When a grommet provided with a wire insertion tubular portion is mounted in a through-hole of a vehicle body panel by engaging a vehicle body engagement recess on an outer periphery of the grommet with a peripheral edge of the through-hole, the present invention prevents the wire insertion tubular portion from being caught by the peripheral edge of the through-hole, bending toward the vehicle body engagement recess side, and being wedged in between the peripheral edge of the through-hole and the vehicle body engagement recess, and thus enables the grommet to be securely mounted in the through-hole. A rib is provided between an outer peripheral surface on a central axis line side of a wire insertion tubular portion and a peripheral wall of a central tubular portion in order to reinforce a base on the central axis line side of the wire insertion tubular portion.

Conventionally, a grommet is externally fitted to a wire harness routed from an engine compartment to a passenger cabin in an automobile and is mounted in a through-hole in a vehicle body panel that partitions the engine compartment and the passenger cabin. Thereby, the wire harness inserted to the through-hole is protected, and water, dust, and sound are prevented from leaking from the engine compartment side to the passenger cabin. Further, in many cases, wire materials routed from the engine compartment to the passenger cabin, such as a hood opener cable for opening a hood, a washer hose, a circuit for dealer options, and the like, are inserted through the grommet.
Examples of grommets of this type include a grommet described in Japanese Patent Laid-Open Publication No. 2009-296741 (Patent Literature 1). As shown in FIGS. 7 to 9, a grommet 1 includes a small diameter tubular portion 2 and a large diameter tubular portion 3. The small diameter tubular portion 2 has a central through-hole 2a to which a wire harness W/H is snugly inserted. The large diameter tubular portion 3 is externally fitted so as to be concentric with the small diameter tubular portion 2 and to have a space between an increased diameter side of the large diameter tubular portion 3 and an outer peripheral surface of the small diameter tubular portion 2. On an outer peripheral surface of the increased diameter end side of the large diameter tubular portion 3, a vehicle body engagement recess 4 is provided to engage with a peripheral edge 7a of a through-hole 7 in a vehicle body panel 6 partitioning an engine compartment (X) and a passenger cabin (Y). In addition, a wire insertion tubular portion 5 projects toward a decreased diameter end side from a position off a center of the large diameter tubular portion 3, the wire insertion tubular portion 5 having a wire material, such as an opener cable, a washer hose, or the like, inserted therethrough. While a tip of the wire insertion tubular portion 5 is a closed end, a rib-shaped cut line 5a indicating a position to cut and open up the closed end is provided on an entire periphery of the wire insertion tubular portion 5. Accordingly, the closed end of the wire insertion tubular portion 5 can be opened up by making a cut at the cut line 5a when the wire material such as the cable, the hose, or the like is to be inserted.
The grommet 1 attached to the wire harness W/H is simply pressed into the through-hole 7 of the vehicle body panel 6 with the decreased diameter end side first in a direction from an engine compartment (X) to a passenger cabin (Y), as shown with arrows in FIG. 8(A). The vehicle body engagement recess 4 of the grommet 1 thus engages with the peripheral edge 7a of the through-hole 7, as shown in FIG. 8(B), and thereby, mounting of the grommet 1 in the through-hole 7 is completed.
When the grommet 1 is mounted in the through-hole 7, however, it is difficult to straightly insert the grommet 1 such that a central axis line of the grommet 1 is aligned with an axis line of the through-hole 7. The grommet 1 is thus often in a shifted state to some extent when inserted. In such a case, when the through-hole 7 is a hole having a burr, the rib-shaped cut line 5a of the wire insertion tubular portion 5 may be caught by the projecting peripheral edge 7a, as shown in FIG. 9. Accordingly, the wire insertion tubular portion 5 may bend toward the vehicle body engagement recess 4 side and be wedged in between the peripheral edge 7a of the through-hole 7 and the vehicle body engagement recess 4. Such wedging of the wire insertion tubular portion 5 causes an incomplete fitting between the vehicle body engagement recess 4 of the grommet 1 and the peripheral edge 7a of the through-hole 7, resulting in an unsecured mounting of the grommet 1 in the through-hole 7.


Provided is a composition of detection agents for living cells, especially epithelial tumor cells; the composition contains 0-5% folic acid, 0-10% folic acid complex, 0.01-5% methylene blue, 0.1-10% carbohydrate reducing agent, 2-6% acetic acid, and 3-95% water. Also provided is a preparation method for the composition of detection agents and kits containing the composition of detection agents.

Currently, methods for vital staining of human epithelial tumor cells primarily include methods based on acetowhite test, iodine test, toluidine blue test, methylene blue staining, hematoxylin staining and the like.
Specifically, the acetowhite test is to smear acetic acid solution, for example, 3˜5% acetic acid solution, on the cervical/vaginal epithelial tissue, and observe whether there is any acetowhite responsive region in the smeared epithelial tissue after waiting for some time. If there is any acetowhite region, this epithelial tissue is suspected to contain tumor cells. However, although this method has high sensitivity, its specificity is poor, that is because besides tumor cells, some inflammatory cells can also generate acetowhiteness, thereby producing false positive results. Moreover, the specificity of this method is heavily affected by the operator's skill level and experience.
The mechanism of the iodine test is reaction with glycogen. It involves smearing Lugol's iodine on cervical epithelial tissues and detecting by observing the iodine staining of the epithelial cells, in which normal epithelium exhibits red-brown or black, whereas abnormal epithelium exhibits thick mustard yellow or yellowish brown. However, if there is epithelial inflammation, these regions may not be stained by iodine, or exhibit colorless loading. Therefore, iodine test has poor specificity on the staining of the epithelial cells[1].
Methods using toluidine blue may cause the staining of the nuclear debris of neutrophils and bacterial, resulting in high false positive rate. It is also difficult to stain cancer and leukoplakia with surface keratinization, which tends to cause false negative[2].
After staining of epithelial tissues with hematoxylin, a high power microscope is needed for observation with complicated operation and high requirements on the expertise and experience of the operator, as well as long inspection time.
The affinity between methylene blue and cancer cells makes malignant tissues prone to blue staining. It is reported that using it for in situ biopsy sampling of esophageal epithelial tissues has the effect of improving positive rate of biopsy[3]. However, there is no report in the art to combine the redox color change reaction of methylene blue with folic acid or folic acid complex so as to rapidly locate and detect epithelial tumor cells by staining and color change reaction.
A composition for detecting epithelial tumor cells, especially, for cervical/vaginal epithelial tissue tumor cells by staining and color change which has high sensitivity, high specificity and simple and rapid operation is urgently needed in the art.

Composition of detection agents for epithelial tumour cells and preparation method therefor


A method of transmitting an uplink (UL) control signal of a relay station is provided. The method includes: configuring a UL relay zone for transmitting a signal by the relay station to a base station in a frame; configuring a resource unit including a plurality of symbols and a plurality of subcarriers to allocate the UL control signal in a subframe of the UL relay zone; and transmitting the UL control signal by using the resource unit, wherein, if a transition gap required for switching of signal transmission and reception of the relay station is included in the subframe, the UL control signal is transmitted in the remaining symbols other than the plurality of symbols constituting the resource unit including the transition gap.

1. Field of the Invention
The present invention relates to wireless communications, and more particularly, to a method and apparatus for transmitting an uplink control signal of a relay station in a wireless communication system.
2. Related Art
The institute of electrical and electronics engineers (IEEE) 802.16e standard was adopted in 2007 as a sixth standard for international mobile telecommunication (IMT)-2000 in the name of 'WMAN-OFDMA TDD' by the ITU-radio communication sector (ITU-R) which is one of sectors of the international telecommunication union (ITU). An IMT-advanced system has been prepared by the ITU-R as a next generation (i.e., 4th generation) mobile communication standard following the IMT-2000. It was determined by the IEEE 802.16 working group (WG) to conduct the 802.16m project for the purpose of creating an amendment standard of the existing IEEE 802.16e as a standard for the IMT-advanced system. As can be seen in the purpose above, the 802.16m standard has two aspects, that is, continuity from the past (i.e., the amendment of the existing 802.16e standard) and continuity to the future (i.e., the standard for the next generation IMT-advanced system). Therefore, the 802.16m standard needs to satisfy all requirements for the IMT-advanced system while maintaining compatibility with a mobile WiMAX system conforming to the 802.16e standard.
An orthogonal frequency division multiplexing (OFDM) system capable of reducing inter-symbol interference (ISI) with a low complexity is taken into consideration as one of next generation wireless communication systems. In the OFDM, a serially input data symbol is converted into N parallel data symbols, and is then transmitted by being carried on each of separated N subcarriers. The subcarriers maintain orthogonality in a frequency dimension. Each orthogonal channel experiences mutually independent frequency selective fading, and an interval of a transmitted symbol is increased, thereby minimizing inter-symbol interference. In a system using the OFDM as a modulation scheme, orthogonal frequency division multiple access (OFDMA) is a multiple access scheme in which multiple access is achieved by independently providing some of available subcarriers to a plurality of users. In the OFDMA, frequency resources (i.e., subcarriers) are provided to the respective users, and the respective frequency resources do not overlap with one another in general since they are independently provided to the plurality of users. Consequently, the frequency resources are allocated to the respective users in a mutually exclusive manner.
In an OFDMA system, frequency diversity for multiple users can be obtained by using frequency selective scheduling, and subcarriers can be allocated variously according to a permutation rule for the subcarriers. In addition, a spatial multiplexing scheme using multiple antennas can be used to increase efficiency of a spatial domain. In order to support the various schemes described above, a control signal must be transmitted between a mobile station (MS) and a base station (BS). Examples of the control signal include a channel quality indicator (CQI) for reporting a channel state from the MS to the BS, an acknowledgement/not-acknowledgement (ACK/NACK) signal in response to data transmission, a bandwidth request signal for requesting allocation of a radio resource, precoding information in a multiple antenna system, antenna information, etc. The control signal is transmitted through a control channel.
Meanwhile, a wireless communication system employing a relay station (RS) has recently been developed. The RS is employed for cell coverage extension and transmission capability improvement. A BS provides a service to an MS located in a coverage boundary of the BS via the RS, and thus can obtain an effect of extending the cell coverage. In addition, the RS improves signal transmission reliability between the BS and the MS, thereby improving transmission capacity. Even if the MS is located inside the coverage of the BS, the RS may be used when the MS is located in a shadow area.
The wireless communication system employing the RS requires a new frame structure different from the conventional frame structure. A frequency band used when the RS transmits a signal to the BS may be equal to a frequency band at which a signal is received from a relay MS. Alternatively, the frequency band used when the RS receives the signal from the BS may be equal to a frequency band at which a signal is transmitted to the relay MS. Due to self interference, it is difficult for the RS to simultaneously perform transmission and reception of a signal at the same frequency band. Therefore, a time for switching an operation mode between transmission and reception of the signal is required. In general, it is assumed that the RS cannot transmit or receive the signal during the operation mode switching time. Some subframes included in an RS frame may include a symbol used as a transition gap by considering the operation mode switching time. In this symbol, the RS cannot transmit an uplink control signal.
Therefore, when the conventional method of transmitting the uplink control signal between the BS and the MS is equally used between the BS and the RS, a problem may occur due to the transition gap. For example, there may be a problem in multiplexing of an uplink control signal transmitted by the RS and an uplink control signal transmitted by the MS or in maintaining orthogonality of multiplexed signals.
Accordingly, there is a need for a method of transmitting the uplink control signal by the RS to the BS in the RS frame including the transition gap.

