In one embodiment, a method for forming a pair of aligned holes is provided. The method comprises determining a diameter of a cleanup hole associated with a plurality of misaligned holes, in which the cleanup hole diameter may also correspond to a fastener diameter. Additionally, a tapered reamer is at least partially inserted into a gap defined by the plurality of misaligned holes. The tapered reamer has a longitudinal axis and may be configured such that the longitudinal axis aligns with a center of the cleanup hole when the tapered reamer is inserted into the gap defined by the plurality of misaligned holes. The plurality of misaligned holes may then be reamed with the tapered reamer to form the cleanup hole defined by the plurality of aligned holes having a same center and a same diameter.

Field
Devices and methods are disclosed for producing aligned holes from misaligned holes. More particularly, systems and methods are disclosed for determining the size of a fastener to be used and for producing aligned holes from the misaligned holes.
Background
When multiple objects are to be connected together, fasteners of various sizes are commonly used. A circular hole is then drilled into each object, and ideally the objects are then placed next to one another such that the respective holes in the objects overlap each other and circumferences of the holes align. For the purposes hereof, when two or more such holes overlap with one another, the passageway through the holes is referred to as the gap. The virtual hole diameter of the gap is defined as the bisector of the gap with the smallest length. As will be understood, it is the length of the smallest bisector through the gap which determines whether a given fastener will fit through the (mis)aligned holes. Presuming the holes in the objects align properly, the gap should have the same shape as either of the holes, such that the virtual hole diameter of the gap is equal to the diameter of either hole. This is because with aligned holes, all bisectors of the gap have the same length, which is equal to the diameter of either hole. A fastener which would fit through either of the holes should therefore fit through the gap defined by the aligned holes as well, so as to secure the objects together.
However, a hole in one of the objects may not align properly with the corresponding hole in the other object when the objects are brought together. Misalignment of the holes reduces the size of the resulting gap through the objects, and specifically results in a gap in which the shortest bisector is shorter than the diameter of either original hole. Thus, the misaligned holes result in a gap with a virtual hole diameter that is smaller than the diameter of either hole and that could potentially be too small for the intended fastener to fit therethrough. As will be understood, a virtual hole that has a diameter equal to the virtual hole diameter is theoretically the diameter of the largest fastener which would fit through a misaligned set of holes.
A common technique for correcting misaligned holes is to drill or ream a cleanup hole through the misaligned holes, centered on one of the misaligned holes. A cleanup hole is preferably large enough in diameter that all of the misaligned holes fit fully within the cleanup hole, such that nothing of the original misalignment remains. Once the cleanup hole has been created, a fastener—which may also have a larger diameter than the diameter of the originally intended fastener—is placed through the cleanup hole to secure the objects together.
Conventionally, cleanup holes are created on a trial-and-error basis. Progressively larger and larger diameter cutters are used to incrementally remove minimal amounts of material from the misaligned holes. Multiple sizes of go/no-go gages and visual inspection are used to determine whether the newly-created cleanup hole meets fastener installation requirements. This trial-and-error method involves an element of subjectivity and is labor intensive. Special drill jigs are clamped to two or more adjacent holes or surfaces and are adjusted to center on the near-side misaligned hole. Not only is this process time consuming, but also requires a larger diameter hole to be produced to clean up the misaligned holes.

Methods and systems for forming aligned holes


A water heating system has a tank, a first heating element, a first temperature sensor, and a controller. The first heating element is mounted on the tank, and the controller is electrically coupled to the first temperature sensor. The controller is configured to detect a stacking condition based on the first temperature sensor and to disable the first heating element in response to detection of the stacking condition.

Devices such as hot water heaters, furnaces, and other appliances commonly include one or more heating elements that are controlled by a controller such as a thermostat. A heating element is activated (i.e., placed in an on-state) when heat is needed and deactivated (i.e., turned to an off-state) when heat is not required. The change of states normally occurs when a control signal turns a power relay on or off. Power relays have a pair of contacts capable of meeting the current requirements of the heating element. In a typical home-use hot water heater, approximately 220 volts AC is placed across the heating element and a current of about 10 to 20 amperes flows.
A heating element is typically associated with an upper temperature threshold, referred to as the "upper set point," and a lower temperature threshold, referred to as the "lower set point," that are used for control of the heating element. When the temperature of water in a tank exceeds the upper set point, as measured by a thermal sensor mounted on a wall of the water heater, the heating element is deactivated, and heating of the water by the heating element stops. If the water temperature drops below the lower set point, the heating element is activated and, therefore, begins to heat the water. As heated water is repeatedly withdrawn from the water tank and replenished with cold water, the heating element goes through activation/deactivation cycles.
One problem associated with water heaters is "stacking" wherein water in the upper section of the tank reaches high temperatures that are significantly greater than the upper set point and often much higher than expected by a user. Because a hot water supply pipe of a water tank typically draws water from the top of the tank, stacking may cause the water drawn from the tank to significantly exceed the upper set point. Such an undesired effect can result in pain or injury to a user that touches the overheated water coming from the hot water supply pipe.
Thermal lag can also cause water within the tank to become overheated. "Thermal lag," as used herein, refers to a delay in the temperature of the water reaching the upper set point and a detection by the thermal sensor that the upper threshold has been reached. Thermal lag can cause water temperature to overshoot the upper set point value and, therefore, reach undesirably high levels. Hence, there is a need for reducing undesirable overheating of water within a water heater due to stacking and thermal lag.

This patent is subject to a terminal disclaimer.

System and method for preventing overheating of water within a water heater tank


A disk drive apparatus drives, by means of a motor, a disk mounted thereon so as to reproduce signals recorded in the disk. The disk drive apparatus has an edge detecting unit for generating an edge signal XEG indicating a timing of phase switching, in accordance with a plurality of signals CU, CV and CW induced when the motor is driven. The disk drive apparatus further has a drive voltage controlling unit for controlling, in accordance with the edge detection signal XEG, the maximum value of a drive voltage VS for driving said motor. This arrangement implements optimal motor control, while reducing circuit scale and cost and, at the same time, enhancing adaptability of the disk drive apparatus.

1. Field of the Invention
The present invention relates to a disk drive apparatus for driving a disk mounted thereon to allow signals recorded in the disk to be reproduced.
2. Description of the Related Art
In systems having rotary components, such as portable MD players, noise produced by a spindle motor incorporated in the rotary component is becoming a matter of concern. In a system known as a PWM system in which a spindle motor is driven directly by a pulse-width-modulated signal, a problem also is caused by noise that is generated by a quick variation in electric current occurring at the time of switching of the phase of the electric current.
In order to obviate this problem, a technique known as the "soft-switching" driving or control method has been proposed in which the motor current is reduced immediately before and after a phase switch of the spindle motor.
Such a soft-switching driving method has been implemented by using an analog circuit. The analog circuit is composed of transistors included in a motor driver and, therefore, cannot be formed with a high degree of integration, thus failing to contribute to an appreciable reduction in the cost.
The known circuit implementing the soft-switching driving method involves another problem in that changes or modifications of parameters concerning the driving system by using an external device, such as a microcomputer (MCU), cannot easily be effected because of the fact that, as described above, the circuit is formed in the motor driver in accordance with predetermined design specifications. In other words, modification of the motor-driver circuit is necessary to accommodate any variation in the motor characteristics which may occur.
Current portable mini-disk (MD) players employ as means for driving an MD a brush-less, three-phase motor (referred to simply as "motor", hereinafter) which does not have any hall element for detecting rotational positions. In operation, the speed of rotation of the motor rotor is computed based on the phase difference between counter-electromotive edge signals which are obtained as a result of operation of the motor, and the timing of switching of the phase is determined in accordance with the rotor speed.
The term "counter-electromotive edge" is used in this specification to mean an output from a comparator which compares an intermediate potential as a reference and a counter-electromotive force that is induced in the coil of each phase. This method of motor control will be referred to as "control under first delay mode", hereinafter.
It is to be pointed out that any inter-phase offset existing in the comparator for generating detection signals corresponding to rotational positions of the motor rotor tends to cause an undesirable effect, particularly when the rotation speed is low. In other words, error which is involved in the detection signal corresponding to the rotational position of the motor rotor is significant as compared with the case where no offset exists in the comparator. Such a detection signal involving an error may undesirably be masked by a mask signal, which is intended to avoid erroneous detection of the edge, thus hampering correct control of the motor.
A motor control method also has been known in which the motor is controlled by computing a rotation speed based on the time interval between counter-electromotive edges corresponding to one period of a single counter-electromotive edge, i.e., the time interval of counter-electromotive edge corresponding to ¼ rotation of the motor rotor. In the following description, this type of motor control method will be referred to as "control under second delay mode"
In the control under second delay mode, the rotation speed is computed based on the time interval between the counter-electromotive edges corresponding to ¼ rotation of the motor rotor. Therefore, when the motor is abruptly accelerated or decelerated, the counter-electromotive edge tends to be deformed, posing a risk that the phase switching cannot be performed at proper timing.


