these have capability of printing on web material those units are essentially a variation of similar sheet fed copiers. They all have operating speeds in the eighty to ninety copy/minute range, and this speed is fixed. Their exposure and development systems will not tolerate variation in speed. Such prior art copiers, by their very nature, are also sensitive to characteristics of the copy material, e.g. the sheet on which the copy is made. In general, those copiers have difficulty making good reproductions on certain coated papers, or on material of variable thickness as where blank labels are already adhered to the material.
Diode array exposure systems have been known, such as disclosed in U.S. Pat. Nos. 4,455,562, 4,596,995 and 4,780,731, however due to limitations in data handling capacity and LED optical output power, prior art arrays have been limited to relatively low speeds and to array lengths in the order of twelve inches (the top-to-bottom dimension of most text to be copied). Higher speeds are not attainable due to the manner in which data is transferred to the individual LEDs of an array, and in the power limitations which prevent light radiated from such prior art arrays from effectively forming an electrostatic image on a photoreceptor surface.
Furthermore, it is known that an array of large numbers of LEDs will exhibit differences in light intensity output among the individual LEDS. Such intensity variations can cause significant differences in the discharging of pixel areas on a charged photoreceptor surface (such as on a rotating drum). As speeds are increased, the resulting problems magnify. Thus, a number of ways have been suggested to compensate for the LED light output variations. One scheme requires that the array be scanned, one LED at a time, and the observed differences in light output from the individual LEDS is used to develop a look-up table. Such a table in turn is read to modify the on-time of the LEDs to produce a closer average light output from all LEDs in the array each time they are individually driven in response to a character generating input. Another scheme uses a light detector in the array to detect the outputs of the LEDs when they are driven, and to provide immediate feedback compensation to the driving circuit.
However, the clocking and scanning circuits used for driving the LED arrays are generally synchronized to motion of the photoreceptor, e.g. drum rotation. Such compensation schemes have not, heretofore, taken into account the fact that by lengthening the on-time of certain ones of the LEDs, the mid-point of LED on-time is varied. In other words each LED to be driven, in exposing desired ones of a row of pixels across the photoreceptor, will initiate exposures at the same instant, but exposures will stop at different times. Thus, centering of the LED on-time with respect to the desired center of the pixel area on the photoreceptor is disturbed by those compensation schemes.


The invention discloses a method for detecting an activity of an endoglycosidase. The method includes providing the endoglycosidase with a substrate of the endoglycosidase and detecting cleavage of the substrate. The method further includes at least partly inhibiting the transglycosidase activity of the endoglycosidase. The transglycosidase activity may be inhibited by chemically modifying the substrate such that transglycosylation of the substrate by the endoglycosidase is at least partly inhibited while the endoglycosidase is still capable of cleaving the substrate. In one embodiment, the substrate comprises an oligosaccharide chain. Compounds and kits suitable for use in a method of the invention are also disclosed. Methods involving competitive inhibitors are also disclosed as are methods for the synthesis of glycosylated substrates involving the transglycosidase activity of an endoglycosidase.