Method and apparatus for transmitting uplink control signal in relay station


A system and method for replaying the activity on request to individuals and to the group at large within a virtual reality (VR) arena for training and efficiency improvement purposes from within the VR system or outside is disclosed. The virtual reality (VR) system does real time tracking and response feedback to the players, using light markers and cameras connected to multiple slave-server systems that are controlled by a master-server. The hierarchical data collection system collects all the activity and tracking data from the arena. The master-server combines and correlates all the data collected from the VR arena and sends that to the game-server to be saved in a dedicated storage memory coupled to the game server. This data is then played back as VR play back on request to individuals or to all players and supervisory staff within or outside the VR arena for training and efficiency improvement purposes.

Field
This invention relates to the field of virtual reality (VR) or augmented reality (AR) and, in particular to systems and methods which track object locations and activity using colored tracking marker lights and multiple color cameras, where in the tracked activity can be saved and replayed for review and training.
Related Art
Virtual reality (VR) and Augmented reality (AR) are currently improving by leaps and bounds. The virtual reality and augmented reality ideas have long been considered the best tools for training individuals especially where the actual training sites are not available or accessible.
The problem is also the lack of tools that can present a realistic practice training background at a cost that is reasonable. Though virtual reality systems have been adopted for use in training, for flight simulators, hazardous duty simulations, medic training, and vehicle simulation. The advantage of virtual reality for high-risk service providers is that interactive scenarios can be experienced without any personal danger and at lower cost than other types of simulation. Virtual reality practice training is conducted in which personnel are given virtual reality glasses using head-mounted displays (HMD) which are worn to create a three-dimensional visual illusion of seeing a particular-place or field of action which can be simultaneously viewed by a group of participants.
Augmented reality may consist of projecting additional information on a real-world scene by combining computer-generated graphics with what a person perceives by eye. An example of such AV is Google Glass, which is a wearable computer with an optical head-mounted display (OHMD) developed by Google. Google Glass communicates by Bluetooth with a smartphone to display information or take movies or pictures which are shown as images projected in front of the wearer. Such a scene provides a realistic practice training or teaching capability without the individuals being put into real time, possibly hazardous situations.
Conventional virtual reality systems which allow free-roaming for players use infrared tracking to determine the positions of players and other objects. Such systems are relatively expensive. Alternatively, a tracking system using colored marker lights has advantages in the ability to differentiate players and objects, however accurately tracking markers over a relatively broad space or other virtual reality environment is difficult without using a plurality of cameras. Using a plurality of cameras presents a challenge with respect to position calibration, coordination, and synchronization. Also, issues related to colored tracking markers conflicting with each other as players roam about a space used for virtual reality environment also present a challenge as markers with the same color may come within a close proximity to one another.
As discussed above what has also been missing is the capability to provide a cost-effective scheme for VA and VR training implementation with a capability to use replay and review of actions that happen within the VR or AR training and practice arena.

System and method for saving tracked data in the game server for replay, review and training


One or more of a plurality of alarm conditions can be detected by respective alarm detectors. The detected alarm conditions can be reported to one or more respective monitoring stations. The system includes circuitry for controlling the consumption of power.

1. Field of the Invention
The invention relates to an apparatus for detecting fire and other alarm conditions and transmitting a corresponding emergency signal to a remote central monitoring station. More specifically, the invention relates to such apparatus which includes battery conserving means.
2. Description of Prior Art
Various emergency reporting or alarm systems exist for installation in houses and other buildings, which link up the alarm system to a central monitoring station which in turn, can take steps for notifying the police or the fire department or a medical organization. Known such systems are quite costly and they often require a special dedicated telephone line. They are also very demanding on the batteries powering them in that the systems have to be powered up so that they can detect alarm conditions.
Generally speaking such a known alarm system comprises a central unit and a series of detectors such as infra-red sensors which mainly serve to detect a non-desired presence. These known systems must be armed when the house occupant leaves the premises and must be disarmed when the occupant comes back to the house. This requirement is constraining with the result that the occupant often abandons or forgets the arming and disarming procedure.
Also the house occupant, in an emergency and therefore stressful situation, must use a conventional telephone apparatus to communicate with the attendant at the central monitoring station. Both the attendant and the occupant may dial at the same time and the communication becomes impossible. Frequently, the attendant, in an intrusion situation, is under directives not to call the occupant. In such a situation, the occupant must call the attendant and frequently he does not have the required central telephone number at hand, so much so that the is in a stressful situation. Delays therefore occur which are highly harmful in an emergency situation.


An elongated extruded door sill member is supported by a wood base and includes a sloping top wall and a rear wall connected by integral channel portions and a thermal barrier. The channel portions and barrier cooperate to define an upwardly facing cavity, and strips of resilient closed cell foam material are mounted within the channel portions. A vertically adjustable rail member extends longitudinally within the cavity and has side flanges projecting downwardly into the foam strips to form fluid-tight continuous seals. Opposite end portions of the rail member carry pads of the resilient foam material between the flanges for engaging the strips, the channel portions and the thermal barrier to form fluid-tight seals at the ends of the rail member.

In the art of adjustable threshold assemblies, for example, of the general type disclosed in U.S. Pat. No. 3,762,100 and No. 3,967,412, a vertically adjustable horizontal rail member extends below the bottom edge of the movable door and is supported by a wooden base member which also supports an extruded aluminum sill member. An extruded vinyl sealing element is retained by the sill member and engages the front surface of the adjustable rail member to form a seal with the rail member to avoid the accumulation of dirt and the flow of water and air into and through the cavity under the rail member. It is also known to construct the sill member in two sections and to connect the sections with a thermal barrier of plastics material, for example, as disclosed in U.S. Pat. No. 3,346,994.
As indicated above, it is highly desirable to prevent water from seeping into the cavity below the rail member and then through or around the threshold assembly into the sub-flooring or the adjacent floor covering, especially after vertical adjustment of the rail member. It is also desirable to obtain a dependable water-tight seal between opposite ends of the threshold assembly and the adjacent door jambs so that water does not flow around the ends of the sill and rail members and back into the cavity under the rail member and/or into the sub-flooring or floor covering.

Adjustable threshold assembly with water-tight seals


A circuit such as a duplexer which isolates a first and second frequency signals respectively directed to and from an antenna terminal. A transmitter filter has a output terminal connected to a connecting point through a first inductor. A receiver filter has an input terminal connected to the connecting point. The connecting point is connected to the antenna terminal, and to ground through a second inductor. In a modified circuit the output terminal of the transmitter filter and the input terminal of the receiver filter are respectively connected to the connecting point through first and second capacitors. In the preferred embodiments the transmitter filter and the receiver filter are mounted to one side of a dielectric plate and the inductor and/or capacitors are formed by electrically conductive step lines and a capacitance patterns formed on the opposite side of the dielectric plate.