A new variety of hybrid lily plant bearing large upright-facing flowers of excellent form and long persistence, both on the plant and as cut-flowers. The flowers of the new plant are particularly characterized by their pure white color, their lightly ruffled margins, their large size and substance, their upright to semi-upright orientation, and the sharply ascending pedicels of the upper flowers. The plant is particularly characterized by its dark green leaves and an unusually broad leaf under the lowest flower of the stem. This combination is completely new in the Oriental hybrid divisions of lilies suited to forcing and to mass commercial cultivation. The bulbs may be precooled and forced for cut-flower production.

My new variety of lily plant originated as a seedling which first flowered in't Zand, Netherlands, in 1988. The breeding efforts had as their objective the production of Oriental hybrid lilies with upright or semi-upright white flowers without conspicuous spotting, suited to forcing into flower out of season, heretofore unknown in the lily breeding art.
I achieved the desired objective by intercrossing selected upright and semi-upright white Oriental seedlings selected for their suitability to forcing for year-round use as cut-flowers and carrying the recessive gene for pure white flowers.
The flowers of my new lily are characterized by an upright orientation, large size and broad-tepalled "bowl-shaped" form, unusually thick substance, lightly ruffled tepal margins, and a distinctive pure white, unspotted coloration, unique among Oriental hybrid lilies. The pedicels of the upper flowers are ascending. The clone possesses unusually strong, stout stems. In addition, the clone possesses to a high degree desirable characteristics of hybrid vigor. The clone is a good grower and propagator, as observed at't Zand, Netherlands, and at Salem, Oreg.
My new variety of lily plant has been asexually reproduced by me and under my direction at't Zand, Netherlands, and at Salem, Oreg. Successive generations produced by natural propagation from bulblets, by bulb scale propagation, and by tissue culturing from bulb scale explants have demonstrated that the novel and distinctive characteristics of my new variety are fixed and hold true under asexual propagation from generation to generation.

Oriental hybrid lily plant named `Euroblanca`


Financial products, such as a mortgage, homeowner's insurance, and various forms of life insurance, can be packaged together and marketed around a move event. A customer can apply for a mortgage on a web site. As part of the application process, certain data is collected from the customer, and other data may be retrieved from one or more databases. This information can be used to offer and price homeowner's insurance and life insurance, and to suggest an amount of insurance. The web site may offer the customer the chance to buy a mortgage and insurance as a package, after answering a small number of questions that are used to assess the insurance-related risk. The customer may also be offered the chance to make a unified monthly payment for the package of both mortgage and insurance products.

Purchase of a home is an event that can involve various financial issues. Raising the money to buy the home through a mortgage loan is one issue, but other issues exist. For example, many people choose to obtain life insurance to cover the amount of money borrowed, in order to ensure that there are sufficient assets for the person's family to remain in the home in the event of the death of the family's primary income provider. As another example, purchase of a home is usually accompanied by purchase of homeowner's insurance.
The time when a person moves from one home to another (a "move event") provides an opportunity to consider various types of financial products in addition to the purchase money mortgage itself—e.g., various types of insurance may be considered. However, these types of financial products are typically offered and marketed separately, and are not structured around a move event.

System and method for bundling financial services products with a mortgage in connection with a move event

United Services Automobile Association (USAA)


The wheel comprises an inner rim attached to a wheel hub e.g. by spokes, an outer rim for receiving a tire, and a resilient member between the rims which in use serves to absorb shocks from the surface over which the wheel passes. An opening for a valve is provided. The material of the member is polymeric, e.g. polyurethane foam.

This invention concerns wheels for example, but not exclusively, for wheelchairs and other means of conveyance, for example bicycles.
Cycle and wheelchair wheels were originally made with solid rubber tires. Subsequently the solid rubber tire was replaced by tires with pneumatically inflatable inner tubes, these having the advantage that they act as shock absorbers when travelling over uneven surfaces.
The change to pneumatic tires dramatically improved the comfort, road holding and safety of vehicles which used them, especially at the higher speeds which could be obtained with their use.
More recent developments have led to cycles of more sophisticated design which include separate shock absorbers to absorb greater shocks than can be absorbed by pneumatic tires alone, for example spring suspensions of the forks for the front and/or rear wheels.
Despite improvements in the suspension of cycles, apart from the use of pneumatic tires, wheelchairs have generally relied on no more than the use of rubber bushings for mounting the axles to provide shock absorption. Such suspension systems serve to reduce the unsprung weight of the wheelchair to more nearly that of the wheel which is supported by the tires and so improve their ride.
The introduction of battery powered assistance for cycles, wheelchairs and other types of conveyance which include motors in the wheels has resulted in an increase in wheel weight which demands increased shock absorbing performance from the tires due to the increased weight leading to increased rolling resistance for the tires and decreased lateral stability. However, the suspension systems referred to above do not in general improve the situation because the wheels themselves are unsprung.
According to the present invention there is provided a wheel for a bicycle, wheelchair or the like comprising an inner rim attached to a wheel hub, an outer rim for receiving a tires, and a resilient member between the inner and outer rims which in use serves to absorb shocks from the surface over which the wheel passes.
The invention also provides bicycles and wheelchairs including at least one wheel in accordance with the present invention.


A system for detecting abnormalities or inconsistencies and a method to utilize the same are provided. In particular, a computer system may be adapted to detect the abnormality or inconsistency within at least a portion of a subject by generating internal impedance data which indicates that an impedance change within the portion of the subject has occurred. For example, the impedance change may be associated with a change in at least one characteristic of a blood vessel within the subject (such as a change in a fluid flow rate within at least a portion of the subject), a change in a fluid volume within at least a portion of the subject, etc. The impedance change also may be associated with the presence of a foreign object within the portion of the subject. In an exemplary embodiment, it is possible to detect the abnormality or inconsistency within the subject by generating a continuous, real time internal impedance map indicating the impedance change within the subject. Alternatively, the abnormality or inconsistency may be detected within the subject by generating a plurality of static internal impedance maps which indicate that the impedance change within the subject has occurred.

Conventional electroencephalography (EEG) systems have been employed to record brain waves in a patient by measuring intrinsic voltages or currents produced by the brain of the patient. Specifically, conventional EEG systems detect and amplify brain waves, and convert the brain waves into digital data to be compared with data associated with normal brain waves. These systems may be employed to detect possible spinal cord injuries, stroke, epilepsy and a variety of brain dysfunctions related to a psychology of a patient ranging from substance abuse to psychosis. For example, certain conventional EEG systems include a plurality of electrodes which can be positioned on the scalp of a patient. The electrodes are coupled to a switching system, which in turn is coupled to a preamplifier that is connected to an amplifier. The amplifier is connected to a sixteen (16) bit analog to 30 digital (A/D) converter, and the A/D converter is connected to a display. The A/D converter samples the EEG waves, and converts the EEG waves into the digital data to be shown on the display. However, such conventional system only may be adapted to obtain EEG recordings.
Conventional electrical impedance tomography (EIT) systems have been employed to produce electrical impedance images in medical applications. These EIT systems measure current or voltage distributions resulting from the currents being applied to a portion of the body of the patient, and generate an image of such portion of the body based on the measured current or voltage distributions. These conventional systems have been employed, e.g., to display changes in the thorax during breathing, the stomach during a gastric emptying, the heart during intraventricular hemorrhage, and the brain due to a physiological cerebral activity, and to monitor the progression of various lung diseases. For example, the conventional EIT system can be adapted to image changes in the brain due to a physiological cerebral activity may include a current generator coupled to a switching arrangement, such as a computer controlled multiplexor. A plurality of electrodes are positioned in contact with the patient's scalp, and are coupled to the switching arrangement. An amplifier is coupled to the electrodes, a sixteen (16) bit A/D converter is connected to the amplifier, and a computer is connected to the A/D converter.
In operation, the current generator applies current to the electrodes. For example, the current may be applied sequentially to the electrode pairs, or simultaneously to multiple pairs of electrodes, which is known as a parallel data collection. Moreover, potential differences between the electrode pairs may be measured to obtain analog signals, and these analog signals may be amplified by the amplifier. Subsequently, the A/D converter converts the analog signals to digital signals, and forwards the digital signals to the computer. In this manner, the data may be processed by the reconstruction software to obtain image changes in the brain due to a physiological cerebral activity, and provide these images on a display. However, such conventional system may be adapted to only obtain EIT recordings that are e.g., associated with the physiological cerebral activity, and may also be adapted to only monitor only certain organs. Moreover, such convention system only may obtain EIT recordings at a particular frequency.

Arrangement and method for detecting inconsistencies and abnormalities in a body


A method for implementing network virtualization, and a related apparatus and a communications system are provided. The method for implementing network virtualization may include: receiving, by an SDN controller, a virtual network creation request that carries virtual network topology information; creating a virtual network in response to the virtual network creation request; establishing, by the SDN controller, a device mapping relationship; establishing, by the SDN controller, a port mapping relationship; allocating, by the SDN controller, a virtual SDN controller to the virtual network; and registering, by the SDN controller, a first virtual forwarding device and a second virtual forwarding device with the virtual SDN controller. Technical solutions of embodiments of the present invention help to improve networking flexibility, reduce service costs, and shorten a service deployment period.