Glycopolymers are major components of the extracellular matrix of organisms. These matrixes can be remodeled and/or degraded by endoglycosidases and exoglycosidases. Examples of endoglycosidases are chitinase, lysozyme, heparanase, hyaluronidase, and cellulase. Chitinase.
Chitin is the linear polymer of beta 1-4 linked N-acetylglucosamine residues. It is the second most abundant glycopolymer on earth that is present in cell walls and coatings of a very large variety of organisms. Chitin is degraded in a stepwise manner by the concerted action of endoglycosaminidases (chitinases) and exoglucosaminases. The chitinases are widely distributed in nature and are known to fulfill several critical biological functions. Examples are roles in food processing, remodeling and defense against chitin-containing pathogens. Chitinases can be also industrially employed, for example in crop protection, food preservation, bio-degradation of chitin-containing waste product and production of chito-oligomers or other fine chemicals. A novel area of application is in the field of diagnosis and monitoring of specific human disease conditions as well as the assessment of chitinase deficiency as potential risk factor for specific infections.
The existence of endogenous chitinases in man has only recently been unequivocally demonstrated (Hollak et al., 1994). The enzyme was initially discovered in patients with Gaucher disease, an inherited lysosomal storage disorder that is caused by a deficiency in the lysosomal enzyme glucocerebrosidase. The level of chitinase activity is generally 1000-fold increased in plasma of symptomatic Gaucher patients. The corresponding enzyme, characterized in great detail at the level of protein, RNA and gene, has been named chitotriosidase. The features of the enzyme have been described in a series of publications (Renkema et al., 1995; Boot et al., 1995; Renkema et al., 1997; Renkema et al., 1998; Boot et al., 1998; Boot et al., 2001). It was shown by us that in tissues of Gaucher patients, macrophages transform to lipid-laden pathological cells that synthesize and secrete large quantities of chitotriosidase. The concomitant marked elevation of enzyme in plasma reflects the presence of abnormal macrophages in tissues and is currently used for the diagnosis, the detection of onset and progression of disease and the monitoring of efficacy of therapeutic intervention (Aerts et al., 1997; Cox et al., 2000; Casal et al., 2002, Giraldo et al., 2002). Deficiency in the enzyme is a frequent trait and is predominantly caused by a 24 bp duplication in the chitotriosidase gene (locus 1q31). In various ethnic groups the frequency of carriers for this mutation is about 35%. A convenient test for establishing an individual's chitotriosidase genotype has been developed (Boot et al., 1998; Choi et al., 2001).
Chitotriosidase is the true analogue of chitinases from lower organisms. It can efficiently degrade chitin, releasing chitotriose and chitobiose fragments from the reducing end of the polymer. Recently, a human mucinase was discovered which also displays chitinase activity (Boot et al., 2001). The enzyme shows an extreme acid stability and acid pH optimum for activity. This enzyme has been named acidic mammalian chitinase (AMCase). It is not present in serum in contrast to chitotriosidase.
It has been earlier conceived that expression of chitinase activity is a very specific phenomenon that is uniquely related to chronic activation of tissue macrophages. This novel thought might be exploited for various diagnostic purposes and could also revolutionize non-invasive monitoring of progression of diseases and correction by therapies. Proof of concept has indeed been obtained: chitotriosidase has been found to be expressed by chronically activated macrophages in several pathological conditions resulting in elevated enzyme activity levels in bodily fluids such as plasma, cerebral spine fluid or urine. Examples of conditions showing such type of abnormalities are several lysosomal lipid storage disorders (Guo et al., 1995) sarcoidosis and visceral Leishmaniasis (Hollak et al, 1994), thalassemia (Barone et al., 2001), arteriosclerosis (Boot et al, 1999), HES (hydroxyethylstarch)-induced prunitis, CGD (chronic granulomatosis disease), Crohn's disease, Tangier disease, and arteriosclerosis (Aerts and coworkers, not yet published observations).
Detection and quantitation of chitotriosidase protein in plasma with immunological techniques is problematic. In healthy subjects the protein concentration is on average only 5 ng/ml of serum.
The fact that the protein can catalyse a specific reaction allows in principle a more sensitive and quantitative detection by measuring this enzymatic activity. Unfortunately, again several limitations exist in this connection. Chitin degradation is generally followed using colloidal chitin as substrate and the indirect detection of released fragments. The latter is accomplished by hydrolysis of fragments upon incubation with hexosaminidase, whereafter free N-acetylglucosamine moieties are detected. This method is very insensitive and not directly proportional to the initial chitinase activity. Assays using as substrate radiolabeled chitin or chitins conjugated with chromophores have also a very poor sensitivity and do not render reliable results with plasma samples. A several hundred-fold more sensitive assay has been earlier described by us (Hollak et al.,1994). The assay is based on the use of 4-methylumbelliferyl-chitotrioside as substrate. Alternatively, 4-MU-chitobiose or 4-MU-chitotetraose can be used as substrate (Hollak et al., 1994). Chitotriosidase is able to cleave these synthetic substrates, thus releasing the fluorescent 4-methylumbelliferone. The assay with the above mentioned 4-MU-substrates has a major drawback. No use can be made of saturating substrate concentrations due to apparent substrate inhibition (see for example FIG. 1). Consequently, the assay has to be performed at sub-saturating substrate concentration. As inevitable result of this, the measured enzymatic activity is intrinsically not strictly related to the input of enzyme and only linear in time for a very short period. The results of assays with plasma samples can only be well interpreted if additionally parallel assays are run with standard (pure) chitotriosidase preparations and assay time and input of plasma protein are extensively varied. Considerable expertise is required to obtain reproducible results with this method. In conclusion, at present no convenient and widely applicable method is available that allows very sensitive and quantitative detection of chitotriosidase and comparable chitinases.
Lysozyme.
Lysozyme catalyzes the hydrolysis of certain mucopolysaccharides of bacterial cell walls. Specifically, it catalyzes the hydrolysis of the bacterial cell wall beta(1-4) glycosidic linkages between N-acetylmuramic acid and N-acetyiglucosamine, but not the glycosidic bond between N-acetylglucosamine and N-acetylmuramic acid. Lysozyme is involved in bacteriolytic defensive and immune response. It is present in organs and bodily fluids of the human, including plasma, where it is found in monocytes and macrophages, neutrophils and g˜andular cells. Serum lysozyme is a potential marker for activity of monocytes and macrophages. The serum level of lysozyme is for instance elevated in patients with an infection, autoimmune disease and/or cancer. Examples of bacterial and viral infections are tuberculosis, pneumonia, meningitis, otitis media, urinary tract infections, sepsis and acquired immunodeficiency syndrome. Examples of autoimmune diseases are rheumatic disorders as e.g. rheumatoid arthritis, Inflammatory Bowel Disease, as e.g. Ulcerative Colitis and Crohn's disease, chronic respiratory inflammatory diseases as e.g. chronic bronchitis and chronic sinusitis, interstitial pulmonary diseases as sarcoidosis, and diabetes. Examples of cancer are colorectal cancer, leukemia as e.g. Hodgkin's disease and lung carcinoma.