The invention relates to a duplexer which is well adapted for a mobile telephone.
In duplex operation of a radio transmitter and a receiver connected to a common antenna, a duplexer is required so as to effectively isolate the transmitter and the receiver to permit simultaneous operation, especially, where the transmitting and receiving frequencies are closely spaced. A conventional duplexer is described in detail in U.S. Pat. No. 3,656,162 and Japanese Laid-open Patent Publication Nos. 87-136104 and 87-136105.
A duplexer described in U.S. Pat. No. 3,656,162 employs two coaxial cables which are respectively connected between an antenna terminal and a receiver terminal through a filter, and between a transmitter terminal through a filter and the antenna terminal. The length of one of the coaxial cables connected to the transmitter terminal, must be equal to around a quarter wavelength of the receiver frequency in order to reject the transmitter noise or harmonics at or near the receiver frequencies. The length of the other coaxial cable connected to the receiver terminal similarly must be equal to around a quarter wavelength of the transmitter frequency in order to reject the receiver noise or hermonics at or near the transmitter frequencies.
Another conventional duplexer, which has been proposed in order to reduce the size of the duplexer, is disclosed in Japanese Laid-open Patent Publication Nos. 87-136104 and 87-136105, both of which were issued on June 19, 1987 and assigned to the assignee of the present invention. The duplexer employs two distributed constant lines such as a strip line, in place of the two coaxial cables, both of which are formed on a dielectric material plate made of alumina or glass-epoxy resin materials by a thick-layer printing method or a plating method. The duplexer further employs a transmitter dielectric filter which is connected in series relation with one of the distributed constant lines to an antenna terminal and a receiver dielectric filter which is connected in series relation with the other distributed constant line to the antenna terminal. The lengths of the distributed constant line can respectively be calculated, for example, in the following manner:
An element S.sub.11 (1) of the dispersion matrix S showing a characteristic of the network comprised of the transmitter distributed constant line and the transmitter filter connected in series, is generally expressed by the following equation (1): ##EQU1## wherein r is the real part of the input impedance of the transmitter filter when the input impedence is expressed as r+j z;
z is the constant term of the imaginary part thereof: PA0 j is the imaginary unit thereof; PA0 .lambda. is the wavelength of the receiver frequency; PA0 l is the length of the transmitter distributed constant line; .theta.=.beta.l; and .beta.=2.pi./.lambda..
If the above equation (1) satisfies the following equation (2) EQU cos .theta.=z sin .theta. (2)
an input impedance of the network can be increased at and near the receiver frequencies so as to effectively reject the transmitter noise and harmonics at and near the receiver frequencies. If, in accordance with the equation (2), z sin .theta. is substituted for cos .theta. in the equation (1), equation (1) becomes ##EQU2## The element S.sub.11 (1) can also be expressed in terms of the input impedance Zin of the network as in the following equation (4) when the driving impedance of the network is assumed to be 1 ohm: EQU S.sub.11 (1)=(Zin-1)/(Zin+1), (4)
From the foregoing equations (3) and (4), the input impedance (Zin) can be expressed by the following equation (5): EQU Zin=[(1+z.sup.2)/r]-j z. (5)
According to equation (5), the real part r of the transmitter filter's input impedance can be assumed to be much less than 1 because Zin>>1, that is, the input impedance (Zin) of the network is required to be increased at and near the receiver frequencies, and the phase angle of the network can also be assumed as zero degree because the real part [(1+z.sup.2)/r] of the input impedance (Zin) is increased at and near the receiver frequencies. Tests have been performed with transmitter and receiver distributed constant lines (in the form of strip lines) used in mobile telephones whose transmitter frequency band is from 825 to 845 MHz and whose receiver frequency band is from 870 to 890 MHz. Each line had a width of 1.8 mm and a characteristic impedance of 50 ohm, and was formed on a glass-epoxy plate whose thickness was 1.0 mm and specific inductive capacity (dielectric constant) was 4.8. The lines were respectively connected to the transmitter and the receiver dielectric filters and were respectively set to have a phase angle around zero degree. To obtain the required large input impedance, the tests showed that the length of the transmitter line must be 84 mm and that of the receiver line must be 60 mm. However, the distributed constant lines of the above mentioned duplexer are still subject to having lengths equal to the corresponding quarter wavelengths of the rejected frequencies (these quarter wavelengths being reduced in the strip lines on the dielectric plate as compared to coaxial cables) so that formulation of a duplexer in this manner thereby presents an obstacle to further reduction of the size of the duplexer.

Duplexer with an isolating circuit on a dielectric plate


A soldering iron holder for holding an electric. Soldering iron having a large square tip at the end of a barrel, such as an iron that is used with surface mounted integrated circuits, has a base with a shield attached to a depressible mounting rod that extends through the upper surface of the base. The shield has a large frontal opening and mounted inside the shield, offset to one side, is a bracket with a side facing slot. The large opening allows a soldering iron with a large tip to be inserted into the shield, then moved sideways to insert the barrel of the iron into the slot of the bracket. When the iron is inserted into the slot, it depresses the shield which activates a weight switch connected to the base of the mounting rod. Activating the weight switch starts a timer that removes power from the iron if the iron remains in the holder for a long period of time. Also disclosed is a spring clip that may be attached to the slot in the bracket to aid in inserting the barrel of the iron into the slot.

This invention relates to electrical heating apparatus and more particularly to hand-held electrical heating apparatus such as soldering irons. Even more particularly, this invention relates to a holder for such soldering irons.
As integrated circuits get larger and larger, and particularly with the advent of surface mounted integrated circuits, soldering irons capable of handling these types of devices have become more sophisticated. To handle the larger, square, integrated circuits and surface mounted integrated circuits, the tips on these soldering irons have a large surface area while the barrel between the handle and the tip remains long and slender. Traditional soldering irons have a handle, a barrel to conduct heat to the tip, and a slender, pointed, tip. Using this type of iron, integrated circuits must be soldered or un-soldered one pin at a time. Irons capable of soldering large square integrated circuits and surface mounted integrated circuits must solder, or un-solder, all pins of the integrated circuit at once. To accomplish this, the tips of these irons have a surface that is similar in shape and size to the integrated circuit. Consequently, the tip is much larger than the barrel, and oftentimes even larger than the handle of the soldering iron. Also, because of the requirements for soldering surface mounted integrated circuits, and the tips have a very short lifetime.
Conventional soldering iron holders consist of a base, sometimes including the power supply for the soldering iron, and a vertical slot on top to hold the iron. With this type of holder the iron is exposed, allowing anyone near the iron to easily touch the hot iron. The exposure problem has been solved for the 15 conventional soldering iron with a shield consisting of a coil of heavy wire having a center opening into which the iron is inserted. This coil is mounted at about a 45 degree angle with respect to the base and the center opening is larger than the barrel and tip, but smaller than the handle. This allows the tip of the iron to be inserted into the coil, while the handle stays outside the coil. The iron is in such a position that it can easily be grasped in the same manner the user would grasp a pencil. The iron is typically turned on and off by a switch mounted on the base.
The large square tip of an iron for soldering surface mounted devices causes a problem with the conventional holder. Since this tip is much larger than the barrel, and often larger than the handle, the conventional wire coil holder is not satisfactory. If the center opening is large enough for the square tip, it is too large to hold the handle, and the iron falls to the bottom of the coil where it is cooled rapidly, or where it might be damaged. Also, with so large a center opening, the tip can easily touch the shield and quickly be cooled far below the desired soldering temperature, thus causing the user to have to wait for the iron to reheat each time it is to be used.
The problem of short tip life has been addressed by the device of U.S. Pat. No. 4,418,268 issued Nov. 29, 1983 to Munshaw. This device provides two vertical slots to hold a conventional soldering iron. The handle rests in a first slot, and the barrel of the iron rests in a second slot. Alongside the second slot is a detector, consisting of a light source and photocell, used to detect the presence of the iron. A circuit connected to this detector removes power from the iron when the iron has been in the holder for a predetermined period of time. This device has several disadvantages, however. First, there is no shield around the tip of the iron to prevent someone from touching the hot tip. Secondly, the iron is held in a horizontal position, and the holder contacts the handle of the iron, so it is difficult for a user to grasp the iron when it is in the holder. That is, soldering irons are most often used while being held like a pencil, so after grasping the iron while it is in the holder of the Munshaw device, a user must shift the position of the iron in their hand to a usable position, and when replacing the iron, the user must shift the iron's position again before it can be inserted back into the holder. A more convenient holder would allow a user to place and remove the iron while holding it like a pencil. Another disadvantage of the Munshaw device is that the detector is very close to the iron so it is subject to deterioration from the heat of the iron and therefore more likely to fail. Having the sensor close to the iron also requires that connecting wires be placed near the iron causing assembly problems and deterioration. Because of the way the holder of this device is constructed, if a shield were placed around the iron, the iron would be difficult to insert and remove from the holder. This problem would be exacerbated if the iron had a large square tip.
It is thus apparent that there is a need in the art for a soldering iron holder that allows an iron having a large square tip to be inserted in the holder, and provides a shield around the tip while keeping the tip from touching the shield. There is a further need in the art for such a holder that will remove power from the soldering iron after it has been in the holder for a long time, so as to preserve tip life, but which also has a long lasting sensor. A further need in the art is for such a holder that allows the soldering iron to be held in a position that is convenient for a user to grasp the iron the way they would hold a pencil. Yet another need is for such a holder that has a shield that can easily be removed for cleaning and replacement.

Holder with automatic timed shut-off for large tipped electric soldering irons


The present invention relates generally to viral variants exhibiting reduced sensitivity to particular agents and/or reduced interactivity with immunological reagents. More particularly, the present invention is directed to hepatitis B virus (HBV) variants exhibiting complete or partial resistance to nucleoside or nucleotide analogs and/or reduced interactivity with antibodies to viral surface components including reduced sensitivity to these antibodies. Vaccines and diagnostic assays are also contemplated herein.