As cloud computing is popular gradually, more small- and medium-sized enterprise users hope that an operator provides a private network service. However, a current virtual private network (VPN) has many problems. For example, the VPN can support only a star topology, a full-mesh topology, or a partial full-mesh topology, but a virtual network of any topology cannot be deployed according to a user requirement. VPN configuration is complex and a service deployment period is long (approximately 16 days). However, currently applying for and creating a cloud data center may be implemented instantly, and a deployment speed of the VPN cannot match a creation speed of the cloud data center.
Route exchange is implemented between VPN stations by using a Border Gateway Protocol (BGP). BGP route propagation and exchange are limited, and a router supports a maximum of 4096 VPNs. Consequently, VPN service costs are high, a VPN service price is high, and most small- and medium-sized enterprises do not use the VPN service.
Due to features of a conventional VPN solution in aspects such as a service deployment period, service networking flexibility, and costs, it is increasingly difficult to meet diversified customer requirements.

Method for implementing network virtualization and related apparatus and communications system


Parkinson's disease is caused by the preferential loss of substantia nigra dopamine neurons. A Parkin Interacting Substrate, PARIS (ZNF746) is identified. The levels of PARIS are regulated by the ubiquitin proteasome system via binding to and ubiquitination by the E3 ubiquitin ligase, parkin. PARIS is a KRAB and zinc finger protein that accumulates in models of parkin inactivation and in human brain Parkinson's disease patients. PARIS represses the expression of the transcriptional co-activator, PGC-1α and the PGC-1α target gene, NRF-1 by binding to insulin response sequences in the PGC-1α promoter. Conditional knockout of parkin in adult animals leads to progressive loss of dopamine (DA) neurons that is PARIS dependent. Overexpression of PARIS causes selective loss of DA neurons in the substantia nigra, which is reversed by either parkin or PGC-1α co-expression. The identification of PARIS provides a molecular mechanism for neurodegeneration due to parkin inactivation.

Parkinson's disease (PD) is a progressive neurodegenerative disorder that is characterized phenotypically by bradykinesia, rigidity, tremor, and neuropsychiatric disturbances (Savitt et al., 2006). Although the cause of PD in the majority of cases is unknown, there are rare familial cases for which the genes have been identified. There are at least sixteen PD associated loci (Gasser, 2007). Mutations in α-synuclein and leucine rich repeat kinase 2 (LRRK2) cause autosomal dominant PD. Four genes have been linked to autosomal recessive PD (AR-PD) and include mutations in parkin, DJ-1, PINK1, and ATP13A2. Investigating the biology of these genes and their mutant protein has provided tremendous insight into the pathogenesis of both familial and sporadic PD (Gasser, 2007; Savitt et al., 2006).
Parkin is an ubiquitin E3 ligase (Shimura et al., 2000; Zhang et al., 2000). In general, PD-associated mutations in parkin lead to loss of its E3 ligase function (Tanaka et al., 2004). Moreover, oxidative, nitrosative, and dopaminergic stress, which play important pathogenic roles in PD, inactivate parkin, suggesting that parkin inactivation may play a role in sporadic PD (Chung et al., 2004; LaVoie et al., 2005; Winklhofer et al., 2003). Thus, substrates of parkin that are subject to proteasomal degradation should accumulate in animal and cellular models of parkin inactivation and AR-PD due to parkin mutations, and also in sporadic PD. There are a diverse array of parkin substrates that has hindered the generation of a consensus in the field on parkin's physiologic function and pathologic role in PD. Moreover, parkin's ability to mono- and poly-ubiquitinate, as well as, ubiquitinate proteins with both lysine-48 and lysine-63 chains has made it difficult to reconcile a common biochemical pathway for parkin's role in PD (Dawson and Dawson, 2010).
A new Parkin Interacting Substrate, PARIS, has been identified, which provides a molecular mechanism for neurodegeneration due to parkin inactivation in PD. Parkin regulates the levels of PARIS via the ubiquitin proteasome system (UPS). PARIS is a major transcriptional repressor of peroxisome proliferator-activated receptor gamma (PPARγ) coactivator-1α (PGC-1α) expression and that conditional knockout (KO) of parkin in adult mice leads to progressive loss of dopamine (DA) neurons through PARIS overexpression and transcriptional repression of PGC-1α.

Transcriptional repression leading to parkinson's disease


A semiconductor device and fabrication method are presented which advantageously combine TAB and wire bonding techniques to increase integrated circuit I/O pad density. The semiconductor device includes an integrated circuit, a substrate, and a carrier film (i.e., a TAB tape). The integrated circuit has a set of input/output (I/O) pads arranged upon an upper surface. The substrate has a die cavity within an upper surface and a set of bond traces arranged about the die cavity. An underside surface of the integrated circuit is attached to the substrate within the die cavity. The carrier film is positioned over the upper surface of the substrate such that the upper surface of the integrated circuit is exposed through a die aperture and portions of the members of the set of bond traces are exposed through corresponding members of a set of bond trace apertures. Each conductor has a first end connected to a member of the set of bond traces and an opposed second end connected to a corresponding member of a portion of the set of I/O pads. Each of the remaining members of the I/O pads are connected to respective bond traces adjacent to the die cavity by bonding wires. By combining TAB and wire bonding techniques, the number of I/O pads per unit of upper surface area of the integrated circuit may be increased.

1. Field of Invention
This invention relates to semiconductor device packages, and more particularly to bonding techniques used to connect integrated circuit input/output (I/O) pads to bond traces of semiconductor device packages.
2. Description of Related Art
During manufacture of an integrated circuit (e.g., a microprocessor), signal lines formed upon the silicon substrate and to be connected to external devices are terminated at flat metal contact regions called input/output (I/O) pads. Following manufacture, the integrated circuit is typically secured within a protective semiconductor device package. Each I/O pad of the chip is then connected to a bonding pad of the device package, and ultimately to a terminal which typically extends from the periphery of the package.
As integrated circuit fabrication technology improves, manufacturers are able to integrate more and more functions onto single silicon substrates. As the number of functions on a single chip increases, however, the number of signal lines which need to be connected to external devices also increases. The corresponding numbers of required I/O pads and device package terminals increase as well, as do the complexities and costs of the device packages.
Common methods used to connect the I/O pads of the integrated circuit to bond traces of the device package include wire bonding and tape automated bonding (TAB). In wire bonding, connections are made using fine metal wires (e.g., gold or aluminum wires). FIG. 1a is a partial perspective view of an integrated circuit 10 attached to an upper surface of a substrate 12 of a semiconductor device package. I/O pads 14 of integrated circuit 10 are arranged at or near the perimeter of integrated circuit 10, wherein I/O pads 14 are placed in close lateral proximity to bond traces 16 (often referred to as bonding "fingers"). Bonding wires 18 extend and make electrical connection between I/O pads 14 and bond traces 16. Bonding traces 16 are connected to terminals of the device package by electrically conductive signal traces.
TAB techniques connect I/O pads of the integrated circuit to bond traces of the device package using fine-line conductors etched from one or more sheets of metal (e.g., copper). The electrically conductive sheet is bonded to a sheet of a dielectric material (e.g., polyimide film), then portions of the conductive sheet are selectively removed in order to form the TAB conductors. The sheet of dielectric material maintains proper conductor spacing. FIG. 1b is a partial perspective view of integrated circuit 10 having I/O pads 14 bonded to etched metal "beam" conductors 20 of a flexible TAB "tape" 22. Conductors 20 are bonded to a sheet of dielectric material 23 and connected to terminals of the device package.
In wire bonding, each bonding wire is typically installed one after another in sequence. In TAB, on the other hand, multiple connections are made at the same time (i.e., in parallel). Thus wire bonding is a relatively slow process compared to TAB. In wire bonding, two or more bonding wires may inadvertently touch one another, causing an electrical short circuit and improper operation of the packaged semiconductor device. TAB tapes prevent conductors from coming into contact with one another. TAB tapes are, however, more expensive than bonding wire. However, the TAB tapes may also function as semiconductor device packages. Thus wire bonding and TAB techniques have benefits and drawbacks.
It would be advantageous to combine wire bonding and TAB techniques to form a hybrid bonding technique which includes the advantages of both methods. For example, the current states of wire bonding and TAB technologies place lower limits on the minimum distances between I/O pads of integrated circuits (i.e., I/O pad "pitch"). By combining the two technologies, however, it is possible to increase the number of I/O pads per unit of integrated circuit surface area (i.e., I/O pad density). Increasing I/O pad density not only helps solve the increasing I/O pad problem, but also allows the dimensions of semiconductor device packages employing the hybrid approach to be reduced. Such size reductions are advantageous, especially in portable applications.

Semiconductor device and fabrication method which advantageously combine wire bonding and tab techniques to increase integrated circuit I/O pad density


A probe suitable for use in unilateral nuclear magnetic resonance imaging and adapted to be embedded in a sample to be analysed, the probe comprising; a static magnetic field generator; a radiofrequency magnetic field generator adjacent to the static magnetic field generator; a circuit controlling the frequency response of the radiofrequency magnetic field generator, adjacent to the static magnetic field generator; an input cable coupled to the frequency control circuit and the frequency control circuit coupled to the radiofrequency magnetic field generator.