For measurement of the activity of lysozyme several assays are available. Lysozyme is most frequently analyzed by a variety of methods using Micrococcus lysodeikticus cells as substrate, such as the turbidimetric assay. Some improvement in the turbidimetric method was obtained by Morsky (1983). This modified lysozyme assay has improved routine clinical use in regard to analysis speed, sensitivity, linearity and reproducibility. The reaction course of bacterial cell wall lysis for quantifying lysozyme in serum and urine can also be applied to the solid phase with agarose gel as reaction medium: the lysoplate method (Maeda et al., 1980). The reproducibility of this method is reasonable but labour intensive. Furthermore the results are not always reproducible due to biological factors in the sample or agar batch.
In contrast to the turbidimetric method, the enzyme-linked immunosorbent assay (ELISA) (Taylor et al., 1992), the double-antibody radioimmunoassay (Thorsteindottir et al., 1999) and the electroimmunodiffusion technique measure the concentration of lysozyme. Comparison of lysozyme values obtained with the ELISA and turbidimetric methods showed good correlation. The major drawback in both the ELISA, radioimmunoassay and electroimmunodiffision assay is still the fact that neither of these immunological techniques measures the activity of lysozyme. Their use is also limited by their degree of sensitivity and the presence of lysozyme isozymes. Another drawback concerning lysozyme assays is the lack of uniformity in standardization of lysozyme assays. Thus, the results are not always unambiguously interchangeable, and clinical reference values differ greatly. In conclusion, a simple, rapid, sensitive and specific assay to measure the lysozyme activity is not available.
Hyaluronidase
Hyaluronan, hyaluronic acid (HA), is one of the principal glycosaminoglycans of the extracellular matrix. It consists of a high molecular weight polymer of repeating units of N-acetylglucosamine and D-glucuronic acid. It is believed to have numerous important biologic functions, including modulation of cell proliferation, migration and differentiation and is believed to be crucial in tissue remodeling, e.g. during embryogenesis and wound healing, in tumorigenesis, angiogenesis and inflammation.
Clinically, aberrations of HA metabolism are associated with processes such as adult respiratory distress syndrome, organ transplant oedema and rejection, and as a marker for cancer remission and relapse. The binding of exogenous FIA to cell surface receptors, the most important one being CD44, mediates endocytosis of extracellular HA, leading to its degradation by lysosomal hyaluronidase. Hyaluronidase is the enzyme that degrades HA. This endoglycosidase cleaves the N-acetyl-(1-*4)-glucosaminic bonds in HA, forming even-numbered oligosaccharides, with mainly tetrasaccharides as the smallest fragments (Menzel et al., 1998); digestion with testicular hyaluronidase results in the exclusive cleavage of the N-acetylhexosaminidic linkages, the products comprising a series of oligosaccharides with N-acetylglucosamine at the reducing terminus. Upon exhaustive digestion, the tetrasaccharide is the major product, closely followed by the hexasaccharide and smaller amounts of higher oligosaccharides, while only a small proportion of disaccharide is found in a digest of this type.
Hyaluronidases from vertebrate tissues can be separated into two classes that have very different biological functions. The major hyaluronidase in human plasma is the hyaluronoglucosamindase-1. This enzyme is expressed in multiple tissues. In the sperm plasma membrane and acrosomal membrane an enzyme with hyaluronidase activity is present, the sperm adhesion molecule 1 gene or PH-20. To penetrate the cumulus layer, a hyaluronan-rich extracellular matrix surrounding the oocyte, the sperm uses this enzyme to break down the hyaluronan. This enzyme is a marker for the sperm function.
Hyaluronan (HA) and hyaluronidase (HAase) are involved in malignant transformation and cancer progression. In many malignancies, levels of HA correlate with metastatic behaviour while HAase suppress malignant progression. In bladder cancer, hyaluronic acid and hyaluronidase are used as biological markers for bladder tumour, angiogenesis and metastasis, being secreted in urine. An elevated urinary HA indicates the diagnosis of bladder cancer regardless of tumour grade and the urinary HAase levels correlates with the malignant potential of bladder cancer, being grade 2 and grade 3 (Lokeshwar et al., 2000). The hyaluronic acid and hyaluronidase (HA-HAase) test is the only non-invasive assay described that detects HA and HAase, because it measures in urine. Other HA and HAase measuring tests use sera as biological samples. The HA-HAase test for urine is an ELISA-like assay using e.g. an avidin-biotin-peroxidase color detection system. This test has 90-92% sensitivity and 80-84% specificity for bladder cancer (and is currently evaluated in multicenter trial settings (Lokeshwar, 2001).
Despite the sensitivity and specificity of the HA-HAase test, in current practice cystoscopy is the gold standard for detecting bladder cancer and evaluating tumor recurrence, while voided urine or bladder wash cytology is often used as an adjunct to cystoscopy for detecting high-grade bladder cancer. The voided urine cytology is the standard non-invasive tumor specific marker and evaluates malignancy based on cellular morphology. Voided urine cytology has an excellent specificity but a poor sensitivity (Brown 2000). However, it is not sensitive for detecting low-grade disease. Also variability among those interpreting cytology findings is significant. Moreover, urine cytology is not quantitative. In conclusion, urine cytology in its present form cannot replace cystoscopy as a method for detecting and monitoring bladder cancer, but should be used as an additional application. An ideal non-invasive test should be sensitive, specific, rapid, technically simple and have low intra-assay and interassay variability.
The most commonly used hyaluronidase assays, which are either insensitive or lack specificity, are based upon the measurement of the generation of new reducing N-acetylamino groups, or loss of viscosity or turbidity. Other assays are dye binding assays, zymogram electrophoretic technique or enzyme activity measurement based on the Morgan-Elson reaction. All these assays are relatively cumbersome and insensitive. For large-scale measurements application of the modern ELISA-like microtiter assay by Frost and Stem (1997) may be more convenient. This study describes a sensitive, rapid microtiter-based assay for hyaluronidase activity that does not require highly specialized biological reagents. However, this assay is not accurate, time- and dose-dependent. Hyaluronidase activity can also be measured in venoms using capillary electrophoresis or by USP XXII assay but also these assays are not sensitive as described by Pattanaargson et al., 1996.
Heparanase.