Bibliographic details of the publications referred to in this specification are also collected at the end of the description.
The reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that that prior art forms part of the common general knowledge in any country.
Hepatitis B virus (HBV) can cause debilitating disease conditions and can lead to acute liver failure. HBV is a DNA virus which replicates via an RNA intermediate and utilizes reverse transcription in its replication strategy (Summers and Mason, Cell 29:403-415, 1982). The HBV genome is of a complex nature having a partially double-stranded DNA structure with overlapping open reading frames encoding surface, core, polymerase and X genes. The complex nature of the HBV genome is represented in FIG. 1. The polymerase consists of four functional regions, the terminal protein (TP), spacer, reverse transcriptase (rt) and ribonuclease (RNAse).
The polymerase gene of HBV overlaps the envelope gene, mutations in the catalytic domain of the polymerase gene can also affect the nucleotide and the deduced amino acid sequence of the envelope protein and vice versa. In particular, the genetic sequence for the neutralization domain of HBV known as the 'a' determinant, which is found within the HBsAg and located between amino acids 99 and 169, actually overlaps the major catalytic regions of the viral polymerase protein and in particular domains A and B.
The presence of an HBV DNA polymerase has led to the proposition that nucleoside or nucleotide analogs could act as effective anti-viral agents. Examples of nucleoside or nucleotide analogs currently being tested are penciclovir and its oral form (FCV) [Vere Hodge, Antiviral Chem Chemother 4: 67-84, 1993; Boyd et al, Antiviral Chem Chemother. 32:358-363, 1987; Kruger et al, Hepatology 22:219 A, 1994; Main et al, J. Viral Hepatitis 3:211-215, 1996], Lamivudine [(−)-.beta.-2′-deoxy-3′-thiacytidine]; (3TC or LMV) [Severin et al, Antimicrobial Agents Chemother. 39:430-435, 1995; Dienstag et al, New England J Med 333:1657-1661, 1995]. New nucleoside or nucleotide analogs which have already progressed to clinical trials include the pyrimidines Emtricitabine, ((−)-.beta.-L-2′-3′-dideoxy-5-fluoro-3′-thiacydidine; FTC), the 5-fluoro derivative of 3TC, and Clevudine (1-(2-fluoro-5-methyl-.beta.-L-arabino-furanosyl) uracil; L-FMAU), a thymidine analog. The beta-Lthymidine analogue (LdT has recently been given FDA approval other similar compounds include beta-L-2′-deoxycytidine (LdC) and beta-L-2′-deoxyadenosine (LdA) [Standring et al., Antivir Chem Chemother. 2001; 12 Suppl 1:119-29]. Like 3TC, these are pyrimidine derivatives with an unnatural "L"-configuration. Several purine derivatives have also progressed to clinical trials; they include Entecavir (BMS-200, 475; ETV), a carbocyclic deoxyguanosine analog, diaminopurine dioxolane (DAPD), an oral pro-drug for dioxolane guanine ((−)-.beta.-D-2-aminopurine dioxolane; DXG) and Adefovir dipivoxil, an oral prodrug for the acyclic deoxyadenosine monophosphate nucleoside or nucleotide analog Adefovir (9[phosphoryl-methoxyethyl]-adenine; PMEA). Other drugs in pre-clinical and clinical trials include FLG [Medivir], ACH-126,443 (L-d4C) [Archillion Pharmaceuticals], ICN 2001-3 (ICN) and Racivir (RCV) [Pharmassett].
Whilst these agents are highly effective in inhibiting HBV DNA synthesis, there is the potential for resistant mutants of HBV to emerge during long term antiviral chemotherapy. In patients on prolonged LMV therapy, key resistance mutations are selected in the rt domain within the polymerase at rtM204I/V+/−rtL180M as well as other mutations. The nomenclature used for the polymerase mutations is in accordance with that proposed by Stuyver et al, 2001, supra. LMV is a nucleoside or anucleotide analog that has been approved for use against chronic HBV infection. LMV is a particularly potent inhibitor of HBV replication and reduces HBV DNA titres in the sera of chronically infected patients after orthotopic liver transplantation (OLT) by inhibiting viral DNA synthesis. LMV monotherapy seems unlikely to be able to control HBV replication in the longer term. This is because emergence of LMV-resistant strains of HBV seems almost inevitable during monotherapy.
Adefovir dipivoxil (ADV: formerly, bis-pom PMEA) is an orally available prodrug of the acyclic deoxyadenosine monophosphate analog adefovir (formerly, PMEA) (FIG. 2). ADV is also a potent inhibitor of HBV replication and has been given FDA approval for use against chronic HBV infection. Adefovir dipivoxil differs from other agents in this class in that it is a nucleotide (vs. nucleoside) analog and as such bypasses the first phosphorylation reaction during drug activation. This step is often rate-limiting. Adefovir dipivoxil has demonstrated clinical activity against both wild-type and lamivudine-resistant strains of HBV and is currently in phase III clinical Testing (Gilson et al, J Viral Hepat 6:387-395, 1999; Perrino et al, Hepatology 32:129-134, 2000; Peters et al, Transplantation 68:1912-1914, 1999; Benhamou et al, Lancet 358:718-723, 2001). During phase II studies a 30 mg daily dose of adefovir dipivoxil resulted in a mean 4 log.sub.10 decrease in viremia over 12 weeks (Heathcote et al, Hepatology 28:A620, 1998).
ADV is a substituted acyclic nucleoside phosphonate. This class of compounds also includes tenofovir disoproxil fumarate (also referred to as tenofovir DF, or tenofovir, or (TFV) or 9-R-(2-phosphonomethoxypropyl)adenine (PMPA) and is marketed as Viread by Gilead sciences).
TFV has antiviral activity against both HBV and HIV (Ying et al, J Viral Hepat. 7(2):161-165, 2000; Ying et al, J. Viral Hepat. 7(1):79-83, 2000, Suo et al, J Biol Chem. 273(42):27250-27258. 1998).
FTC has activity against HBV and HIV (Frick et al, Antimicrob Agents Chemother 37:2285-2292, 1993).
LdT, LdC and LdA have activity against HBV (Standring et al, in supra)
Nucleoside or nucleotide analog therapy may be administered as monotherapy or combination therapy where two or more nucleoside or nucleotide analogs may be administered. The nucleoside or nucleotide analogs may also be administered in combination with other antiviral agents such as interferon or hepatitis B immunoglobulin (HBIG).
There is a need to monitor for the emergence of nucleoside/nucleotide-analog- or antibody-resistant strains of HBV and to develop diagnostic protocols to detect these resistant viruses and/or to use them to screen for and/or develop or design agents having properties making them useful as anti-viral agents. Defective forms of these resistant strains or antigenic components therefrom are also proposed to be useful in the development of therapeutic vaccine compositions as are antibodies directed to viral surface components.

This patent is subject to a terminal disclaimer.

Detection and use of antiviral resistance mutations


A mobile terminal including a wireless communication unit configured to wirelessly communicate with at least one other terminal; a display unit including a touchscreen; and a controller configured to display on the display unit a log information region representing page edges of an e-book executed on the mobile terminal, determine a variable characteristic of the executed e-book including at least one of 1) a number of times prescribed pages of the e-book have been displayed, and 2) an amount of time spent displaying the prescribed pages of the e-book, and distinctively mark the page edges of the e-book in accordance with the determined variable characteristic of the executed e-book.

1. Field of the Invention
The present invention relates to a mobile terminal, and more particularly, to a mobile terminal and controlling method thereof. Although the present invention is suitable for a wide scope of applications, it is particularly suitable for providing various kinds of functions using log information of an e-book.
2. Discussion of the Related Art
Generally, terminals can be classified into mobile/portable terminals and stationary terminals. The mobile terminals can be further classified into handheld terminals and vehicle mount terminals according to possibility of user's direct portability.
As functions of the terminal are becoming more diversified, the terminal is implemented as a multimedia player provided with composite functions such as photographing of photos or videos, playback of music or video files, game play, broadcast reception and the like for example.
Recently, an e-book reading function is included in a mobile terminal. In this instance, the e-book is a special format of a file that can be viewed via a portable device (e.g., mobile phone, PMP, PDA, etc.). In general, an e-book means a special format of a file in which a DRM function is loadable for copyright protection rather than such a universal file format as a text file. Despite a difference in a display type of an e-book on a mobile terminal, the e-book may support a memo function, a lining function, a search function and/or the like. However, these functions are limited.

Mobile terminal and controlling method thereof


A method, apparatus and system for template-controlled, precision laser interventions is described that greatly improves interventions such as laser microsurgery, particularly ophthalmic surgery, and industrial micromachining. The instrument and system are applicable to those specialties wherein the positioning accuracy of laser lesions is critical, such as whenever precise operations on a target or series of targets subject to movement during the procedure are to be effected. The system includes a user interface, wherein the user can either draw, adjust, or designate particular template patterns overlaid on a live video images of the target (such as the cornea) which are stabilized and produce an apparently stationary display of the target and provide the means for converting the template pattern into a sequence of automatic motion instructions to direct a laser beam to be sequentially applied replicating the designated template pattern into the corresponding surgical or industrial site.