Despite growing interest in magnetic resonance of porous materials such as soils and concrete, critical limitations exist in terms of the types of measurements that can be made. Both spectroscopic and spatially resolved studies requiring superconducting magnets can only be carried out on samples of limited size. New advances in open, portable NMR instrumentation allow bulk relaxation and diffusion measurements to be made on arbitrarily large samples such as described in G. Eidmann, R. Savelsberg, P. Blümler, B. Blümich, J. Magn. Res. A 1996; 122:104-109. However, experiments of this type are limited by the penetration depth of B0 and B1. This constraint has permitted higher field (10-20 MHz) near surface studies (see Boguszynska, J. et al., Cem. Concr. Res, 2005 35:2033-2040), along with lower field measurements at a greater, but still limited, depth.
In many situations, it may be desirable to measure NMR parameters from deep within a sample. Examples in the porous media regime could include larger concrete structures and soil formations. Previous work has used RF coils embedded within concrete samples in order to alleviate the B1 penetration problem (see Boguszynska, above).
Extending this idea, a small, low cost NMR sensor suitable to be embedded within a large sample has been developed. NdFeB disk magnets provide a local B0 field for a 1H resonant frequency of between 6-10 MHz depending on the design. A printed circuit board surface coil is located immediately above one face of the magnets, and tuned to resonance with capacitors on the opposite face. The entire arrangement is connected to a 2.5 mm diameter coaxial cable, and encased in epoxy. The inhomogeneous B0 and B1 fields define a local sensitive spot in which bulk relaxation time or diffusion measurements can be made.
According to one aspect of the present invention, there is provided a probe suitable for use in unilateral nuclear magnetic resonance imaging and adapted to be embedded in a sample to be analysed, the probe comprising; a magnet having a north and south pole; a radiofrequency coil adjacent one of the poles of the magnet; a capacitive tuning circuit adjacent the other pole of the magnet; a coaxial cable electrically connected to the tuning circuit and the tuning circuit electrically connected to the coil.
According to another aspect of the present invention, there is provided a probe suitable for use in unilateral nuclear magnetic resonance imaging and adapted to be embedded in a sample to be analysed, the probe comprising; a static magnetic field generator; a radiofrequency magnetic field generator adjacent to the static magnetic field generator; a circuit controlling the frequency response of the radiofrequency magnetic field generator, adjacent to the static magnetic field generator; an input cable coupled to the frequency control circuit and the frequency control circuit coupled to the radiofrequency magnetic field generator.
According to another aspect of the present invention, there is provided a method for magnetic resonance imaging of a sample comprising the step of embedding a probe in the sample to be imaged.
According to another aspect of the present invention, there is provided a system for use in unilateral nuclear magnetic resonance imaging comprising: a probe adapted to be embedded in a sample to be analysed, an RF supply module connected to probe suitable for generating an RF signal compatible with nuclear magnetic resonance.
An RF coil suitable for nuclear magnetic resonance imaging wherein the coil in bowtie shaped. The coil may have multiple windings.
Other aspects and features of the present invention will become apparent to those ordinarily skilled in the art upon review of the following description of specific embodiments of a probe, system and method suitable for unilateral nuclear magnetic resonance in conjunction with the accompanying drawing figures.
Like reference numerals are used in different figures to denote similar elements.

Probe, system and method suitable for unilateral nuclear magnetic resonance


A fuel cell apparatus which runs on liquid fuel includes a first inlet manifold which is a way to supply air to the anode of the fuel cell apparatus, a second inlet manifold which is a way to supply the liquid fuel to the cathode of the fuel cell apparatus, an outlet manifold which is a way in which fluid discharged from the anode and the cathode flows.

1. Field of the Invention
The present invention relates to fuel cell apparatus, and it particularly relates to a fuel cell apparatus which runs on liquid fuel.
2. Description of the Related Art
In recent years, much attention has been focused on the direct methanol fuel cell (hereinafter referred to as "DMFC") as a form of fuel cell. With a DMFC, methanol, which is the fuel therefor, is directly supplied to the negative electrode without having it reformed, and electric power is produced by an electrochemical reaction between methanol and oxygen. Methanol has higher energy per unit volume than ion proton, can be easily stored, and is far less prone to explosion. Because of these advantages, there are growing expectations of the DMFC being used as a power supply for automobiles, portable equipment or the like (see, for example, Reference (1) in the following Related Art List).
Related Art List
    (1) Japanese Patent Application Laid-Open No. 2002-32154.
To utilize a fuel cell system as a power supply in a mobile device, it is further required that such a fuel cell system be made smaller in size and lighter in weight. The inventors of the present invention have thus contemplated from various angles technologies that can improve fuel cell systems by making them smaller and lighter.

Fuel cell apparatus including manifolds therein


A composition for delivering a tumor therapeutic agent to a patient includes a fast-release formulation of a tumor apoptosis inducing agent, a slow-release formulation of a tumor therapeutic agent, and a pharmaceutically acceptable carrier. An apoptosis-inducing agent in a pharmaceutically acceptable carrier may be administered before or concomitantly therewith. Nanoparticles or microparticles (e.g., cross-linked gelatin) of the therapeutic agent (e.g., paclitaxel) also may be used. The nanoparticles or microparticles may be coated with a bioadhesive coating. Microspheres that agglomerate to block the entrance of the lymphatic ducts of the bladder to retard clearance of the microparticles through the lymphatic system also may be employed. This invention also uses drug-loaded gelatin and poly(lactide-co-glycolide) (PLGA) nanoparticles and microparticles to target drug delivery to tumors in the peritoneal cavity, bladder tissues, and kidneys.