Heparan sulfate (HS) and heparan sulfate proteoglycans (HSPGs) are acidic complex polysaccharides found on the cell surface, in the extracellular matrix and vascular basal lamina. These biopolymers play an important role in cell proliferation, differentiation, migration and shape. The HS chains are originally synthesized as a polysaccharide of alternating N-acetyl-glucosamine (GlcNAc) and glucuronic acid (GlcUAu) that are enzymatically modified to a complex polysaccharide containing sulphate rich and sulphate poor regions. The enzyme heparanase (Hpa) cleaves the heparan sulfate glycosaminoglycans from the proteoglycan core proteins and degrade them to small oligosaccharides. Heparanase is an endoglucuronidase, cleaving the linkage between glucuronic acid (GIcUA) and N-acetyl-glucosamine (GlcNAc). Hpa I, the dominant heparanase in mammalians, is a hydrolase cleaving the HS chains at specific places and not an eliminase as heparinase from Flavobacterium heparinuin. Heparanase is expressed in a wide variety of tissues and cells. (Barne, 2001 and Parish et al, 2001). It plays a major role in early embryogenesis, morphogenesis, pregnancy and development to inflammation, wound healing, and tumor angiogenesis and metastasis. Human platelets have been shown to contain high levels of heparanase activity, capable of degrading endothelial cell surface, tumour-derived and ECMderived HSPG as well as free HS chains and heparin. Heparanase is able to facilitate cell invasion by degrading the extracellular matrix and the vascular basement, needed for invasion of cancer in the metastatic phase and neovascularization. (See for review Parish et al, 1998 and Vlodavsky et al, 2001). The metastatic potential of tumour cells is related to their increased heparanase content. A heparanase assay is a diagnostic tool for cancer staging, since it has been suggested that heparanase plays a prominent role in cancer-associated processes. Indeed, it has been found that cancer patients had twice the serum heparanase levels as normal healthy adults.
It has been shown that HpaI can cleave the antithrombin-binding site in heparin, low molecular weight heparin (LMWH) and synthetic pentasaccharides containing an intact antithrombin III binding site, thereby inhibiting the anticoagulation function of these drugs that are given therapeutically or prophylaxis to patients with an increased risk for thrombosis. Heparin, LMWH and synthetic pentasaccharides are indicated as therapeutical in the acute phase of deep venous thrombosis or pulmonary embolism treatment and as prophylaxis for e.g. general surgery, acute myocardial infarction, ischemic stroke, intensive care patients and bedridden patients with a risk factor.
During therapy of patients with heparin, LMWH or pentasaccharides it is essential to monitor the activated clotting time to guide the heparin therapy during cardiac surgery, cardiac catherication and coronary interventions. The available clotting assays to measure the coagulation status of patients in heparin therapy are sensitive to the presence of small traces of heparin and tissue factor pathway inhibitor (Bladbj erg et al., 2000) and the presence of the endogenous heparanase in plasma. A simple heparanase/heparinase assay would be medical useful to monitor the therapy of the patients with heparin, LWMHs or synthetic polysaccharides and scientific useful to elucidate the pathways.
It has been shown that synthetic heparin mimicking compounds can inhibit heparanase and decrease the incidence of metastases. The role of heparanase in cancer and angiogenesis has not been elucidated, although the heparanase activity has been known for several decades. A major reason for the lack of studies of heparanase activity and heparanase inhibition has been due to the absence of a simple, rapid and sensitive assay for heparanase activity (Parish et al., 1999). Also for monitoring the heparanase activity in cancer and during therapy of patients with anticoagulants a reliable assay is necessary. In addition, a simple assay to measure heparanase activity would also be helpful in studying the activity of homologous proteins as e.g. the mammalian gene Heparanase 2 (McKenzie et al., 2000).
Different kinds of assays have been described for measuring heparanase activity. In one type of assay heparanase activity is detected by separating cleaved from uncleaved radioactivity labelled and fluorescence labelled HS using electrophoresis. In another type of assay heparanase activity is detected by incubating the sample in the presence of a solid phase support having immobilized thereon a substrate for the heparanase and separating cleaved from uncleaved substrate. Freeman et al. (2001) describe an example for this type of assay using histidine-rich glycoprotein as heparan sulphate binding protein. Another example is the assay described by Brenchley (2000), wherein two solid phase supports are used, one to bind the uncleaved and one to bind the cleaved HS. These assays are laborious. A simple, rapid, sensitive and specific assay to measure the heparanase activity is not available.
Cellulase.
Cellulose, the most abundant carbohydrate produced by plants, is an unbranched (1-4)-˜-D-glucose polymer with repeating unit of cellobiose (glucose dimer) instead of glucose. Although cellulose is a simple polymer, it forms insoluble, crystalline microfibrils, but it also contains regions with less structure, the so-called amorphous zones. All organisms known to degrade cellulose efficiently produce a battery of enzymes with different specialties, which act together in synergism. This enzymatic hydrolytic system consists of three different enzymes and so catalytic reactions: (i) endoglucanases (EC), which can randomly hydrolyse the 1,4-˜-glycosidyl linkages within the water-insoluble cellulose chains; (ii) exoglucanase or cellobiohydrolases (CBHs), which hydrolyse the 1,4-˜-glycosidyl linkages of either the reducing or non-reducing ends of cellulose chains to form cellobiose and (iii) ˜3-glucosidases or cellobiose, which converts the water soluble cellobiose into two glucose residues. Microorganisms, especially fungi, produce often mixtures of these enzymes. Together, these enzymes form a cellulolytic system and hydrolyse insoluble cellulose, both crystalline and amorphous, in a very efficient and synergistic way.
Several applications of cellulases are being developed for textile, food, and paper pulp processing (Beguin et al, 1994). Today, cellulase enzymes are used in different segments of the cotton textile industry. For the characterization of the cellulase in these contexts and for the insight in the complex mechanisms of hydrolysis, a rapid, sensitive test is desired.
Glucanase.
Beta-Glucans with 1,3-˜3-glycosidyl linkages are present in a variety of organisms. Various beta 1,3 glucanases that cleave 1,3-˜3-glycosidyl linkages have been described in lower organisms and plants. The cell wall of various pathogenic organisms contains beta 1,3-glucan and this structure exerts a potent effect on the immune system in man. Nothing is so far known about the catabolism of beta 1,3 glucan in man. Accurate detection of beta 1,3-glucanase activity is therefore highly desired.
Thus, endoglucanases are involved in a wide range of important (patho)biological processes. The concentration of such enzymes is often altered during a disease and during the process of counteracting/curing of a disease. Hence, the concentration of a certain endoglucanase is often indicative for the status of an individual. Detection of the concentration of such enzymes provides important information about a disease and/or the treatment of a disease. However, in spite of different tests developed in the art, detection of these enzymes is still cumbersome. The aim of the present invention is to provide improved, sensible and simple methods for detecting an activity of an endoglycosidase.