The invention relates to methods and apparatus for performing precise laser interventions, and in particular those interventions relevant to improved methods and apparatus for precision laser surgery. In one preferred embodiment, the system of the invention is used for effecting precise laser eye surgery. In other embodiments the invention is applicable to non-surgical diagnostic procedures or non-medical procedures involving precision laser operations, such as industrial processes.
When performing laser interventions, whether in medical surgery, industrial processes, or otherwise, several fundamental considerations are common to most applications and will influence the viability and effectiveness of the invention. To influence the outcome of the intervention, the present invention addresses both the technical innovations involved in an apparatus to facilitate precision laser interventions, and the methods by which a user of such apparatus can achieve a precise result.
The present invention addresses the following considerations: (1) how does the user identify a target for the laser intervention, (2) how does the user obtain information as to the location and other pertinent features of the target and its important surroundings, (3) how does the user lock onto that target so that the user has the assurance he is affecting the intended target, (4) how does the user localize the effect to the target site, (5) how does the user treat a large number of individual targets, whether continuously connected, piecewise connected, or disconnected, (6) how does the user assess the effect of the intervention, (7) how does the user correct errors committed either during the course of the intervention or as a result of previous interventions, (8) how does the user react to changing conditions during the course of the intervention to ensure the desired result, and (9) how is safety ensured consistent with U.S. Food and Drug Agency regulations for medical instruments and good commercial practice guidelines for industrial applications.
Of particular interest are medical interventions such as surgical procedures described by Sklar et al. (U.S. Pat. No. 5,098,426 and U.S. patent application Ser. No. 475,657 (now abandoned), which are incorporated herein by reference). Although many different kinds of surgery fall within the scope of the present invention, attention is drawn to corneal refractive surgery in ophthalmology for the treatment of myopia, hyperopia, and astigmatism.
For corneal refractive surgery, the above nine considerations reduce to the following objectives (in accordance with the present invention described below): (1) identify the location on or in the cornea to be treated, (2) assure that the target is at the desired distance from the apparatus, determine the topography of the cornea, and determine the location of sensitive tissues to be avoided, (3) identify, quantify, and pursue the motion of suitable part of the cornea which can provide a reference landmark that will not be altered as a result of the surgical intervention and, likewise, the depth of variations (for example, distance form the corneal surface to the front objective lens changing due to blood pressure pulses) of the corneal surface with respect to the apparatus such that said motions become transparent to the user of the apparatus, (4) provide a laser beam which can be focused onto the precise locations designated by the user such that peripheral damage is limited to within the tolerable levels both surrounding the target site and along the laser beam path anterior and posterior to the target site, (5) provide a user interface wherein the user can either draw, adjust, or designate particular template patterns overlaid on a live video image of the cornea and provide the means for converting the template pattern into a sequence of automatic motion instructions which will traverse the laser beam to focus sequentially on a number of points in three dimensional space which will in turn replicate the designated template pattern into the corresponding surgical intervention, (6) assure that items (1)-(3) above can be performed continuously during the course of and subsequent to the surgery to monitor the evolution of the pertinent corneal surface and provide a means of accurate comparison between pre-operative and post-operative conditions, (7) ensure that the structural and physiological damage caused by the surgery to the patient is sufficiently small to permit continued interventions on the same eye, (8) automate the interaction between the various components so that their use is transparent to the user and so that sufficiently fast electronics accelerate completion of the surgical intervention within pre-selected error tolerances, and (9) provide dependable, fail-safe safety features of sufficiently short reaction times to prevent any chance of injury to sensitive corneal tissues. With these objectives fulfilled, the speed of surgery will no longer be limited by human perception delay and response times but by the capability of the apparatus to recognize changing patterns and adjust to the new conditions. Equally important, the accuracy of the surgery will not be constrained by the bounds of human dexterity, but by the mechanical resolution, precision, and response of advanced electro-optical and electromechanical systems.
There are substantial number of different functions which the apparatus of the present invention addresses. Each of the complementary and at times competing, functions requires its own technologies and corresponding subassemblies. The present invention describes how these various technologies integrate into a unified workstation to perform specific interventions most efficaciously. For example, for corneal refractive surgery, as per (1) and (2) above, identify the location to be treated on or in the cornea, the surgeon/user would use a combination of video imaging and automated diagnostic devices as described in Sklar et al. (U.S. Pat. No. 5,098,426 and U.S. patent application Ser. No. 475,657 (now abandoned)), depth ranging techniques as described in Fountain (U.S. Pat. No. 5,162,641), surface topographical techniques, as described in Sklar (U.S. Pat. No. 5,054,907) together with signal enhancement techniques for obtaining curvatures and charting the contours of the corneal surface as described by McMillan and Sklar (U.S. Pat. No. 5,170,193), profilimetry methods as disclosed by McMillan et al. (U.S. Pat. No. 5,283,598), image stabilization techniques as described by Fountain (U.S. Pat. No. 5,162,641), which may all be combined using techniques as described by Sklar et al. (U.S. Pat. No. 5,098,426 and U.S. patent application Ser. No. 475,657 (now abandoned)). All of the above listed patent applications and the patent of Fountain (U.S. Pat. No. 5,391,165) are herein incorporated by reference.
Aspects of the above-referenced disclosures are further used to provide means of satisfying the key aspects (3)-(9) noted above, such as verification of target distance from the apparatus, tracking the motion of the cornea in three dimensions, providing a laser whose parameters can be tuned to selectively generate photodisruption of tissues or photocoagulation as desired, automatically targeting and aiming the laser beam to precise locations, and supplying a surgeon/user with a relatively simple means of using the apparatus through a computer interface.
It is well known that visible light, which is passed without significant attenuation through most ophthalmic tissues, can be made to cause a plasma breakdown anywhere within eye tissue whenever the laser pulse can be focused to sufficiently high irradiance and fluence levels to support an avalanche process. The ensuing localized photodisruption is accomplished by using a strongly focused laser beam such that only in the immediate focal zone is the electric field sufficiently strong to cause ionization and nowhere else. By using short pulses of controllably small laser energy, the damage region can be limited in a predictable manner while still guaranteeing the peak power necessary for localized ionization.
Furthermore, was lasers of increasingly higher repetition rate becoming available, the sometimes intricate patterns desired for a given surgical procedure can be accomplished much faster than the capabilities of a surgeon manually to aim and fire recursively. In prior systems and procedures, the surgeon would aim at a target, verify his alignment, and if the target had not moved, then fire the laser. He would then move on to the next target, and repeat the process. Thus, the limiting factor to the duration of the operation under these prior procedures was the surgeon""s reaction time while he focused on a target and the patient""s movement while the surgeon found his target and reacted to the target recognition by firing the laser. In practice, a surgeon/user can manually observe, identify, move the laser focus to aim, and fire a laser at not more than two shots per second.
By contrast, a key object of the instrument and system of the present invention is to stabilize the motion of the patient by use of an automated target acquisition and tracking system which allows the surgeon to predetermine his firing pattern based on an image which is automatically stabilized over time. The only limitations in time with the system of the present invention relate to the repetition rate of the laser itself, and the ability of the tracking system to successfully stabilize the image to within the requisite error tolerances for safety and efficacy, while providing a means to automatically interrupt laser firing if the target is not found when a pulse is to be fired. Thus, where it would take several hours for a surgeon/user to execute a given number of shots manually (ignoring fatigue factors), only a few minutes would be required to perform the same procedure when automatic verification of focal point position and target tracking are provided within the device.
It is an object of the present invention to accommodate the most demanding tolerances in laser surgery, particularly eye surgery but also for other medical specialties, through a method, apparatus and system for high-precision laser surgery which provides the surgeon xe2x80x9clivexe2x80x9d video images containing supporting diagnostic information about depth and position at which a surgical laser will be fired. In a computer, the full information content of a given signal is interpreted so as to provide this supporting diagnostic information, and the resulting accuracy achievable is within a few human cells or better.
The system, apparatus and method of the present invention for precision laser surgery, particularly ophthalmic surgery, take a fully integrated approach based on a number of different instrumental functions combined within a single, fully automated unit. For example, previous conventional diagnostic instruments available to the ophthalmic surgeon have included several different apparatus designed to provide the surgeon/user limited measurement information regarding the cornea of the eye, such as the corneoscope, the keratometer, and the pachometer. The corneoscope provides contour levels on the outer surface of the cornea, or corneal epithelial surface, derived, typically, from projected concentric illumination rings. The keratometer gives cross sectional curvatures of the epithelial surface lens of the eyexe2x80x94the corneal epithelium surface. Only one group of points is examined, giving very limited information. Pachometers are used to measure the central axis thicknesses of the cornea and anterior chamber.
The diagnostic functions fulfilled by these devices are instrumental to characterizing the subject tissue in sufficient detail to allow the surgeon/user to perform high precision ophthalmic surgery. Unfortunately, these and other similar instruments require considerable time to operate. Further, their use required near-total immobilization of the eye or, alternatively, the surgeon/user had to be satisfied with inherent inaccuracies; the immobilization methods thus determined the limitations on the accuracy and efficacy of eye surgery. Nor did the different apparatus lend themselves to being combined into one smoothly operating instrument. For all of the above reasons, operation at time scales matched to the actual motions of the tissues targeted for therapy and/or limited by the fastest human response times to those motions (xe2x80x9creal timexe2x80x9d) has not been possible with any of the conventional instruments used to date.