Drug-Loaded Microparticles
Multiple types of cancer originate from organs located within the peritoneal cavity, e.g., pancreatic, liver, colorectal, and ovarian cancer. The peritoneal cavity also is a site for metastasis of cancer originating from organs outside of the peritoneal cavity during the late stage of disease, e.g., lung cancer. Within the peritoneal cavity, tumors can be found in pelvic and abdominal peritoneal surfaces, other peritoneal organs, e.g., intestinal mesenteries, bladder, omentum, diaphragm, lymph nodes and liver. Obstruction of the diaphragmatic or abdominal lymphatic drainage by tumor cells leads to decreased outflow of peritoneal fluid resulting in carcinomatosis or ascites.
Intraperitoneal chemotherapy, where the drug is directly instilled into the peritoneal cavity, has been used to treat peritoneal cancer, e.g., advanced ovarian and colon cancer (Otto, S. E., J Intraven. Nurs., 18:170-176, 1995; Collins, J. M., J Clin Oncol, 2:498-504, 1984). Intraperitoneal administration of platinated compounds, e.g., cisplatin, and Taxol®, the commercially available formulation of paclitaxel, has produced some benefits in patients and extended the survival time by about 20% (Gadducci, et al., Gynecol Oncol 76:157-162, 2000; Markman, et al. J Clin Oncol, 19:1001-1007, 2001). However, intraperitoneal chemotherapy has the following drawbacks that limit its use. Intraperitoneal treatments are usually administered through indwelling catheters, every 3 weeks for 6 treatments. The two major side effects are infection associated with the prolonged use of a catheter and abdominal pain due to the presentation of high drug concentrations in the peritoneal cavity (Francis, et al., J Clin Oncol, 13:2961-2967, 1995). Further, intraperitoneal administration requires hospitalization and is associated with substantial costs. These reasons have contributed to the reluctance of the medical community to use intraperitoneal treatments in spite of its demonstrated survival benefits. The current invention overcomes these various deficiencies.
In an earlier invention (U.S. patent application Ser. No. 09/547,825), Applicants showed that when anticancer drugs (e.g., paclitaxel, doxorubicin) are administered to the exterior of a solid tumor, as would be the case during regional intraperitoneal therapy, the drug penetration into solid tumors is very slow and limited to the tumor periphery. Applicants further disclosed a method to overcome this penetration problem. This method consists of using an apoptosis induction treatment (e.g., treatment with paclitaxel or doxorubicin) to expand the interstitial space within a tumor and thereby improve the penetration and distribution throughout solid tumors of the concurrently and subsequently administered drugs. This method is referred to as the "Tumor Priming" method in the current application, and has two requirements. The first requirement is that the drug concentrations must be sufficient to induce apoptosis. Applicants have shown that treatment with 200 nM paclitaxel for 3 hours is sufficient to induce apoptosis in multiple human tumor cells (Au, et al., Cancer Res., 58:2141-2148, 1998). The second requirement is that the time interval between the apoptosis-inducing pretreatment and subsequent treatments must be sufficient to allow apoptosis to occur, e.g., 16-24 hours for paclitaxel (Au, et al., Cancer Res., 1998; Jang, et al., J. Pharmacol. Exper. Therap., 296:1035-1042, 2001). These requirements are captured in the current invention.
Applicants further discovered that after intraperitoneal administration, the commercial Taxol® formulation was rapidly cleared from the peritoneal cavity, due to rapid absorption through the peritoneum, a thin membrane lining the peritoneal cavity, and due to drainage through the lymphatic system (see Examples 4 and 6, infra).
Based on these various considerations and discoveries, Applicants arrived at the conclusion that therapeutically useful intraperitoneal chemotherapy can be accomplished, if the treatment satisfies some or most of the following desired properties. First, the drug should have activity against the intended target cancer type. Second, the treatment should be easy to administer, does not require the use of indwelling catheter over long period of time, e.g., longer than one day or two days, and does not require frequent administration, e.g., no more than once a week. Third, the rate of drug presentation should be optimized so that the drug amount and, therefore, the drug concentration in the peritoneal cavity is high enough to provide adequate control of the disease but at the same time low enough to not produce significant local toxicity. Fourth, the drug or drug formulation must be able to penetrate into and widely distribute within solid tumors. Fifth, the drug or drug formulation should have a long retention in the peritoneal cavity where the tumors are located. Sixth, the drug or drug formulation should have high affinity to tumor cells and localize on tumor surface or within the tumor mass. Seventh, the distribution of the drug or drug formulation should be similar to the distribution or dissemination of tumor cells, within the peritoneal cavity or organs. Most or all of these desired features are captured in the current invention, i.e., drug-loaded microparticles.
The drug-loaded microparticles are designed to release the drug at two rates; a rapid release to provide sufficiently high drug concentration to induce apoptosis and a slower release to provide sustained drug delivery to tumors. The apoptosis induction promotes the penetration and distribution of the remaining microparticles and the remaining drug subsequently released from the slow-release particles. The slow drug release over a long time period, e.g., days, weeks or months, offers the patient the convenience of a single administration, reduces the frequency of treatments, eliminates the need of hospitalization, reduces the health care costs, eliminates the need of using indwelling intraperitoneal catheters and thereby reduces the risk of infections and improves the quality of life for a patient, and reduces the local toxicity due to the high local concentrations in the peritoneal cavity resulting from rapid bolus presentation of the entire dose all at once. These particles, due to their sizes and properties, are retained in the peritoneal cavity, adhere to tumors, and show similar distribution within the peritoneal cavity or organs.
The particles also can be combinations of two or more types of particles, with at least one type releasing the drug rapidly to induce apoptosis while the remaining types release the drug more slowly. Examples of microparticles loaded with a widely used anticancer drug paclitaxel are provided to demonstrate the utility of these particles, with respect to producing superior tumor targeting and antitumor activity in mice bearing peritoneal tumors, as compared to the commercial paclitaxel formulation, i.e., Taxol®, where paclitaxel is solublilized in Cremophor and ethanol.
Applicants further disclose that other drugs or agents can be formulated in the same microparticles for the purpose of treating peritoneal cancer.
Applicants further describe that drug-loaded particles can be used to treat tumors located in organs or regions that are readily accessible by local or regional administration.
The current invention uses biodegradable particles made of gelatin and PLGA polymers, loaded with agents of therapeutic utility. One of the agents formulated in the gelatin and PLGA particles is paclitaxel. A variety of biodegradable polymer bound paclitaxel formulations have been developed and have been shown to inhibit tumor growth and angiogenesis in animal models with minimal systemic toxicity; however, the release kinetics of paclitaxel in these systems, which range from about 10-25% of the drug released in approximately 50 days, are, most likely, not optimal for clinical use (U.S. Pat. No. 6,447,796). In addition, the purpose of most of these earlier studies was to achieve systemic, rather than regional, delivery of the drug. The advantages of biodegradable polymers as a carrier for agents of therapeutic utility are art-recognized (U.S. Pat. No. 6,447,796), and include: (1) complete biodegradation, requiring no follow-up surgery to remove the drug carrier when the drug supply is exhausted; (2) tissue biocompatibility; (3) ease of administration; (4) controlled, sustained release of the encapsulated drug upon hydrolysis of the polymer; (5) in case of regional use, minimization or elimination of systemic toxicity, such as neutropenia; and (6) the convenience of the biodegradable polymer system itself, in terms of versatility. Many of these advantages, similarly, apply to gelatin drug release particles.
Paclitaxel-Loaded Nanoparticles for Intravesical Therapy of Bladder Cancer
Intravesical chemotherapy is used to reduce bladder cancer recurrence and/or progression (Kurth, K. H., Semin. Urol. Oncol., 14: 30-35, 1996). Intravesical chemotherapy provides the advantage of selectively delivering drugs in high concentration to the tumor-bearing bladder, while minimizing the systemic exposure. Applicants have shown that treatment failure in superficial bladder cancer patients to chemotherapy, e.g., mitomycin C, e.g., doxorubicin, is in part due to the low drug delivery to tumors located in the bladder tissue (Dalton, et al., Cancer Res., 51: 5144-5152, 1991; Schmittgen, et al., Cancer Res., 51: 3849-3856, 1991; Wientjes, et al., Pharm. Res., 8: 168-173, 1991; Wientjes, et al., Cancer Res., 51: 4347-4354, 1991; Wientjes, et al., Cancer Res., 53: 3314-3320, 1993; Chai, et al., J Urol., 152: 374-378, 1994; Wientjes, et al., Cancer Chemother Pharmacol. 37: 539-546, 1996; Au, et al., J. Natl. Cancer Inst., 93: 597-604, 2001; U.S. Pat. No. 6,286,513 B1). The low drug delivery, in turn, was due to several reasons. First, only a fraction of the mitomycin C or doxorubicin dose, e.g., ˜3% to ˜5%, was able to penetrate the urothelium that lines the inner surface of the bladder cavity. Second, the concentration of the drug was diluted by the presence of residual urine when the drug was administered and by the urine produced during the treatment interval, e.g., 2 hours. Third, the total exposure of tumor cells to the drug, e.g., mitomycin C, was restricted to the length of the treatment interval due to the patient's need to empty his or her bladder. Fourth, the residence of the drug, e.g., mitomycin C, in the bladder tissue is dictated by the treatment duration and is largely terminated within minutes after the patient empties his or her bladder.
Based on these various considerations and discoveries, Applicants arrived at the conclusion that therapeutically useful intravesical chemotherapy can be accomplished, if the treatment satisfies some or most of the following desired properties. First, the drug should have activity against bladder cancer. Second, a large fraction of the drug present in the urine must be able to penetrate the urothelium. Third, the residence time of the drug in the bladder tissues should exceed the duration of the treatment. Fourth, the drug concentration in the urine should be independent of the urine volume. Paclitaxel is active against bladder cancer (Roth, B., J. Semin. Oncol., 22: 1-5, 1995) and, as shown by Applicants, readily partitioned across the urothelium, e.g., 50% of the dose (Song, et al., Cancer Chemother. Pharmacol., 40: 285-292, 1997). Applicants further discovered that paclitaxel is retained in tumor cells after removing drug from the extracellular matrix (Kuh, et al., J. Pharmacol. Exp. Ther., 293: 761-770, 2000), a property that offers the opportunity of extending drug action beyond the 2 hour treatment duration. However, the commercial paclitaxel formulation, e.g., Taxol®, is not useful, because the Cremophor used to solubilize paclitaxel, by entrapping paclitaxel in micelles, reduces the free fraction of paclitaxel and consequently lowers the drug penetration into the bladder tissue (Knemeyer, et al., Cancer Chemother. Pharmacol., 44: 241-248, 1999).
Applicants, therefore, invented paclitaxel-loaded nanoparticles that satisfy all of the desired properties identified in Applicants' discoveries. These nanoparticles release a significant fraction of the drug load within the 2-hour treatment interval, such that the paclitaxel concentration in the tissue is sufficient to produce antitumor activity in human bladder tumors (e.g., Example 8). The amount of paclitaxel released from the nanoparticles is limited by the drug solubility in the urine. Hence, the drug concentration in the urine remains relatively constant and is independent of the urine volume (e.g., Example 10). The paclitaxel released from the nanoparticles and penetrated into the bladder also is retained in the bladder tissues for periods extending beyond the 2-hour treatment duration (e.g., Example 8). Finally, Applicants determined that the nanoparticles were effective against naturally occurring bladder cancer in pet dogs (e.g., Example 10).