Means and methods for detecting endoglycosidase activity

Academisch Ziekenhuis bij de Universiteit van Amsterdam


A bed includes a base frame, a deck coupled to the base frame, an electrical communication network, an air handling unit mounted on the base frame, a plurality of air therapy devices located on the bed, and a plurality of control modules. Each control module includes a connector for coupling a corresponding air therapy device to the air handling unit and to the electrical communication network. Each control module also includes a controller for operating the corresponding air therapy device with the air handling unit based on command signals received from the electrical communication network.

The present invention relates to a bed having modular therapy and support surfaces. More particularly, the present invention relates to a hospital bed having an on-board air handling unit and electrical communication network capable of connecting to and controlling a plurality of different modular air therapy and support surfaces for providing a plurality of different therapies or treatments to a patient.
The present invention provides a plurality of different air therapy and support surfaces, all of which can be connected to the bed to provide a complete therapy line that is rapidly installed or exchanged on demand as census or diagnostic population varies. In an acute care environment, a hospital typically needs decubitus prevention, decubitus treatment (stage one and two minimum), pulmonary therapies including rotation therapy and percussion and vibration therapy, and venous compression therapy capabilities.
The modular therapy and support surface design of the present invention allows several air support surfaces and air therapy devices to be driven by a common air source, a common graphical interactive display device, and a distributed communication network. The modular therapy and surface support system of the present invention is designed to provide a one bed solution for acute care including critical care, step down/progressive care, med-surg, high acuity subacute care, PACU, and sections of ED. The modular therapy and support surface system of the present invention provides therapies that benefit a large percentage of the patient population in an acute care hospital.
The bed of the present invention includes an air handling unit located on a bed frame which is capable of supplying air pressure and/or a vacuum to all the therapy and support surface modules. Typically, the air handling unit is mounted on the base frame of the bed. Preferably, the air handling unit drives two lines simultaneously for supplying both air pressure and vacuum to the air therapy modules. A header connector is coupled to the air handling unit by a plurality of air lines. The header connector is configured to couple the air handling unit to a selected modular air therapy device support surface.
The modular therapy and support surface components for the different therapies are contained within the sleep surface on the bed, enabling a caregiver to install, initiate, or remove a desired air therapy from the bed without moving the patient off the original support surface. The modular design of the present invention allows modules for air therapy to have reduced size. Therefore, the modules can be delivered after the bed and stored easily. The air handling unit of the present invention is coupled to therapy control modules that contain air distribution means such as adjustable valves and sensors by a simple connection of pneumatic lines to the control modules.
According to one aspect of the present invention, a bed includes a base frame, a deck coupled to the base frame, an electrical communication network, and an air handling unit mounted on the base frame. The bed also includes a plurality of air therapy devices located on the bed, and a plurality of control modules. Each control module includes a connector for coupling a corresponding air therapy device to the air handling unit and to the electrical communication network. Each control module also includes a controller for operating the corresponding air therapy device with the air handling unit based on command signals received from the electrical communication network.
The bed further includes a control unit coupled to the electrical communication network for transmitting command signals for the plurality of air therapy devices over the electrical communication network to control operation of the plurality of air therapy devices. The control unit includes a display and a user input. Each control module transmits display commands to the display related to the corresponding air therapy device. The display commands from the control modules provide a menu driven list of options to the display to permit selection of control options for the plurality of air therapy devices from the user input.
In the illustrated embodiment, one of the plurality of air therapy devices is a support surface air bladder located on the deck. The support surface air bladder includes a plurality of independently controlled air zones. One of the plurality of control modules is a decubitus prevention control module coupled to the support surface air bladder to control each of the plurality of air zones of the support surface with a common connection to the air handling unit. Another of the plurality of control modules is a decubitus treatment control module for independently coupling the plurality of air zones of the support surface air bladder to the air handling unit.
Another of the plurality of air therapy devices is a pulmonary rotation bladder located between the deck and the support surface air bladder. A pulmonary rotation control module is provided for coupling the pulmonary rotation air bladder to the air handling unit. The pulmonary rotation control module is coupled to the electrical communication network.
Yet another of the plurality of air therapy devices is a sequential compression therapy device. A sequential compression device air control module is provided for coupling the sequential compression device to the air handling unit. The sequential compression device air control module is coupled to the electrical communication network.
Still another of the plurality of air therapy devices is a pulmonary percussion and vibration bladder located on the deck for providing pulmonary percussion and vibration therapy. A pulmonary percussion and vibration control module is provided for coupling the percussion and vibration bladder to the air handling unit. The percussion and vibration module is coupled to the electrical communication network. Alternatively, the percussion and vibration control module is configured to couple a selected air zone of the support surface air bladder to the air handling unit to provide percussion and vibration therapy in the selected air zone.
An auxiliary air port control module is coupled to the air handling unit and to the electrical communication network. The air port control module provides an auxiliary air outlet on the bed.
According to another aspect of the present invention, a control module is provided for activating an air therapy device on a bed which includes a base frame, a deck coupled to the base frame, an electrical communication network, an air handling unit mounted on the base frame, a graphical interactive display coupled to the electrical communication network for transmitting and receiving command signals from the communication network, and a plurality of air therapy devices stored on the bed. The control module includes at least one electrically controlled valve having an input and an output, at least one pressure sensor having an input and an output, and an electronic controller coupled to and controlling the at least one electrically controlled valve and coupled to the output of the at least one pressure sensor. The control module also includes a connector for coupling the input of the valve to the air handling unit on the bed, for coupling the output of the valve to the selected air therapy device, for coupling the input of the pressure sensor to the selected air therapy device, and for coupling the controller to the electrical communication network on the bed so that the controller receives the command signals from the graphical interactive display to control the selected air therapy device.
The graphical interactive display includes a display and a user input. The controller transmits display command signals to the graphical interactive display to display information related to the selected air therapy device on the display. The display commands from the controller provide a menu driven list of control options for the selected air therapy device to the display to prompt selection of various control options for the selected air therapy device from the user input.
If the selected air therapy device includes a plurality of air zones, the control module includes an electrically controlled valve for each of the plurality of air zones to couple the plurality of air zones to the air handling unit on the bed independently. The control module also includes a separate pressure sensor for each of the plurality of air zones.
According to yet another aspect of the present invention, a bed includes a base frame, a deck coupled to the base frame, an electrical communication network, an air handling unit mounted on the base frame, and a header connector including an electrical connector coupled to the electrical communication network and a pneumatic connector coupled to the air handling unit. The bed also includes a plurality of exchangeable air therapy devices. Each of the air therapy devices includes at least one air zone, a therapy control module having a controller, a valve coupled to each air zone of the air therapy device, and a module connector configured to mate with the header connector to couple the valve to the air handling unit and to couple the controller to the electrical communication network so that each of the plurality of exchangeable air therapy devices use the same air handling unit and electrical communication network.
In the illustrated embodiment, the module connector includes a first connector coupled to an input of the valve and a second connector coupled to the controller, the first connector of the module connector being configured to mate with the pneumatic connector of the header connector on the bed to couple the air handling unit to the at least one air zone of the air therapy device through the corresponding valve and the second connector being configured to mate with the electrical connector of the header connector on the bed to couple the electrical communication network to the controller so that the controller receives commands from the electrical communication network to control air flow to the air therapy device through the valve.
According to still another aspect of the present invention, the modular support surface of the present invention includes an improved surface foot section specifically designed for use with a bed having an articulating deck movable from a normal bed position to a chair position. The surface foot section is configured to retract or shorten as the bed moves to the chair position to enable a patient's feet to be placed on the floor or on a foot prop. The foot section also collapses or thins to maintain an acceptable chair seat size which also enables the patient's feet to be placed on the floor or foot prop.
In the illustrated embodiment, a surface foot section apparatus is provided for a bed including a base frame, an articulating deck coupled to the base frame, the articulating deck including a generally planar foot deck section, the articulating deck being movable from a bed configuration to a chair configuration. The surface foot section apparatus includes a first set of air bladders configured to collapse in a first direction generally parallel to the foot deck section when the first set of air bladders is deflated, and a second set of air bladders located adjacent the first set of air bladders. The second set of air bladders is configured to collapse in a second direction normal to the foot deck section when the second set of air bladders is deflated so that the surface foot section has a substantially reduced thickness and a substantially reduced length when the first and second bladders are deflated. The surface foot section apparatus also includes a foot section control module for selectively inflating and deflating the first and second sets of air bladders. The foot section control module deflates the first and second sets of air bladders when the articulating deck is in the chair configuration, and the foot section control module inflates the first and second sets of air bladders when the articulating deck is in the bed configuration.
Preferably, the length of the surface foot section is reduced by at least 40% when the first and second air bladders are deflated and the thickness of the surface foot section is reduced by at least 80% when the first and second air bladders are deflated. This feature maintains an appropriate size for a seat section of the chair and permits a patient's feet to touch the floor when the bed is in the chair configuration. The foot deck section is movable from an extended position to a retracted position to shorten the foot deck section as the articulating deck moves to the chair configuration.
Also in the illustrated embodiment, each of the second air bladders is independently controlled as a separate air zone by the foot section control module. The foot section control module selectively inflates and deflates the second air bladders to provide a heel pressure relief in the surface foot section. The first set of air bladders is commonly controlled as a single air zone by the foot section control module.
According to a further aspect of the present invention, a pulmonary rotation therapy apparatus is provided for use on a bed having a base frame, a deck coupled to the base frame, and a support surface located on the deck. The pulmonary rotation therapy apparatus includes a normally deflated rotation air bladder located between the support surface and the deck. The rotation air bladder remains deflated during normal use of the bed. It is understood that the rotation air bladder can be normally inflated and used as a support surface for the bed, if desired. The pulmonary rotation therapy apparatus also includes a pulmonary rotation control module coupled to the rotation air bladder. The pulmonary rotation control module selectively inflates and deflates portions of the rotation air bladder to provide rotational therapy to a body located on the support surface.
In the illustrated embodiment, the rotation air bladder includes a plurality of elongated air bladders extending generally parallel to a longitudinal axis of the bed. The pulmonary rotation control module selectively inflates or deflates the plurality of air bladders to control rotation of the patient on the support surface. The rotation air bladders are divided into at least three separate air zones which are independently controlled by the pulmonary control module.