By contrast, the methods and apparatus disclosed herein, aim to incorporate a mapping and topography means for reconstructing the corneal surface shape and thickness across the entire cornea. It is furthermore within the scope of the present invention to provide such global measurements of the corneal refractive power without sacrificing local accuracies and while maintaining sufficient working distance between the eye and the front optical element of the instrument (objective lens), said measurements to be executed on-line within time scales not limited to human response times. Most standard profilometry techniques were judged inadequate per the above requirements, requiring compromises in either accuracies of the computed curvatures (such as, e.g., standard xe2x80x98kxe2x80x99 readings of keratometers), speed and ease of operation (scanning confocal microscopes) or left no working distance for the ophthalmologist (corneoscope and keratoscopes based on xe2x80x9cplacido diskxe2x80x9d illumination patterns). It is therefore a key objective of the present invention to include a new topography assembly that can overcome the limitations of existing instruments while combining, on-line, and in a cost effective manner, many of the functions of conventional diagnostic instruments presently available to the surgeon, as an integral part of a complete surgical laser unit.
In one embodiment of the present invention, the corneal refractive power is measured using a unique projection and profilometry technique coupled with signal enhancement methods for surface reconstruction as disclosed by McMillan and Sklar in U.S. Pat. No. 5,170,193 and further extended in larger corneal cross-sections via techniques described in McMillan et al. in U.S. Pat. No. 5,283,598, both incorporated herein by reference. In another embodiment, digitized slit lamp video images are used to measure the local radii of curvature across the entire corneal surface as well as the thickness of the cornea, with no built-in a-priori assumptions about the corneal shape. Both embodiments of the topography system benefit greatly from the availability of 3-D tracking capability contained within the apparatus. The feature allows elimination of many of the errors and ambiguities that tend to compromise the accuracy of even the best currently available instruments utilizing fine point edge extraction and advanced surface fitting techniques. With the computerized topographic methods of the present invention, surfaces can be reconstructed (and viewed in 3-D) with accuracies that go well beyond the approximate photokeratometric and pachometry readings as advocated by L""Esperance (U.S. Pat. No. 4,669,466), or even the more sophisticated (but complex) corneal mapping methods as disclosed by Bille (U.S. Pat. No. 5,062,702) and Baron (U.S. Pat. No. 4,761,071).
While tissue topography is a necessary diagnostic tool for measuring parameters instrumental to defining templates for the surgery (e.g., refractive power), such instrumentation is not conducive to use during surgery, but rather before and after surgery. Also, the information thus obtained is limited to those parameters characteristic of surface topography (such as radii of curvature of the anterior and/or posterior layers of the cornea or lens). Yet, in many cases, it is desirable to simultaneously image the target area and deposit laser energy at a specific location within the tissue itself. To allow reliable, on-line monitoring of a given surgical procedure, additional mapping and imaging means must therefore be incorporated. The imaging means is intended to record, in three-dimensions, the location of significant features of the tissue to be operated upon, including features located well within the subject tissue. It is therefore another object of the present invention to provide continuously updated video images to be presented to the surgeon/user as the surgery progresses, said images to be produced in a cost effective manner yet compatible with high resolution and high magnification across a large field of view and at sufficiently low illumination levels to prevent any discomfort to the patient.
The imaging system, or the surgical microscope, requires viewing the reflected light form the cornea, which has two components: (a) specular (or mirror) reflection from a smooth surface, which returns the light at an angle opposite the angle of incidence about the normal from the surface and also preserves the polarization of the incident beam, and (b) diffuse reflection, in which light returned from a rough surface or inhomogeneous material is scattered in all directions and loses the polarization of the incident beam. No surface or material is perfectly smooth or rough; thus all reflected light has a specular and a scattered component. In the case of the cornea there is a strong specular reflection from the front surface/tear layer and weak scattered light from the cellular membranes below. Various standard xe2x80x98specular microscopesxe2x80x99 have been used to suppress the front surface reflection. We have chosen a combination of techniques: some aim at observing the combined reflections without differentiating between specular or diffuse signals (for operations at or in immediate proximity to the surface of the cornea); in others the surface is illuminated with polarized light, with the reflected images then microscopically viewed through a crossed polarizer for operation within deeper layers, after selectively filtering the more anterior reflections. A rejection of the polarized component can thus be achieved, greatly enhancing resolution at low enough light levels to prevent any discomfort to the patient. In either embodiment, the imaging system contained within the apparatus of the invention represents a significant improvement over standard xe2x80x9cslit lampxe2x80x9d microscopes such as are in use with most ophthalmic laser systems.
Other efforts at imaging the eye, such as performed with Heidelberg Instrument Confocal Microscope, or as described by Bille (U.S. Pat. No. 4,579,430), either do not lend themselves to inclusion as part of an on-line, cost effective, integrated surgical system (for the former), or rely upon scanning techniques which do not capture an image of the eye at a given instant in time (for the latter). The method of the present invention benefits from having an instantaneous full image rather than a scanned image; for full efficacy, the method does, however, require that the targeted area be stabilized with respect to both the imaging and the laser focal region, so as to enhance the accuracy of laser deposition in tandem with the viewing sharpness.
Tracking is therefore considered a critical element of a system designed onto only to diagnose, but also select treatment, position the treatment beam and image the tissue simultaneously with the treatment, while assuring safety at all times. In the case of corneal surgery, movements of the eye must be followed by a tracking system and, suing dedicated microprocessors, at closed-loop refresh speeds surpassing those achievable by unaided human inspection, by at least an order of magnitude. Tracking by following the subject eye tissue, i.e., recognizing new locations of the same tissue and readjusting the imaging system and the surgical laser aim to the new location, assures that the laser, when firing through a prescribed pattern, will not deviate from the pattern an unacceptable distance. In preferred embodiments of the invention, this distance is held within 5 xcexcm in all situations during ophthalmic surgery, which sets a margin of error for the procedure. It is possible that with future use and experimentation, it may be found that either more stringent or alternatively more lax displacement error tolerances are desirable to improve overall system performance.
Stabilization of a moving target requires defining the target, characterizing the motion of the target, and readjusting the aim of the apparatus of the present invention repeatedly in a closed-loop system. To meet accuracy goals also requires that the moving parts within the apparatus not contribute internal vibrations, overshoots, or other sources of positioning error which could cumulate to an error in excess of the prescribed dispositioning tolerances. There have been several previous attempts at achieving this result. Crane and Steel (Applied Optics, 24, pp. 527, 1985) and Crane (U.S. Pat. No. 4,443,075) described a dual Purkinje projection technique to compare the displacement of two different-order Purkinje projections over time, and a repositioning apparatus to adjust the isometric transformation corresponding to the motion. The tracking methods disclosed therein are based on a fundus illumination and monitoring device that aspires to distinguish translational from rotational eye movements, thus stabilizing an illuminating spot on the retina. However, localization of the Purkinje points can be influenced by transient relative motions between the various optical elements of the eye and may provide significantly fictitious position information for identifying the surface of the cornea. Motility studies as described by Katz et al. (American Journal of Ophthamology, 107: 356-360, xe2x80x9cSlow Saccades in the Acquired Immunodeficiency Syndromexe2x80x9d, April 1989) analyze the translations of an image on the retina from which the resulting coordinate transformation can be computed and galvanometric driven mirrors can be repositioned. In addition to the fictitious information discussed above due to relative motions between different layers of the eye, the galvanometer drives described by Katz usually are associated with considerable overshoot problems. Since saccades can be described as highly accelerated motions with constantly changing directions, overshoot errors can easily lead to unacceptable errors.
Bille et al. (U.S. Pat. No. 4,848,340) describes a method of following a mark on the epithelial surface of the cornea, supposedly in proximity of the targeted surface material. However, in one of the uses of the present invention, a mark made on the epithelial surface would change its absolute location due to changes in the structure and shape of the material, caused by use of the instrument itself rather than by eye motions. Therefore, a target tracking and laser positioning mechanism that relies on a mark on the surface of the cornea in order to perform corneal surgery such as described by Bille""s tracking method would be expected to lead to misdirected positioning of laser lesions below the surface when combined with any suitable focused laser, as intended in one of the uses of the present invention. Moreover, one of the features of the present invention is to be able to perform surgery inside the cornea without having to incise the cornea. The main advantages of such a procedure are in avoiding exposure of the eye to infection and in minimizing patient discomfort. It would hence be counterproductive to mark the surface of the cornea for the purpose of following the motion of said mark. In another embodiment taught by Bille et al., the tracking is based on a reference provided by either on the eye""s symmetry axis, or the eye""s visual axis, with an empirically determined offset between the two. Tracking is then accomplished by monitoring the reflection form the apex of the cornea, thus avoiding the need to mark the eye, and/or rely solely on patient fixation. However, with this technique, as in the preferred embodiment taught by Bille et al., the tracking does not follow tissue features generally at the same location as the targeted surgical site on or inside the eye. Instead, Bille et al.""s techniques track reference points that are, in all cases, separate, remote from and may be unrelated to the targeted surgical site. Such methods compromise accuracy of tracking in direct proportion to the degree of their remoteness relative to the surgical site. Therefore, they do not adequately provide for the fact that the eye is a living tissue, moving and changing shape to some extent constantly. Tracking a single point on the cornea, when the cornea itself actually shifts considerably on the eye, thus cannot be expected to reflect positional change of the targeted surgical site.
By contrast, in the preferred embodiment of the present invention the tracking information is obtained through means contiguous to the target region, which is mechanically and structurally considered as part of the cornea, but is unlikely to be affected by the course of the surgery and can thus provide a significant representation of non-surgically induced displacements. This is a critical feature of the tracking method disclosed herein, in that involuntary motions of the eye (such as are caused by blood vessel pulsing) can now be accurately accommodated, unlike techniques that rely on remote reference points.
