A pressure-applying garment particularly suited for locating and applying pressure to transmitters is formed by a main inflatable bladder inflated to first pressure to press its inner wall toward a wearer and conform the inner wall to contours of said wearer and to apply the desired pressure between the wearer and a transmitter interposed between the main bladder and the wearer. A plurality of auxiliary inflatable bladders positioned relative to the main bladder and oriented to having their inner walls facing toward said wearer. The auxiliary bladders are provided with separate inflating systems so that at least some of said auxiliary bladders are inflated to a selected pressure different from (higher than) the first pressure to deform inner wall of its auxiliary bladder to conform with and press towards adjacent portions of said wearer and preferably to apply the desired pressure between the wearer and a transmitter interposed between the auxiliary bladder and the wearer.

The present invention relates to a garment, more particularly to a garment for applying pressure to a wearer and/or for positioning and applying pressure to transmitters (e.g. tactors or bio-feedback sensors) to press them against the wearer of the garment while accommodating body movement under positive or negative G (gravity pressure).
Loss of situation awareness (SA) and spatial disorientation (SD) are situations encountered for example by aviators and have been blamed for a significant number of aviation mishaps. SD can occur for example when there are missing or conflicting visual cues (e.g. in fog or white-out conditions) or when flight maneuvers greater than 1-G produce a false perception of rotation to the aviator.
The Tactile Situation Awareness System (TSAS), developed by the US Naval Aerospace Medical Research Laboratory (NAMRL) presents 3 dimensional orientation information to pilots and aircrew by taking advantage of an intuitive response produced upon stimulation of skin tactile receptors. TSAS uses for example, electromechanical or pneumatic transmitters generally known as tactors to provide tactile stimuli to the receptors (skin). The tactors produce small, rapid displacements of the skin, typically perpendicular to the skin surface of enough magnitude to excite the receptors. For example, tactile stimuli applied to the pilot""s chest in a fixed-wing aircraft indicate that the nose is going down. In a helicopter, tactile stimuli on the pilot""s right side or back indicate that the aircraft is sliding in those directions, helping the pilot to maintain a stationary hover without reference to the ground or instruments.
To maximize the transduction of the tactile stimuli to the skin receptors, the tactors are normally mounted to provide direct contact between the tactor and the skin of the wearer.
This pressure garment""s primary function is as a tactor locator system (TLS) to maintain tactor position and press the tactor against the skin by providing a counter pressure of sufficient magnitude to ensure transmission of the stimuli. Furthermore, the counter pressure should remain relatively constant to maintain repeatable tactile stimuli. The pressure that can be provided by a close-fitting garment is largely dependent on the local geometry of the body surface. Obtaining sufficient counterforce against the skin is a challenge particularly over concave body sites such as along the sternum between the pectoral muscles and in the lumbar region, which are among the ideal locations for tactor placement.
An inflatable cooling vest (Frim, J. and Michas, R. D. E, U.S. Pat. No. 5,243,706, issued Sep. 14, 1993; Frim, J. and Michas, R. D. E, CA Patent 2051358, issued Mar. 18, 1997) over the upper torso has successfully functioned as a TLS during rotary wing flight testing (Raj, A. K., Suri, N., Braithwaite, M. G., Rupert, A. (1999) The tactile situation awareness system in rotary wing aircraft: Flight test results. RTO HFM Symposium on xe2x80x9cCurrent Aeromedical Issues in Rotary Wing Operationsxe2x80x9d, RTO MP-19. 16-1 to 16-7) however skin contact was minimal and thus the success was limited.
NAMRL has proposed the use of 8 horizontally spaced (along the height of the user) rows of 12 circumferentially spaced (around the body of the user) tactors. The choice of 12 around the circumference of the garment is based on the hour hand of a clock, which has historically been used to describe location/direction. However, the array is not restricted to this configuration but will depend upon the specific needs of the environment in which TSAS is used.
A TLS providing a minimum of 15 grams (g), of tactor counterforce measured at 1 G (gravitational pressure) with an electromechanical tactor-sized load cell i.e. about 3.0 cm diameter and 7.7 mm thickness was deemed xe2x80x9cacceptablexe2x80x9d by NAMRL for intensity of the TSAS signal. Rotary-wing flight-testing of this system demonstrated that the information transmitted to the pilot via TSAS is easily interpreted with minimal training (Raj et al., 1999). In these devices the sensations transmitted to the user via the tactors are computer activated by sending the signals to and from the tactors to a suitable computer.