Bed with a plurality of air therapy devices, having control modules and an electrical communication network


The invention provides a composite wrapping and shielding tape for use in cable manufacture. Embodiments of the composite tape comprise a single tape configuration to separate and shield individual pairs of insulated conductors housed within a cable such as a high-speed data communications cable. The single tape configurations of the invention are multifolded and assembled from foil/film laminates to form a plurality of longitudinal channels or grooves to accommodate one or more pairs of insulated conductors and a variety of cable designs. During cable manufacture, one or more pairs of insulated conductors is wrapped within a continuous shield provided by each longitudinal channel or groove, thereby separating and shielding each pair of insulated conductors and, hence, isolating or at least substantially reducing crosstalk between pairs of insulated conductors contained within the cable. The invention also provides methods for making a multifolded composite tape. The invention further provides a communications cable comprising a multifolded composite tape to separate and shield insulated conductors.

High-speed data communications cables currently in use include pairs of insulated conductors twisted together to form a two-conductor group or a transmission line. Such pairs of insulated conductors are commonly referred to in the art as "twisted pairs". Multiples of twisted pairs are typically bundled or closely spaced together within high-speed data cables. Such close proximity between twisted pairs often causes electrical energy to transfer from one twisted pair to other adjacent twisted pairs coexisting within a cable. This transfer of electrical energy between twisted pairs is a phenomenon known as crosstalk, which interferes and degrades electrical signals and data transmission. Twisted pairs must, therefore, be sufficiently separated physically and shielded electrically in order to reduce and isolate crosstalk.
Crosstalk presents a particular problem in high frequency applications wherein as the frequency of transmission increases, crosstalk increases logarithmically. Thus, the need to shield twisted pairs increases with the need for greater transmission speed. For instance, a category 7 cable used for relatively high speed data transmission is required to meet specific performance standards for crosstalk isolation established by third party testing organizations. Therefore, in order to meet such performance standards, while providing greater transmission speed and throughput, methods of shielding and isolating twisted pairs become important for maintaining the quality of data transmission.
Various prior art methods attempt to meet standards for crosstalk isolation in high-speed data communications cable and include techniques and cable designs for physically separating twisted pairs and maintaining twisted pairs in fixed positions. In addition, prior art methods include individually shielding twisted pairs to insulate twisted pairs from crosstalk. Such shielding techniques typically include various techniques and shielding tapes for tape wrapping individual twisted pairs prior to cabling. Typically, tape wrapping involves wrapping a metal or metallized tape longitudinally or helically around a twisted pair. Such tape wrapping techniques cause a portion of the metal or tape to overlap upon itself as it is wound around the twisted pair to achieve a continuous wrap. The result is that areas along the twisted cable face a metal-to-nonmetal portion of the wrapping tape at the site of a tape overlap. Typically, shielding or wrapping tape comprises a conductive, often metallic, surface and a dielectric film, often plastic, surface such that the overlap created is a metal-to-film interface. Such overlaps are susceptible to signal leakage, interference and signal degradation as well as contribute to crosstalk between adjacent twisted pairs and proximate cables. In addition, individually wrapping twisted pairs is a lengthy operation and an additional step in manufacturing twisted pairs.
Therefore, it is desirable to provide a shielding tape and techniques for individually wrapping twisted pairs prior to cabling that overcomes the problems associated with the prior art described above. Such a shielding tape and techniques would reduce or eliminate the negative effects upon electrical properties and conductor performance associated with tape overlap and more particularly would isolate crosstalk. In addition it is desirable to provide a communications cable comprising a shielding tape for physically separating and electrically isolating individual insulated conductors contained therein to substantially reduce crosstalk between adjacent conductors situated within the cable as well as between the cable and other proximately located communications cables.

This patent is subject to a terminal disclaimer.

Multifolded composite tape for use in cable manufacture and methods for making same


The invention is related to peptide constructs, i.e., polypeptides obtained by linking together two or more peptides based on or derived from different molecules, which are useful in the treatment or prevention of cancer or the treatment of autoimmune diseases and compositions containing same, methods for producing same, and methods for using same; wherein the peptide constructs have the formula P1-x-P2 where P2 is a peptide associated with forms of cancer or an autoimmune condition and P1 is a peptide which will bind to a class of immune cells such as dendritic cells. The peptide construct can cause the maturation of immature dendritic cells to a more mature state. The peptide construct or the more mature dendritic cells can be administered to a subject to a modulate or to initiate an immune response against cancer cells, and can be used with dyes, radioisotopes, or therapeutic agents for detection of the immune target and/or treatment of cancer and autoimmune conditions.