The accuracy of the apparatus and system of the invention preferably is within 5 xcexcm, as determined by a closed-loop system which incorporates actual measurement of the target position within the loop. (For example, a microstepper motor based assembly may have a single step resolution of 0.1 xcexcm verified against a motor encoder, but thermal gradients in the slides may yield greater variations. Moreover, position of the slide can be verified via an independent optical encoder, but the random vibrations of the target can invalidate the relative accuracy of the motor.) Thus, the surgeon has knowledge of the shape of tissues within the field of view and the precise location of where he is aiming the instrument within those structures, to an accuracy of 5 xcexcm. Such precision was not attainable in a systematic, predictable manner with any of the prior instruments or practices used. The present invention thus seeks to obviate the need for binocular vision used to obtain stereoptic images in some prior methods (see., e.g., Crane, U.S. Pat. No. 4,443,075).
In a preferred embodiment of the invention, the instrument also ensures that a laser pulse is fired only upon command of the computerized controller and after the system has verified that the tracking assembly is still locked onto the desired location, that the energy being emitted by the laser falls within prescribed error tolerances, and that the aiming and focusing mechanisms have reach their requested settings. There is no need to separate aiming beam. In one embodiment of the present system, the method of parallax ranging is implemented to map out surfaces posterior to the cornea, but preceding actual treatment.
Safety is a very important consideration with laser surgery. In prior surgical systems and procedures, some safety shut-off procedures for laser firing have depended upon human reaction time, such as the use of a surgeon""s foot pedal for disabling the instrument when a situation arises which would make firing unsafe. In ophthalmology, some instruments have relied as a safety feature on a pressure sensor located where the patient""s forehead normally rests during surgery. If insufficient pressure were detected by the sensor, the instrument would be disabled from firing.
Such prior safety systems have inherently had slow reaction times, and have not been able to react quickly enough to all of the various problems which can arise during a firing sequence. This is a critical concern in ophthalmic surgery, especially where specific surgical procedures are to be performed near sensitive non-regenerative tissues, such as the corneal endothelium layer and the optic nerve. In contrast, the target capture and tracking system of the present invention makes available a new and highly dependable safety system. If for any reason, either prior to or during a given surgical procedure, the tracking system loses its target, the laser is disabled from firing. Various options are available for blocking emission from the apparatus once the tracking assembly has verified the loss of a tracking signal.
No previous surgical laser system has employed the efficacious combination of features as disclosed herein. For example, in previous art, Bille et al. (U.S. Pat. No. 4,848,340) and Crane (U.S. Pat. No. 4,443,075) taught tracking techniques to follow tissue movements which might occur during surgery, but did not teach simultaneous 3D imaging within the tissue to monitor the effects of surgery on the tissue and provide requisite safety margins; L""Esperance (U.S. Pat. No. 4,669,466 and 4,665,913) also did not suggest any aspects of 3D imaging, teaching only laser surgery on the anterior surface of the cornea; Bille (U.S. Pat. No. 4,579,430) shows a retina scanner, but does not teach simultaneous tracking. Bille et al. (U.S. Pat. No. 4,881,808) teach an imaging system and incorporate a tracker and a beam guidance system by reference (per U.S. Pat. Nos. 4,848,340 and 4,901,718, respectively) but fail to address the very difficult challenges involved in achieving a smooth combination of all these aspects into a single surgical laser unit with built-in high reliability features. By contrast, it is the unique integration of several such diverse aspects (including mapping, imaging, tracking, precision laser cutting and user interface), precisely yet inexpensively, into a fully automated workstation, the uses of which are transparent to the user, that is the main subject of the present invention. The methods and apparatus disclosed herein are thus expected to enhance the capabilities of a surgeon/user in accomplishing increasingly more precise surgical interventions in a faster and more predictable manner. Enhanced safety is expected to be a natural outcome of the methods and apparatus taught herein in that the surgery will be performed without many of the risks associated with competing methods and apparatus as described by L""Esperance (U.S. Pat. No. 4,669,466 and 4,665,913), Srinivasian (U.S. Pat. No. 4,784,135), Bille et al. (U.S. Pat. Nos. 4,848,340; 4,881,808; and 4,907,586), Frankhauser (U.S. Pat. No. 4,391,275), Aron-Rosa (U.S. Pat. No. 4,309,998), Crane (U.S. Pat. No. 4,443,075), and others.
An embodiment of the present invention is herein disclosed, comprising a method, apparatus, and system for precision laser based microsurgery or other laser-based micromachining, and including the following elements, each of which is described below.
(1) A final objective (lens), the axial position of which relative to the tear layer of the corneal vertex (or to a more general target), is held constant by an axial tracking means, and through which pass all optical radiations emitted or accepted by the system. (2) An axial tracking means (including associated optics) for maintaining constant separation between the final objective and its target (which is to be distinguished from the (common) target for the treatment means and the parallax ranging means, and also from the target for the viewing means) as that target moves axially along the final objective""s centerline. The axial tracking means includes a compensation means to preclude it from being adversely affected by the transverse tracking means. (3) A transverse tracking means (including optics) for maintaining constant aiming between the treatment and parallax ranging means and their (common) target, and between the viewing means and its target, as those targets move (together) transversely to the final objective""s centerline. (4) A treatment means for effecting the actual laser microsurgery/micromachining, including a laser, laser-beam directing optics, a treatment aiming means (with optics), and a treatment focusing means (also including optics), all of which are actuated by a computerized control means. (5) A parallax ranging means, which shares optics for the treatment aiming and focusing means, for positioning the common focus of the treatment parallax ranging means at a desired location (independent of the target identified above) by use of the viewing means and without requiring the actual operation to be performed. (6) A viewing means, comprising optics and a low-light-level TV camera, for presenting to the surgeon/user, on the display means, an adjustably magnified image of the volume adjacent to the viewing target, which target may be chosen by the user independently of the other targets identified above. (7) A computerized control means, including a user interface presented on the display means, which performs calculations and accepts and issues signals in order to execute the various functions of the overall system. (8) A display means for presenting to the surgeon/user he image from the viewing means plus computer-generated overlays from the user interface: such overlays include not only menus but also textual and graphic representations of aspects such as the topography of the cornea (or more general surfaces associated with the various targets) and the microsurgery/micromachining templates to be used. (9) A profiling means, including optics, one or more (patterned) profilometry illuminators, and a TV camera, to generate the data from which the computerized control means can calculate the topography of the cornea (or, in other embodiments, a more general surface). (10) An output measurement means to measure parameters of the laser radiation delivered to the eye of the patient or the workpiece. (11) Various illumination means, such as the profilometry illuminators, the coaxial illuminator, and the slit illuminator, to provide the light source(s) for the profilometry means, the transverse tracking means and the viewing means.
The present invention is expected to be useful in a variety of medical specialties, especially wherever the positioning accuracy of laser lesions is critical and where accurate containment of the spatial extent of a laser lesion is desirable. Much of the following discussions will be directed at ophthalmic applications and specifically corneal refractive surgery. This should not be viewed as a limitation on the applicability of the apparatus and method of the present invention. Alternate embodiments of the invention are expected to play a role in several other medical applications.
The system is also useful for non-medical operations, such as industrial operations, especially micromachining and short repair of microchips, wherein a focused laser beam is used to perform high precision operations on an object subject to movement, or in the automated inspection and correction of errors in the manufacture of microprocessors and high-density integrated circuits.
In specific applications to corneal procedures, the present invention is intended to provide a means by which an ophthalmologist can (a) observe the patient""s eye at both low magnification to orient the procedure and at progressively higher magnification to provide great resolution for finer and more accurate procedures, (b) access on-line diagnostic information as to the shape of one or more relevant surfaces or of tissue layers to be treated, (c) describe a pattern of shots to effect a particular lesion shape without requiring manual aiming of each shot by the surgeon, (d) provide a therapeutic laser beam propagating through a beam steering and focusing delivery system which can localize the laser lesions at a particular depth in the immediate neighborhood of the laser focal point without appreciable damage elsewhere and with minimal peripheral necrosis or thermal damage surrounding the affected volume, and (e) provide a target tracking system that can minimize the error in positioning the pattern of the laser lesion in a moving target.
In the user interface, a video monitor screen is provided in front of the surgeon, and the screen provides a variety of choices for imaging and diagnostic information. Among the selections available to the ophthalmologist, for example, is a live video image of the eye superimposed over sectional perspectives of the shape of the corneal anterior surface and displayed along with the location where the proposed surgical lesion is situated. Another choice is to display a wire-mesh contour elevation map of said corneal surface together with an imbedded display of the proposed lesion. These selections can all be enlarged by using the zoom option which augments the live video image, and proportionally also the wire-mesh surface contour, the perspective views of the surface, and all other relevant diagnostics.
Additionally, a library of patterns is available so that the computer can generate templates based on the optical correction prescribed (generated off-line by the physician""s xe2x80x9crefractionxe2x80x9d of the patient) and the measured topography (which templates will automatically correct for edge effects, based on built-in expert-system computational capability). The surgeon/user can move the templates on the screen by means of a trackball, mouse, or other standard pointing device for manipulating points on a video screen and thus, define the shape of the desired lesion and situate it at the optimal treatment location. These templates serve the additional function, once finally approved by the surgeon/user, of automatically controlling the path of the firing of the laser as well as the size and location of the laser-generated lesions to be formed in the course of the microsurgery. Since particular templates can be stored in computer memory, the surgeon/user may, as experience with the apparatus develops, draw on a bank of prior knowledge relating to a particular form of microsurgery, such as ophthalmic surgery directed to a specific type of correction. A physician may therefore choose to select from a set of pre-existing templates containing his preferred prescriptions, lay the template, in effect, on the computer-generated image of the region, and resize and/or re-scale the template to match the particular patient/eye characteristics. The surgery can then be executed automatically in a precisely controlled manner, based on the computer programming sense.