Applicants also disclose a method to modify the drug-loaded nanoparticles to prolong the retention of these particles in the bladder cavity or bladder tissues beyond the treatment duration, e.g., by coating the gelatin framework with bioadhesive molecules (e.g., Example 7).
Applicants further disclose that other lipophilic compounds can be formulated in the same gelatin nanoparticles.
Finally, Applicants disclose that intravenous administration of gelatin nanoparticles resulted in increased localization of the drug contents in the kidney (e.g., Example 11). Hence, methods and compositions for selective drug delivery to the kidney are also provided.
Definitions
In order to provide a clear and consistent understanding of the invention, certain terms employed in the specification, examples, and the claims are, for convenience, collected here.
As used herein, the term "aberrant growth" refers to a cell phenotype, which differs from the normal phenotype of the cell, particularly those associated either directly or indirectly with a disease such as cancer.
As used herein, the term "administering" refers to the introduction of an agent to a cell, e.g., in vitro, a cell in a mammal, i.e., in vivo, or a cell later placed back in the animal (i.e., ex vivo).
As used herein, the terms "agent", "drug", "compound", "anticancer agent", "chemotherapeutic", "antineoplastic", and "antitumor agent" are used interchangeably and refer to agent(s) (unless further qualified) that have the property of inhibiting or reducing aberrant cell growth, e.g., a cancer. The foregoing terms are also intended to include cytotoxic, cytocidal, or cytostatic agents. The term "agent" includes small molecules, macromolecules (e.g., peptides, proteins, antibodies, or antibody fragments), and nucleic acids (e.g., gene therapy constructs), recombinant viruses, nucleic acid fragments (including, e.g., synthetic nucleic acid fragments).
As used herein, the term "apoptosis" refers to any non-necrotic, well-regulated form of cell death, as defined by criteria well established in the art.
As used herein, the terms "benign", "premalignant", and "malignant" are to be given their art recognized meanings.
As used herein, the terms "cancer", "tumor cell", "tumor", "leukemia", or "leukemic cell" are used interchangeably and refer to any neoplasm ("new growth"), such as a carcinoma (derived from epithelial cells), adenocarcinoma (derived from glandular tissue), sarcoma (derived from connective tissue), lymphoma (derived from lymph tissue), or cancer of the blood (e.g., leukemia or erythroleukemia). The term cancer or tumor cell is also intended to encompass cancerous tissue or a tumor mass which shall be construed as a compilation of cancer cells or tumor cells. In addition, the term cancer or tumor cell is intended to encompass cancers or cells that may be either benign, premalignant, or malignant. Typically a cancer or tumor cell exhibits various art recognized hallmarks such as, e.g., growth factor independence, lack of cell/cell contact growth inhibition, and/or abnormal karyotype. By contrast, a normal cell typically can only be passaged in culture for a finite number of passages and/or exhibits various art recognized hallmarks attributed to normal cells (e.g., growth factor dependence, contact inhibition, and/or a normal karyotype).
As used herein, the term "cell" includes any eukaryotic cell, such as somatic or germ line mammalian cells, or cell lines, e.g., HeLa cells (human), NIH3T3 cells (murine), embryonic stem cells, and cell types such as hematopoietic stem cells, myoblasts, hepatocytes, lymphocytes, and epithelial cells and, e.g., the cell lines described herein.
As used herein, the terms "peritoneal", "intraperitoneal", "peritoneally", or "intraperitoneally" are used interchangeably, and are related to the peritoneal or abdominal cavity.
As used herein, the terms "locally", "regionally", "systemically" refer to, respectively, the administration of a therapy "locally", e.g., into a tumor mass, "regionally", e.g., in a general tumor field or area suspected to be seeded with metastases, or "systemically" e.g., orally or intravenously with the intent that the agent will be widely disseminated throughout the subject.
As used herein, the term "pharmaceutically acceptable carrier" is art recognized and includes a pharmaceutically acceptable material, composition or vehicle, suitable for administering compounds of the present invention to mammals.
As used herein, the term "pharmaceutical composition" includes preparations suitable for administration to mammals, e.g., humans. When the compounds of the present invention are administered as pharmaceuticals to mammals, e.g., humans, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient (e.g., a therapeutically-effective amount) in combination with a pharmaceutically acceptable carrier.
As used herein, the term "subject" is intended to include human and non-human animals (e.g., mice, rats, rabbits, cats, dogs, livestock, and primates). Preferred human animals include a human patient having a disorder characterized by aberrant cell growth, e.g., a cancer.
As used herein, the term "microparticles" refers to particles of about 0.1 μm to about 100 μm about 0.5 μm to about 50 μm, 0.5 μm to about 20 μm in size, advantageously, particles of about 1 μm to about 10 μm in size, about 5 μm in size, or mixtures thereof. The microparticles may comprise macromolecules, gene therapy constructs, or chemotherapeutic agents, for example. Typically microparticles can be administered locally or regionally, for example.
As used herein, the term "nanoparticles" refers to particles of about 0.1 nm to about 1 μm, 1 nm to about 1 μm, about 10 nm to about 1 μm, about 50 nm to about 1 μm, about 100 nm to about 1 μm, about 250-900 nm in size, or, advantageously, about 600-800 nm. The nanoparticles may comprise macromolecules, gene therapy constructs, or chemotherapeutic agents, for example. Typically, nanoparticles can be administered to a patient via local, regional, or systemic administration.
As used herein, the term "particles" refers to nanoparticles, microparticles, or both nanoparticles and microparticles.
As used herein, the term "formulation" refers to the art-recognized composition where a therapeutically active agent is incorporated in a dosage form.
As used herein, the terms "fast-release formulation" and "rapid-release formulation" refer to a formulation of a drug which releases preferably >10%, more preferably >20%, more preferably >30%, more preferably >40%, more preferably >50%, and even more preferably >60% of its drug contents within one day. Examples of fast-release formulations include microparticle and nanoparticle formulations. Methods used to prepare these formulations are described in Examples 3 and 7.
As used herein, the term "slow-release formulation" refers to a formulation of a drug wherein the drug is delivered to a site of interest for a sustained period of time and includes formulations which maintain release of its drug contents preferably for several days, more preferably several weeks or longer.
As used herein, the term "tumor priming method" refers to a method of enhancing the penetration of a therapeutic drug by "priming" the tumor with an apoptosis inducing agent to decrease tumor cell density and increase therapeutic agent accessibility to the tumor mass. This method involves the use of an apoptosis inducing agent, such as paclitaxel, in doses and for periods of time sufficient to cause apoptosis in the tissue to thereby allow for enhanced penetration of the tumor therapeutic agent (or simply "therapeutic agent") into the tissue (e.g., by creating channels within the tissues). Thus, the apoptosis inducing agent is used as a pretreatment before the therapeutic dose of the therapeutic agent is delivered to the tissue, and this pretreatment allows for enhanced penetration of the therapeutic agent into the tissue as compared to when the pretreatment is not used. The apoptosis inducing agent may also have therapeutic activity and thus may also be used as the therapeutic agent (i.e., the same drug may be used as the apoptosis inducing agent and the therapeutic agent). Alternatively, the apoptosis inducing agent may be used to enhance delivery of other types of drugs or vehicles for treatment into tissues (i.e., the apoptosis inducing agent and the therapeutic agent may be different drugs, or the therapeutic agent may be contained in nanoparticles or microparticles, where the delivery of the nanoparticles or microparticles to the tumor tissue is enhanced, compared to when the pretreatment is not used).
As used herein, the term "PLGA", or "poly(lactide-co-glycolide)" refers to a copolymer consisting of various ratios of lactic acid or lactide (LA) and glycolic acid or glycolide (GA). The copolymer can have different average chain lengths, resulting in different internal viscosities and differences in polymer properties. PLGA is used for the preparation of microparticles or nanoparticles, usually containing therapeutic agents. Methods used to prepare these particles are described in Example 3.
As used herein, the term "gelatin" refers to a denatured form of the connective tissue protein collagen. Gelatin aggregates, formed in solution, are stabilized by cross-linking the protein chains. Using the preparation method of Example 7, gelatin forms gelatin nanoparticles, usually loaded with paclitaxel. Gelatin is available in different protein chain lengths, indicated by different Bloom numbers. Larger Bloom numbers indicate longer chain lengths.
As used herein, the term "IC50" refers to the drug concentration or dose that results in 50% of the drug effect.
As used herein, the term "burst release" refers to the art-recognized definition of the initial, rapid release of a fraction of the drug load from a formulation, which is typically followed by a slower release of the remainder of the drug load.
As used herein, the terms "localize" and "concentrate" are used interchangeably, to indicate the preferential distribution at a specific site, e.g., tumor tissues.
As used herein the term "bioadhesive" means natural, synthetic or semi-synthetic substances that adhere and preferably strongly adhere to a surface such as skin, mucous membrane, and tumor. Suitable bioadhesives include poly(lysine), fibrinogen, those prepared from partially esterified polyacrylic acid polymers, including polyacrylic acid polymers, natural or synthetic polysaccharides such as cellulose derivatives including methylcellulose, cellulose acetate, carboxymethylcellulose, hydroxyethylcellulose, pectin, and a mixture of sulfated sucrose and aluminum hydroxide.
As used herein, the term "interstitial cystitis" refers to the art-recognized medical condition of chronic, painful inflammatory condition of the bladder wall. As used herein, the terms "biodegradable" or "bioerodible" polymer refer to polymers that can degrade into low molecular weight compounds, which are known to be involved normally in metabolic pathways. The terms also include polymer systems which can be attacked in the biological milieu so that the integrity of the system, and in some cases of the macromolecules themselves is affected and gives fragments or other degradation by-products which can move away from their site of action, but not necessarily from the body.
Broad Statement of the Invention
A composition for delivering a tumor therapeutic agent to a patient, which includes a fast-release formulation of a tumor apoptosis inducing agent, a slow-release formulation of a tumor therapeutic agent, and a pharmaceutically acceptable carrier. An apoptosis inducing agent in a pharmaceutically acceptable carrier may be administered before or concomitantly therewith. Nanoparticles or microparticles (e.g., cross-linked gelatin) of the therapeutic agent (e.g., paclitaxel) also may be used. The nanoparticles or microparticles may be coated with a bioadhesive coating. Microspheres that aggregate to block the entrance of the lymphatic ducts of the bladder to retard clearance of the microparticles through the lymphatic system also may be employed.
This invention also uses drug-loaded gelatin and poly(lactide-co-glycolide) (PLGA) nanoparticles and microparticles to target drug delivery to tumors in the peritoneal cavity, bladder tissues, and kidneys.