Autoimmune conditions are characterized by the body attacking itself by mounting an immune response against self antigens to which it is normally tolerant. As such, approaches to treating autoimmune conditions, have focused on down regulating the "inappropriate" immune response against self. However, many approaches to treating autoimmune and like conditions are not specific to down regulating the immune system's response to a specific antigen. Rather, therapies focus on a general suppression of the immune system. Similarly, cancer can be characterized by increased expression of self oncogenes that are not adequately recognized by the immune system. As such, adjustment of the regulation of the immune system in regards to the identification of self antigens can be used to address both autoimmune conditions and cancer.
Some of these less antigen specific approaches utilize monoclonal antibodies that act on activated T cells and down regulate them such as by anti-CD3 (Protein Design Laboratories) or block APC and T cell interaction by anti-ICAM-3 (ICOS). MEDI-507 (Medimmune) is believed to be a humanized monoclonal antibody, for psoriasis that also targets CD2, presumably for removing or inactivating those cell types. Other diseases, such as, tissue transplantation rejection and allergies are also being tested by this approach. In contrast to acting on cell surface markers, rhu-mAB-E25 (Genentech) is believed to be a humanized monoclonal antibody against IgE that binds to circulating IgE, with the goal of preventing activation of mast cells. In contrast, other researchers are developing monoclonal antibodies to act on symptoms or agents directly causing disease symptoms. Remicade Infliximab (Centocor™) is purported to be a monoclonal antibody to TNF. Anti CD40 ligand has been used for treatment in animal model of multiple sclerosis (MS) (L. M. Howard, et al., 1999, J. Clin. Invest, 103:281). A recombinant generated designed protein Enbrel (Immunex™) is purported to comprise two molecules of r-DNA derived TNF receptor, and is intended to block TNF's action.
It should be noted, however, that many of these agents are not sufficiently disease specific and often recognize and could affect normal cellular and body constituents that have a defined and necessary role in normal immune defenses which are still needed.
Some more antigen or disease specific approaches are exemplified by the attempt to treat MS patients by oral administration of myelin proteins which have recently been reported; the same group of researchers is also using collagen type II for treatment of patients with rheumatoid arthritis. These treatments are designed to attack at the level of the gut associated lymphoid tissues (GALT) to induce tolerance by antigen specific suppression of the immune system. It is not know if these treatments use the intact protein or a hydrolyzate containing smaller peptides. See D. Hafler, et al. 1988, J. Immunol., 141:181; K. Wucherpfennig, et. al. 1990, Science, 248:1016; K. Ota, et al., 1990, Nature, 346:183; and H. Weiner, 1999, PNAS, 88:9161.
Several researchers are testing peptide based materials for treatment of autoimmune conditions. One approach uses peptide as immunogen, given orally in large quantities. The peptide represents a peptide sequence that is though to be the autoimmune epitope itself or a modified form which may also have altered binding or improved stability properties. By use of the peptide it is thought that either the normal peptide or an altered peptide ligand (APL) will bind to the T cell receptor (TCR) and induce a state of anergy since the multiple sets of bindings that would occur with antigen presentation with an antigen presenting cell (APC) do not occur (A. Faith, et al., 1999, J. Immunol., 162:1836; Soares, et al. 1998, J. Immunol., 160:4768; M. Croft, et al. 1997, J. Immunol., 159:3257; L. Ding, et al., 1998, J. Immunol., 161:6614; and S. Hin, et al. 1999, J. Immunol., 163:2363). Some of the approaches with APL include using related amino acids such a D amino acids (U. Koch, et al. 1998, J. Immunol., 161:421), amino acids with substituted side chains (R. DePalma et al. 1999, J. Immunol., 162:1982), methylene groups to replace peptide bonds in the peptide backbone (L. Meda, et al., 1996, J. Immunol., 157:1213) and N-hydroxyl peptides (S. Hin et al. J. Immunol., 163:2363).
The more antigen-specific approaches outlined above rely on using large amounts of antigens to desensitize a subject to the antigen. The possible drawbacks and consequences of the administration of large quantities of antigen include further undesirable and unpredictable immune responses. Peptide-based immunomodulators have the possible advantage of being a well-defined immunogen that would facilitate the generation of a safe and predictable response. However, safety is maximized by the use of small quantities of immunomodulators targeted to specific immune cells instead of the use of large quantities of an antigen introduced into the patient.
Few therapeutics are available as recombinant proteins that can modulate the immune system in active and antigen-specific capacity. Viral vector vaccines have been attempted to promote antigen-specific immunomodulation. However, problems are also associated with viral vector vaccines. One problem is the immune response induced against the vector itself. This induced immune response severely limits the number and frequency of subsequent injections/boosters that can be administered. Moreover, some adenoviruses have the potential for causing allergic conditions such as celiac disease. It is also known that many viral proteins, including some from HIV and HSV contain immunosuppressive epitopes. Viral proteins are also suspected as causative agents for other autoimmune conditions such as type 1 diabetes. Multiple Sclerosis (MS), Myocarditis, and Graves disease.
Another disadvantage in using a DNA-based or viral vector vaccines, including for autoimmune conditions, is the possibility of the vaccine DNA being integrated into the host's genome. One alternative is to conjugate a particular epitope to a carrier protein to avoid such incorporation into the genome. It is known within the art to use large carrier proteins such as Keyhole Limpet Hemocyanin (KLH), Bovine Serum Albumin (BSA), or Antigenics' heat shock proteins (HSP) couple/conjugated or incorporated with a virus protein.
Other options for peptide delivery of peptide epitopes include the use of synthetic biodegradable microparticles like Poly(lactide-co-glycolide) PLG with aggregated antigen. Still other delivery technologies for peptide antigens include AutoVac™ of Pharmexa. Other small molecule delivery technologies for peptides are Antigen Express's 'li-key' delivery, phage display and Multiple Antigen Presentation (MAPS) technologies (Rosenthal 2005 Immune peptide enhancement of peptide based vaccines Frontiers in Bioscience 1:478:482).
Many of the known approaches have the major disadvantage of using large, very immunogenic carriers. Moreover, patient populations requiring such therapeutics have usually been exposed to many of these same antigens during their lifetimes. Hence, and similar to vaccine vector delivery of antigens, clearance of the antigen can be so vigorous in the previously exposed host that no response will occur to the new antigen. On the other hand, a strong immune response may occur upon reintroduction of the vector. For example, in the case of the conjugate VP22 containing HSV-1 protein, the response may be undesirable given that a majority of adults have had one or more exposures to HSV-1 (Muran-yiova et al. 1991 Immunoprecipitation of herpes simplex virus polypeptides with human sera is related to their ELISA titre. Acta Virol, 35:252-9).
In regards to immune-based cancer therapies, cancer can have many causes that result in the uncontrolled growth of cells. One cause of cancers is the mutation or increased expression of oncogenes in cancerous cells. Oncogenes, like all genes, function to code for a protein that is synthesized by the cell. Often, cancers are caused by a DNA mutation that alters the regulation of expression of the oncogene or oncofetal gene or a DNA mutation that causes a change in the amino acid sequence of the oncogene itself. The alteration of regulation of an oncogene or oncofetal gene or a mutation in an oncogene or oncofetal can also affect the expression of other proteins in a cancerous cell. Cancerous cells can, therefore, have different levels of protein expression compared with surrounding healthy tissue. A change in the level of protein expression or the expression of mutated proteins on the surface of cancerous can be used by the immune system to direct an immune response to cancerous cells.
The proteins expressed on the surface of a cancerous cell can act as antigens for an immune response. However, most of the proteins expressed on the surface of cancerous cells are non-mutated self-antigens. Self antigens are usually ineffective in triggering an immune response since they are present in healthy as well as cancerous cells. Even in situations where a cancer cell is expressing a mutated protein, antigenic changes in cancerous cells that are created by individual point mutations may be too subtle from the standpoint of the immune system to trigger a significant immune response. Since cancer cells utilize essentially the same cellular proteins as healthy cells, cancer cells can often grow and survive without generating an anti-cancer immune response.
Peptides can have sufficient structure to be recognized with specificity by immunoproteins, such as antibodies, and by immune cells. That is, short peptides having from about 8 to about 30 amino acid residues have sufficient structure to bind to antibodies and serve as an antigen, epitope or other ligand for proteins involved in the activation of the immune system. However, short peptides often generate no or only a weak immune response when administered alone to a human or animal subject. Often, it is necessary to link or to introduce short peptides with larger proteins or biomolecules to serve as a carrier or an adjuvant to induce an immune response that will generate antibodies specific to the short peptide and to initiate an immune response to these short peptides.
There is a need for peptide-based immunomodulators having a well-defined immunogen to treat cancer that facilitates the generation of a safe and predictable anti-tumor response rather than a mixed response including an immune response to a carrier. There is also a need for the development of peptide-based immunomodulators, and the related need for the identification of peptides capable of being recognized by specific components of the immune systems and generating a specific type of directed immune response.