Such a pre-existing library of templates is also useful in the execution of controlled animal studies. It should be noted, however, that without the accompanying three-dimensional targeting capability and the automatic image stabilization means contained within the hardware of the present invention, the utility of template-generated surgery alone would be severely limited either to no-sensitive tissues (where high three dimensional precision is not usually a consideration) or to relatively stationary or immobilized targets (not usually available at high magnification in a biological system which is xe2x80x9calive).
In another embodiment of the methods and hardware of the present invention, templates can also be generated and stored in similar manner for procedures other than corneal refractive surgery, including iridotomy, posterior capsulotomy, trabeculoplasty, keratotomy, and the like.
Among the advantages of the present invention is the modular design of the multiple assemblies. The multiple assemblies are each individually supported on kinematic mounts. These mounts allow for the separate construction of the multiple assemblies, their alignment to tooling jigs individually, and the precise xe2x80x9chard-aligningxe2x80x9d of the multiple assemblies into a complex optical system. Although such kinematic mounts can add, somewhat, to manufacturing costs, they save considerable alignment time during the assembly of the apparatus and provide a greater measure of reliability that the apparatus shall remain in operational alignment during continued use by non-technical surgeon/users.
Using the instruments of the present invention, the surgeon can generate a proposed pattern of therapeutic treatment, can compare the pattern to the actual tissues targeted, can compare his proposed surgery with what other surgeons have done in similar situations, and can still have the assurance that when he is finally satisfied with the proposed procedure, he can push a button to cause the desired surgery to be carried out at a high rate of independently targeted shots per second. This speed minimizes the risk during surgery at catastrophic patient motion.
In addition, the surgeon has at his disposal a fast reliable safety means, whereby the laser firing is interrupted automatically, should any conditions arise to warrant such interruption of the procedure. The surgeon can also temporarily disable the laser from firing at an point during the course of the surgery via suitable manual controls.
The tracking subsystem of the invention serves two important purposes: it tracks and follows the movements of the patient""s tissuexe2x80x94not only the voluntary movements which can be damped with specialize treatment, but also the involuntary movements which are more difficult to control on a living specimenxe2x80x94and continuously re-presents an image of the same section of tissue. Thus, the surgeon/user is provided a continuous, substantially immobilized view of that tissue regardless of patient movements; and it further provides a fail-safe means for immediately stopping the action of the surgical laser beam in the even the tracking is lost, i.e., the tissue is not recognized by the tracking algorithm following the motion, per the discussion on safety features above.
In accordance with the invention, fast imaging and tracking are achieved using the combined effects of a pivoting tracking mirror which may be under the directional control of a piezoelectric or electromagnetic transducer, or other rapid servo device to pursue eye motions in a plane perpendicular to the optical axis of the final focusing lens (also referred to herein as the X-Y plane), coupled with a motor drive which translates the otherwise fixed final focusing lens assembly along the axial direction of the final focusing lens, herein denoted as the Z axis. Thus, three dimensional motions which fall within the domain of capture of the tracking system can be observed, pursued and captured.
Fast response times are possible with the described embodiment of the invention, limited by the ultimate speed of the tracking detector, the computational capabilities of the apparatus microprocessors and data transfer rates, and the moment of inertia of the tracking servo mirror. It has been determined that such closed-loop target recognition and tracking should occur at least at a rate of approximately 20-to-40 Hz in order to compensate for involuntary eye motion and thus, provide a significant improvement over human reaction times. Tracking rates on the order of 100 Hz for full amplitudes on the order of  greater than 1 mm (about 5xc2x0) in the transverse direction and in excess of 40 Hz over a range of +2 mm axially, would ultimately be achievable with some improvements based on the methods and system of the present system.
In a preferred embodiment of the present invention, the tracking sensors, or detectors, in combination with their circuitry, should be capable of high spatial resolution. Examples are linear position sensing detectors and quadrant detectors. For corneal refractive surgery, the limbus of the eye provides a landmark ideally suited for such detectors. In the retina, landmarks such as the optic disk, or vessel configurations can similarly provide landmarks upon which a magnified view can serve as the tracking landmark. In the present invention, any natural eye feature located in proximity of and structurally contiguous to the target site will serve as the tracking landmark. The important observation is that the location of the tracking landmark must respond to forces and pressures in a manner similar to the targeted tissues, yet it cannot be coincident with the precise target site itself, since this site will change during the course of the surgery.
Since the limbus is the outer edge of the cornea, it is expected that the limbus will respond to changes in position in a similar manner to other corneal tissues. The limbus further has the advantage of being contiguous to the sclera. Correspondingly, it is expected that the transient displacements occasioned by the impact of the laser pulse on the target site will be damped sufficiently at the limbus so as to not induce fictitious tracking signals. Such fictitious tracking signals would normally be a frequent observation if the present invention were to use, for example, a mark on the surface of the cornea in the vicinity of the operative site or a remote symmetry axis. Similar considerations apply when selecting a tracking landmark in other eye segments.
By incorporating intensified cameras, the present instrument and system is of high sensitivity, requiring only low levels of illumination, and produces video images of high contrast and high resolution. Illumination levels are kept well within established safety levels for the human eye. With the optics of the present system the patient""s tissue is observed from an appreciable distance, sufficient for comfort to the patient even during surgery, and sufficient to permit the surgeon/user ready access to the patient in case of emergency, to insure safety at all times, to reassure the patient, or for any other reason which the surgeon/user may feel justifiable.
Zoom optics are included so that the physician an select a range of magnification for the video image, which maybe from about, say 15xc3x97 to 200xc3x97. Different zooming ranges may be appropriate for different types of surgical procedures while maintaining an overall zooming capability of approximately 15-fold. The viewing system may be refocused in depth as well as transversely, independent of the treatment beam, as desired.
In one embodiment of the present invention, a system for use in ophthalmic laser surgery includes a laser source with sufficient output power to effect a desired type of surgery in the ocular tissue, along with an optical path means for delivering the laser beam, including beam directing and focusing means for controlling the aim and depth of focus of the laser beam. In a preferred embodiment of the present invention, a laser firing up to 250 shots per second is employed. Such a laser device can generate an intricate pattern consisting of 50,000 shots aimed separately at different locations in under 4 minutes. For most types of ophthalmic surgery procedures falling in the domain of application for the system disclosed herein, the method of deposition of the laser pulse energy onto the target site calls for achieving irradiances at the target site above the threshold for ionization of molecules within the target site and giving rise to an avalanche process culminating in plasma formation. Since the maximal diameter of the lesion will consequently not be determined by the theoretical spot size of the laser beam but by the maximal outward expansion of the cavitation induced during plasma collapse, and since the maximal lesion capacity of the plasma is related to the amount of energy transferred into the plasma volume (and subsequently into a shock wave) by the laser pulse, considerable attention is needed to maintain the laser pulse energy within narrow variation tolerances. In one preferred embodiment of the present invention, this is achieved by a closed feedback loop, wherein each laser pulse emitted by the system is sampled to determine the actual energy being emitted. Any trends in emission energy can thus be identified allowing subsequent emitted pulse energies to be adjusted accordingly.
U.S. Food and Drug Agency regulations for medical laser devices currently require manufacturers of said devices to provide a means for measuring the output delivered to the human body to within an accuracy of +/xe2x88x9220%. There is no specification on emission tolerances for the laser beyond the constraints of safety and efficacy. However, verification of average pulse emission does not preclude 50% variations between consecutive pulses in a firing sequence. Such variation range is one of the reasons why xe2x80x9cmisfiresxe2x80x9d occur in many ophthalmic devices. It is not that the laser failed to fire, but that insufficient energy was emitted to achieve the desired or expected result because of unforeseen and undetected energy variations. For an automated system, such as the present invention, the emission for the laser needs to be monitored and adjusted to achieve far narrower pulse-to-pulse error tolerances.
In summary, it is among the objects of the present invention to greatly improve the accuracy, speed, range, reliability, versatility, safety, and efficacy of laser surgery, particularly ophthalmic surgery, by a system and instrument which continuously presents information to the surgeon/user during surgery as to the precise location, aim, and depth of the surgical laser and also as to surrounding features of the subject tissue, in three-dimensions. It is also an object of the invention to track movements of the subject tissue during surgery, particularly critical in eye surgery where eye movements can be very rapid and involuntary. It is further an object of the invention to provide a safe means of first establishing a reproducible firing sequence positioned in a three-dimensional space, and then firing the sequence in high repetition rates, thus obviating the time-consuming need to repetitively inspect, aim, and fire each shot before proceeding to the next target. Still another object is to provide a system applicable to non-medical fields wherein a laser beam is used to effect a precise operation on a target or series of targets subject to movement during the procedure. These and other objects, advantages, and features of the invention will be apparent from the following description of preferred embodiments, considered along with the accompanying drawings.
It is an object of the present invention to accommodate much more demanding tolerances in laser surgery, particularly eye surgery but also for other medical specialties, through a method, apparatus and system for high-precision laser surgery which provides the surgeon xe2x80x9clivexe2x80x9d images essentially in real time, containing the full supporting diagnostic information about depth and position at which a surgical laser will be fired. In a computer, the full information content of a given signal is interpreted so as to provide this supporting diagnostic information, and the resulting accuracy achievable is within a few human cells or better.

Automated laser workstation for high precision surgical and industrial interventions