Counter pressure garments have been used for years to protect blood circulation either during shock (McCabe, F. J., U.S. Pat. No. 5,146,932, issued Sep. 15, 1992) or during exposure to increased gravity by aircrew (Clarke, D. M., CA Patent 672429, issued Oct. 15, 1963). Anti-gravity pressure suits (G protection suits) are worn to counter the effect of blood pooling in the lower limbs during unusual aircraft accelerations. Reddemann, H. et al. (U.S. Pat. No. 5,027,437, issued Jul. 2, 1991) combines G protection with active cooling whereas Bassick, J. W. and Dubois, E. A. (U.S. Pat. No. 5,003,630, issued Apr. 2, 1991) combines G protection with passive cooling via evaporation of sweat through vapour permeable bladders. Pressure garments have also been used to treat various medical conditions such as in the treatment of lymphedema (Kloecker, R. J., U.S. Patent Application 2002/0042585 A1, published Apr. 11, 2002) and to reduce scarring in burn patients (Cheng, J. D., Evans, J. H., Leung, K. S. Clark, J. A., Choy, T. T., Leung, P. C. (1984) Pressure therapy in the treatment of post-bum hypertrophic scarxe2x80x94A critical look into its usefulness and fallacies by pressure monitoring. Burns 10, 154-163.). However, there is no known counter pressure garment that conforms to the varied surface geometry of the body. Close fitting garments made of stretchable material such as that sold under the Trademark xe2x80x9cLycraxe2x80x9d will contact the skin around the circumference of the body but will not have contact over the areas of concave curvature such as along the chest sternum, upper and lower spine.
At 1 G (i.e. normal G) It has been found that a person can sense the skin displacement resulting from a counterforce on the tactor of 15 g. As G increases, a greater counter force is needed to hold the tactor against the skin such that the skin tactile receptors are sufficiently stimulated for the pilot to sense the signal.
The Lycra garments (pressure applying garments used to treat various medical conditions) tested by Cheng et al. (1984) had no pressure in the areas of concave curvature between the shoulder blades and lower back. To address this problem, they filled the body surface crevices under the garments with foam and similar materials to build up the contour and thus obtain pressure against the skin.
While the addition of foam in these pressure garments for treating medical conditions received limited success, this solution (addition of foam) is not satisfactory for use in a TLS garment as it adds insulation and contributes to heat stress in the cockpit. Also with repeated wear, the foam generally becomes less effective in applying pressure against the skin due to compression set.
The use of such stretchable garments is not satisfactory because after only a few hours of wear, stretch garments tend to lose elasticity making them less effective in applying pressure against the skin. Cheng et al. (1984) observed that the Lycra pressure garments they tested lost fabric elasticity and tension, reducing pressure against the skin after a 12 hour period.
Integrating sensors etc. into the garment and using the garment to hold them against the skin, is not a new concept. The xe2x80x98SmartShirtxe2x80x99 is an example (see http://www.time.com/time/2001/inventions/health/insensor.html) however; such a garment cannot for example provide sensor/tactor contact in the concave areas of curvature of the body. Furthermore obtaining a sufficient counter pressure against the tactors/sensors in a high gravity (G) environment (i.e. during aircraft acceleration) is a limitation that the SmartShirt concept is unlikely to overcome.
It is an object of the present invention to provide a garment for mounting tactors in strategic locations relative to the body of the user and for applying the desired amount of pressure holding the tactor against the user.
The main objective of the present garment is to provide tactor counter pressure against the skin over areas of the body that include the torso, upper arms and upper legs and other areas providing concave curvatures to the suit. A second objective is to reduce heat stress of aircrew by the removal of metabolic heat via convective cooling when attached to an air source and via the evaporation of sweat through the vapour permeable fabric of the garment.
The present invention could also be used to apply pressure to reduce scarring in bum patients. Broadly the present invention relates to a pressure applying garment comprising a body enclosing garment formed by a main inflatable bladder composed of opposed interconnected inner and outer walls, means interconnecting said inner and outer walls at spaced locations, means for inflating said main inflatable bladder to a first pressure to press said inner wall toward a wearer and conform said inner wall to contours of said wearer, a plurality of auxiliary inflatable bladders each formed by an inner expandable wall and a cooperating outer wall, said inner expandable wall having its outer surface relative to said auxiliary bladder facing toward said wearer when said wearer is wearing said garment, positioning means fixing said auxiliary bladders in selected positions relative to said garment and thereby said wearer when said garment is worn by said wearer, separate means for inflating at least some of said auxiliary bladders to a selected pressure different from said first pressure to deform said expandable inner wall of its auxiliary bladder to conform with and press towards adjacent portions of said wearer when said garment is being worn by said wearer.