When an AC power supply (9) is powered up, a constant current supply section (14) supplies a constant current to a capacitor (C3) to charge the capacitor (C3). When a voltage across the capacitor (C3) becomes equal to or greater than a predetermined voltage, a switch control section (17) sets a switch (13) off. When an output current drops to lead to a light load, a load detecting circuit (15) stops the operation of a PWM control circuit (12) and activates a timer (16). The timer (16) supplies a switch-ON signal to the switch control section (17) when it is activated and a predetermined time measured elapses. When supplied with the switch-ON signal, the switch control section (17) sets the switch (13) on. When the switch (13) is set on, the capacitor (C3) is charged again, applying a voltage to the PWM control circuit (12).

There is a case where some of electronic devices are standing by to be ready to return to the normal operation state. In such a standby state, power is hardly consumed. There is a case where a power supply which supplies power to an electronic device as a load should be stopped if power is not consumed, from viewpoints of reduction in power consumption and noise.
Such a power supply, which determines that a loadless state has come when the current to be supplied to a load becomes smaller, and stops supplying the input voltage to achieve low power consumption, is disclosed in, for example, Unexamined Japanese Patent Application KOKAI Publication No. H2-294267.
If the power supply is not activated, however, the current does not flow in the load, which is the same as the loadless state. Once such a conventional power supply goes into a standby state, therefore, the power supply will never be activated unless an activation signal to activate the power supply is supplied from outside. In other words, the conventional power supply should be supplied with the activation signal from outside, and such a method cannot be adapted to one which cannot be supplied with the activation signal from outside.


The invention is directed to a method for controlling a coordinate measuring apparatus wherein the probe head (2) and the probe pin (19) of the apparatus are control driven in accordance with desired data Pi. The probe pin (19) is movably attached to the probe head (2). In the method, the probe pin for measuring the workpiece (15) can touch down on the surface of the workpiece to be measured or can be lifted off of this surface. The speed of measurement is increased by selecting the angle (.alpha.down, .alpha.up) between the direction of movement vres of the probe head (2) when touching down or when lifting off and the projection of the direction of movement toward the plane tangential to the workpiece surface in the touchdown/liftoff point (Pdown, Pup) to be less than 30.degree..

A method of the above kind is, for example, disclosed in U.S. Pat. No. 5,471,406. In this known method, the geometric data of geometric elements of the workpiece are transferred by a computer to the control system of the coordinate measuring apparatus. In the control system, the geometric data are transferred to the machine coordinate system and transmitted to an interpolator in the control system which generates the position desired values along which the probe head of the coordinate measuring apparatus is control driven. The position desired values are generated in such a manner that the probe head and the probe pin of the coordinate measuring apparatus is moved from an actual position, which lies outside of the surface of the workpiece on a straight line to the first contact point where the probe pin (that is, the probe ball attached to the probe pin) touches down on the surface of the workpiece. The probe pin deflection is so controlled that it corresponds to a preselected probe pin deflection. Thereafter, and in a next step, the measurement of the workpiece to be measured is recorded.
Particular to the method is that the probe head must first come to a complete standstill before the actual measuring operation can begin because, to measure the first contact point (that is, the start point of the measurement), a defined probe pin deflection must be set. In the same manner, the probe pin in conventional methods would be braked to a complete standstill at the end of the scanning operation and then brought via different straight line paths to the next scan point. Here too, the probe head is braked to standstill because of the transition from one straight line path to a new straight line path which is at an angle to the first straight line path.

Coordinate measuring apparatus and method for controlling the same


An infrared temperature sensor including: a sensor case made of metal and including a first airspace (a light guiding region) that guides infrared rays entering from an infrared entrance window, and a second airspace (a light shielding region) that is adjacent to the light guiding region via a partition wall, and where an upper wall that blocks entrance of the infrared rays is formed on an entrance side of the infrared rays; a film that absorbs the infrared rays reaching the film through the light guiding region, and converts the infrared rays to heat; a sensor cover that is made of metal and arranged opposing the sensor case via the film; an infrared detection element and a temperature compensation element arranged on the film, wherein the light guiding region and the light shielding region have substantially symmetrical forms with respect to the partition wall.

As a toner fixing device for use in an image forming apparatus such as a copy machine and a printer, a device using a fixing method of heating unfixed toner while moving a recording paper after forming a toner image to be held on the recording paper corresponding to image information by an electrophotographic operating process is generally used.
The fixing device fuses the toner (made of a resin material, a magnetic material, and a colorant) by moving the recording paper and the toner held on the recording paper by static electricity while sandwiching the recording paper and the toner between fixing means composed of a roller that conveys the recording paper and the toner while rotating, and pressurizing means composed of a roller that rotates in an opposite direction from the fixing means in press contact therewith and applying heat and pressure thereto, and thereby fixes the toner onto the recording paper.
A temperature of the roller greatly affects an image quality. Thus, the temperature of the roller is controlled by detecting a temperature of a roller surface by using a sensor.
There is known an infrared temperature sensor which detects the temperature of the roller in a non-contact manner so as to avoid damage to the roller of the fixing device (e.g., Patent Literatures 1 and 2). The infrared temperature sensor includes an infrared detection element and a temperature compensation element, so that the infrared detection element detects a heat emission amount of infrared rays from the roller as the fixing means that is an object to be detected, and the temperature compensation element further detects an atmosphere temperature to perform temperature compensation, thereby specifying the temperature of the object to be detected.

Infrared temperature sensor and fixing device using the same


This soapbox is capable of draining wet bar soaps very quickly and efficiently and keeps water away from the surface of the bar soap. The unique design of the soap rack and its rack-bars keep the soap bar significantly dry and minimizes the wastage of soap. After its use, the bar soap will be conveniently stored in a compact, watertight box without the worry of spoiling the surroundings with the soapy water.

Ever since the discovery of bar soap, inventors are trying to develop a soapbox that can drain, dry and store the soaps without any wastage. Traditionally, soapboxes are designed to have short ribs, raised ridges, dowels, grills or racks to support the wet bar soaps above the floor of the soap box/dish.
In almost all the cases, the bars which support the bar soaps are flat, rectangular or circular in cross-section and they are not efficient to drain the water away from the wet soap surface. Water sticks to the bottom surface of the soap between the bars and slowly soaks the outer layer of the soap surface.
Most of the conventional soapboxes are designed to support soap bars in the horizontal position and due to the lack of any slope, water is retained on the top surface of the soap and this water slowly soaks the top surface of the soap. When the top surface of the soap is soaked, a thin film of soapy paste will be formed which in turn will retain some more water and damage the soap further.
Some of the designs like U.S. Pat. Nos. 5,253,752 and 5,232,189 employed the concept of inclined supporting members to support the wet soaps but these supporting members are too far apart to restrain the soap in position without falling between the members and touching the floor of the container. When the soap touches any part of the soap dish, the water will be trapped between the surfaces and the soap starts absorbing the water and starts to dissolve. Moreover, these designs were developed for the soap dishes to be supported on the walls or showerheads with elaborate system and are not adaptable for the compact boxes. The inventor did not find any patents that utilize the inclined supporting structure for the compact soapboxes.
In most soapbox designs, the space between the wet soap and the floor of the container is not designed to adequately drain the soapy water collected from the soap. Some of the containers are provided with small holes or narrow slots but they are not effective when the inverted top cover is placed under the bottom dish. Additionally, these holes or slots help the soapy water to escape from the box and create a mess during the storage stage. Apart from this, a large surface area of the soap touches the bottom of the perforated container and the water will thus be trapped between soap and the box bottom. When the wet bar soap touches any other surface, water will be retained between the surface and the soap. This retained water will be absorbed by the soap to form a soft paste.
Most soapboxes are not designed to tolerate any accidental overfill and when the shower water fills the box, the water will submerge the soap and destroy the soap.


A gas lance made of a fireproof material, having an entry surface and an exit surface, having channels having slit-shaped cross-section, which comprise an entry slit and an exit slit. In order to provide a gas lance in which the gas exits in such a manner that a good thorough mixing of the melt is achieved and a simple penetration of the melt by the gas is avoided, the projection of the exit slit of a channel onto the entry surface may be offset in relation to the entry slit of the channel.