Method for inducing an immune response for treatment of cancer and autoimmune diseases or conditions


A method of operating an end node to communicate with a central node, the method comprising: wirelessly receiving, a beacon signal periodically-transmitted from the central node; each beacon signal denoting the start of a single frame; each frame being organized to include a downlink (DL) phase which precedes an uplink (UL) phase; and a payload of the beacon signal including an offset which represents a starting time of the UL phase. The method further comprises: generating a message; selecting, unbeknownst to the central node, at least one UL logical-channel, respectively; and wirelessly transmitting, during the UL phase, at least a portion of the message from the end node over the selected at least one UL logical-channel according to a slotted ALOHA technique.

Circa 2009, the Internet was in a stage of its evolution in which the backbone (routers and servers) was connected to fringe nodes formed primarily by personal computers. At that time, Kevin Ashton (among others) looked ahead to the next stage in the Internet's evolution, which he described as the Internet of Things ("IoT"). In his article, "That 'Internet of Things' Thing," RFID Journal, Jul. 22, 2009, he describes the circa-2009-Internet as almost wholly dependent upon human interaction, i.e., he asserts that nearly all of the data then available on the internet was generated by data-capture/data-creation chains of events each of which included human interaction, e.g., typing, pressing a record button, taking a digital picture, or scanning a bar code. In the evolution of the Internet, such dependence upon human interaction as a link in each chain of data-capture and/or data-generation is a bottleneck. To deal with the bottleneck, Ashton suggested adapting internet-connected computers by providing them with data-capture and/or data-generation capability, thereby eliminating human interaction from a substantial portion of the data-capture/data-creation chains of events.
In the context of the IoT, a thing can be a natural or man-made object to which is assigned a unique ID/address and which is configured with the ability to capture and/or create data and transfer that data over a network. Relative to the IoT, a thing can be, e.g., a person with a heart monitor implant, a farm animal with a biochip transponder, an automobile that has built-in sensors to alert the driver when tire pressure is low, field operation devices that assist fire-fighters in search and rescue, personal biometric monitors woven into clothing that interact with thermostat systems and lighting systems to control HVAC and illumination conditions in a room continuously and imperceptibly, a refrigerator that is "aware" of its suitably tagged contents that can both plan a variety of menus from the food actually present therein and warn users of stale or spoiled food, etc.
In the post-2009 evolution of the Internet towards the IoT, a segment that has experienced major growth is that of small, inexpensive, networked processing devices, distributed at all scales throughout everyday life. Of those, many are configured for everyday/commonplace purposes. For the IoT, the fringe nodes will be comprised substantially of such small devices.
Within the small-device segment, the sub-segment that has the greatest growth potential is embedded, low-power, wireless devices. Examples of low-power, low-bandwidth wireless networks include those compliant with the IEEE 802.15.4 standard, the "Zigbee protocol," the 6LoWPAN standard, the LoRaWAN standard (as standardized by the LoRa™ Alliance), etc. Such networks are described as comprising the Wireless Embedded Internet ("WET"), which is a subset of IoT.
Most of the WET operates in portions of the RF spectrum that are unlicensed by a government's regulatory authority. Examples of unlicensed spectrums include the industrial, scientific and medical (ISM) radio bands reserved internationally for the use of radio frequency (RF) energy for industrial, scientific and medical purposes other than telecommunications, e.g., as regulated in the U.S.A. by FCC Part 15, with such regulations including requirements/constraints on frequency hopping, etc. An example of a telecommunications technique used in the 915 MHz ISM band is the LoRa™ modulation format that is included in the LoRaWAN standard. The LoRa™ modulation format can be described as a frequency modulated ("FM") chirp that is based on the generation of a stable chirp using a fractional-N ("fracN") phase-locked loop ("PLL"). Core LoRa™ technology is described in U.S. Pat. No. 7,791,415, which is assigned to Semtech™ Corporation. It is noted that the LoRa™ modulation format does not itself describe system functionality above the physical layer, i.e., above the RF medium.
It was assumed that Moore's law would advance computing and communication capabilities so rapidly that soon any embedded device could implement IP protocols, even the embedded, low-power, wireless devices of the WET. Alas, this has not proven true for cheap, low-power microcontrollers and low-power wireless radio technologies. The vast majority of simple embedded devices still make use of 8-bit and 16-bit microcontrollers with very limited memory because they are low-power, small and cheap.
Consequently, most of the WET includes resource-limited embedded devices, which typically are battery powered. The physical trade-offs of wireless technology have resulted in most of the WET using short-range, low-power wireless radios which have limited data rates (and consequently limited spreading factors), frame sizes and duty cycles.
Most wireless data networks must deal with the problem of an imperfect transmission channel. Because the transmission channel can vary with time, among some wireless networks, it is known to adaptively set one or the transmission settings, respectively.


A wastewater reuse system has a wastewater treatment system connected to a dwelling for receiving wastewater therefrom. The wastewater treatment system has a pump tank with an outlet that can be connected to a central wastewater collection system. There can be a pump in the pump tank for pumping water from the pump tank to a use recipient of treated wastewater such as an irrigation system.

Field of the Invention
The present invention relates to re-use of wastewater and, more particularly, to re-use of wastewater from wastewater treatment systems; e.g., septic systems, aerobic and other advanced wastewater treatment systems, and the like, for irrigation/sprinkler systems on yards, greenbelts, etc.
Background of the Invention
In general, there are three basis ways that wastewater from a wastewater generating source; e.g., home, business or the like can be disposed of, namely;
(1) direct connection to a municipal wastewater treatment system (MWS);
(2) use of a septic system (SSS); and
(3) use of an advanced or secondary wastewater treatment system (AWTS); e.g., an aerobic wastewater treatment system.
For purposes of the following description and claims, the SSS and AWTS are sometimes referred to as a "wastewater treatment system."
For purposes of the following description, while the words homes, residences or dwellings may be employed, it will be understood that the words include commercial establishments, restaurants and the like.