Gas lances are used in metallurgical melt vessels, such as converters or ladles, in order to treat the melt contained therein by blowing in gases, e.g. CO2. The streaming gas is supposed in particular to cause turbulence, thus causing a thorough mixing of the melt. The gases flow past the entry surface, which preferably faces the floor of the metallurgical vessel, into the gas lance, and exit at the exit surface. The gas lance is integrated into the fireproof lining of the melt vessel.
The gas lance can on the one hand be made of a porous fireproof material, so that the gas flows through the lance as a whole, thus resulting in a finely distributed flow of gas inside the melt. On the other hand, channels can also be situated in the gas lance via which the gas is distributed in the melt.
From DE 36 25 117 C1, on which the present invention is based, a gas lance is known that is fashioned as a truncated cone and has slit-shaped channels running parallel to the axis of the truncated cone whose cross-sections point radially outward in a star-shaped pattern. In addition, the channels taper towards the exit surface in such a way that the length of the slit-shaped cross-section of the channels decreases.
A disadvantage of a gas lance of this type is that there is the risk there will take place merely a penetration of the gas through the melt column situated over the exit opening. In such a case, there will not be a turbulence of the melt; rather, the melt will remain essentially at rest. The desired mixing effect is then not achieved.


A method which exploits the phenomenon that an increase of the collector-emitter voltage U.sub.CE of a semiconductor power component during a load change test can be correlated with the service life expectancy of the relevant IGBT module. A method for estimating the service life of a power semiconductor component, comprising the steps of subjecting the component to a periodic load change, measuring an electrical parameter P of the component that serves as an indicator for reliability or durability against the number N of load changes, calculating a derivative dP/dN of the electrical parameter P according to the number N of load changes; and comparing the derivative dP/dN with a target value representing a determined service life. The characteristic "longer-lived than a reference module" or, respectively, "more resistant to failure" can be allocated to a test module if the derivatives of the respective voltage U.sub.CE satisfy the condition (dU.sub.CE /dN).sub.Test <(dU.sub.CE /dN).sub.Ref after the number N of load changes.

Due to their excellent electrical characteristics and comparatively simply constructed trigger electronics, IGBT (Isolated Gate Bipolar Transistor) power semiconductor modules increasingly are being used, even in failure-critical systems. Since traction control units of track-bound vehicles (locomotives, streetcars and subway trains, etc.) are often subjected to large mechanical and thermal stresses during their often decades-long service life, the users place the highest demands on the reliability and service life of the IGBT modules used.
Currently, there is no standardized method for testing the reliability of IGBT power semiconductor modules. A group of research institutes, manufacturers and users has concerned itself with this problem, and has discussed a corresponding test method. See, Proceedings of the 20th International Symposium for Testing and Failure Analysis, Los Angeles, Nov. 13-18, 1994, pp. 319-325, incorporated herein by reference.
According to the recommendations of this group, an IGBT module should be subjected to a plurality of load changes under defined conditions, and, in particular, should be rated as defective or faulty when the collector-emitter voltage (U.sub.CEsat), measured after several thousand cycles, deviates from an initial value by more than a predetermined percentage (20% divided by the number of chips in the module). Even if this condition is relaxed and a drop off of 10% below the initial voltage is still tolerated, in long-life modules the corresponding degradation first arises after some hundreds of thousands of load changes. Since the duration of the cycle (t.sub.on +t.sub.out) is typically in the range from about 10 to 20 seconds, the test of reliability/service life requires a measurement time of several weeks or even months, which is far too long for routine control in production.
A method for testing the reliability of electronic components specified in H. Koschel, et al., Zeitraffende Zuverlassigkeitsprufungen an Transistoren; offprint from Nachrichtentechnische Zeitschrift, No. 5 (1964), incorporated by reference, rests on the assumption that an increase in the loading of a test object results in an acceleration of the failure mechanism. As long as the failure mechanism is maintained, the test time can then be shortened corresponding to what is called an acceleration curve. The individual points of the acceleration curve are obtained from a plurality of failure distribution curves, measured respectively from samples of test objects, using a mathematical model that approximately describes the expected distribution of the service life.

Method for estimating the service life of a power semiconductor component


A battery capable of obtaining a high energy density and obtaining superior cycle characteristics is provided. The thickness of a cathode active material layer is from 100 μm to 130 μm. The thickness of an anode active material layer is from 85 μm to 120 μm, and the volume density of the anode active material layer is from 1.7 g/cm3 to 1.85 g/cm3. An electrolytic solution contains 4-fluoro-1,3-dioxolane-2-one. Thereby, even when the thicknesses of the cathode active material layer and the anode active material layer are increased, the diffusion and acceptance of lithium in an anode are improved, and superior cycle characteristics can be obtained.

1. Field of the Invention
The present invention relates to a battery using a carbon material as an anode active material.
2. Description of the Related Art
In recent years, downsizing and weight saving of portable electronic devices represented by a mobile phone, a PDA (Personal Digital Assistant), and a notebook personal computer have been actively promoted. As a part thereof, improving an energy density of a battery as a driving power source for such electronic devices, in particular, of a secondary battery has been strongly desired.
As a secondary battery capable of providing a high energy density, for example, the secondary batteries using lithium (Li) as an electrode reactant are known. Specially, the lithium ion secondary batteries using a carbon material capable of inserting and extracting lithium for the anode are widely used practically. However, in the lithium ion secondary battery using the carbon material for the anode, the technology has been already developed to the degree close to its theoretical capacity. Therefore, as a method to further improve the energy density, it has been considered that the thickness of the active material layer is increased to increase the ratio of the active material layer in the battery, and the ratios of the current collector and the separator are lowered (refer to Japanese Unexamined Patent Application Publication No. 9-204936).

Electrolytic solution containing 4-fluoro-1, 3-dioxolane-2-one solvent


An exhaust control device for an internal combustion engine, comprises: a NOx purifying catalyst disposed in an exhaust system; and a rich control means for calculating a fuel injection amount based on a difference between a target exhaust air fuel ratio and an actual exhaust air fuel ratio to feedback-control the actual exhaust air fuel ratio so that a reducing atmosphere is created in the exhaust system to thereby reduce NOx trapped by the NOx purifying catalyst, wherein the rich control means includes a learning means for calculating and updating a control correction value of the fuel injection amount based on an actual control value of the fuel injection amount during the feedback control, and wherein the fuel injection amount is calculated during the feedback control by using the control correction value.

The exhaust passage of a diesel engine is sometimes fitted with a lean NOx catalyst (referred to as LNC hereinafter) for reducing and eliminating nitrogen oxides (referred to as NOx hereinafter) in the exhaust gas, where the NOx is particularly generated in a large amount in lean combustion.
The LNC functions to trap (more specifically adsorb) NOx in an oxidizing atmosphere where an exhaust air fuel ratio is higher than a prescribed value (referred to as "lean" hereinafter) and reducing the trapped NOx into a harmless form in a reducing atmosphere where the exhaust air fuel ratio is lower than the prescribed value (referred to as "rich" hereinafter). The NOx purification ability of the LNC tends to decrease as the amount of trapped NOx increases. Therefore, in order to avoid saturation of amount of NOx trapped by the LNC, a process for regenerating the LNC is conducted by executing a rich spike control from time to time to make the exhaust air fuel ratio rich and reduce the NOx trapped by the LNC.
In the rich spike control, the reducing atmosphere is created in the exhaust system by decreasing an amount of air intake by restricting the opening of the intake control valve and/or increasing an amount of exhaust gas recirculation (EGR) than in a usual operation, and at the same time increasing an amount of fuel injection. It is common that the fuel injection amount is feedback-controlled such that an actual value of exhaust air fuel ratio detected by an O2 sensor or the like approaches a target value.
During the rich spike control, in order to shorten the time period from the start of control to the convergence of the exhaust air fuel ratio to the target value, it is conceivable to add, depending on an actual amount of air intake, a predetermined increment of fuel injection (feedforward term) to the current amount of fuel injection, in addition to an increment of fuel injection (feedback term) that is feedback-controlled based on a difference between the target and actual values of exhaust air fuel ratio. The actual amount of air intake may be measured by an air flow meter.
However, because characteristics of some component parts such as the air flow meter, fuel injection valve or the like may differ from one to another and also may change with time, the predetermined value of the feedforward term can be or become inappropriate, and this can result in unsatisfactory control accuracy and response characteristics, which in turn can lead to increased emission in the exhaust gas and lower fuel economy.
In order to cope with such problems and thereby improve the response characteristics in the rich spike control, Japanese Patent Application Laid-Open Publication No. 2002-201985 has proposed to conduct a stoichiometric (referred to as "stoic" hereinafter) combustion at a constant interval and learn a correction value used in the feedback control.
However, in the technique disclosed in JPA 2002-201985, it is necessary to conduct the stoic combustion only for the purpose of learning the correction value and this can deteriorate the fuel economy and/or drive characteristics. Further, the learning is not always possible and requires a certain time period of stationary driving in order to maintain desired control accuracy, and thus the opportunities for learning are inconveniently limited.

Exhaust control device for an internal combustion engine