Preferably said inner expandable walls of said auxiliary bladders are formed by portions of said inner wall of said main inflatable bladder.
Preferably said pressure applying garment further includes a plurality of transmitters mounted in spaced relationship at strategic locations on said garment in positions wherein said transmitters are located between said inner wall and said wearer when said garment is being worn by said wearer and pressed toward said wearer when said main inflatable bladder is inflated,
Preferably said pressure applying garment includes further transmitters associated with said auxiliary bladders and interposed between said expandable inner wall of their respective auxiliary bladder and said wearer when said garment is being worn by said wearer so that pressure in said auxiliary bladders force said further transmitters against said wearer.
Preferably, the positioning means of the auxiliary bladders comprises connecting means interconnecting said inner and outer wall of said main bladder around the outer periphery of each of said auxiliary bladders.
Preferably, the connecting means comprises welds.
Preferably, said auxiliary bladders include means to impede expansion of said cooperating outer wall of said auxiliary bladder.
Preferably, wherein said means to impede expansion of said cooperating outer wall of said auxiliary bladder comprises a stiffener panel interposed in said garment in facing relationship to said outer cooperating wall of said auxiliary bladder.
Preferably, said garment further comprises substantially parallel, elongated stiffener elements positioned in space relationship around the circumference of said garment and having their longitudinal axis extending substantially perpendicular to the circumferential direction of said garment.


A numerical control apparatus provides for manual shift operation involving feed shafts of a machine tool in terms of a work coordinate system easily and readily understood by an operator. The numerical control apparatus includes a manual shift amount input unit for receiving an amount of manual shift involving linear feed shafts as operator-input data in terms of a work coordinate system defined on the work revolved or rotated by a rotary feed shaft. The numerical control apparatus further includes a manual shift amount cumulative storage for cumulatively storing the received amount of manual shift in terms of a work coordinate system. Also included is a cumulative shift amount coordinate converter for converting the cumulative amount of shift from the work coordinate system data to data in terms of machine coordinate system defined on the machine tool. The apparatus's manual shift amount superimposing unit then superimposes the converted cumulative amount of shift on a controlled variable commanded in a machining program to generate the result to servo drivers.

Certain machine tools are equipped with a plurality of linear feed shafts and rotary feed shafts. Known rotary feed shafts include a type that allows the main spindle head mounting a tool to turn or revolve, a type that allows the table for mounting work to turn, and a combination thereof. In a typical machine tool provided with a rotary feed shaft, in order to cut work, the position of the tip of the tool is controlled along a desired path while operating the rotary feed shaft as well as the biaxial or triaxial linear feed shafts oriented orthogonally to one another.
For example, in the machine tool shown in FIGS. 8A and 8B, a table 1 is supported by a rotary feed shaft 2 with work 3 secured on the table 1. The work 3 is then machined by causing the table 1 to be revolved or turned and the tip of the tool 4 to be linearly moved from P0 to P1 to P2 (P0→P1→P2) on the work 3. During this machining, although the tip of the tool 4 moves linearly in terms of a work coordinate system (Xw-Yw) defined on the work as shown in FIG. 8A, the tip of the tool 4 moves along a curved line in terms of a machine coordinate systems (X-Y) fixed on the tool machine as shown in FIG. 8B.
In a cutting operation that involves revolution or rotation of the table 1, therefore, commands need to be generated that define a large number of minute linear blocks into which the tool path R (P0→P1→P2) is segmented. As such, computer aided manufacturing (CAM) is the commonly employed method for defining such minute line segments. In this approach, however, since CAM is a prerequisite for preparation of a machining program and the program itself tends to be lengthy, various methods have been proposed for directly commanding, in a machining program, the travel path of the tool tip in terms of a work coordinate system.
For example, Japanese Published Unexamined Patent Publication No. 2003-195917 describes a numerical control apparatus capable of shortening and generating a machining program with relative ease by using commands that define the travel path of the tip of a tool in terms of a work coordinate system and controlling a rotary feed shaft and linear feed shafts to cause the travel path to rotate with the table. In the example shown in FIGS. 8A and 8B, a command for the direct linear movement (P0→P1→P2) is generated in terms of the work coordinate system and the angle of the rotary feed shaft 2 and the movement of the tool 4 along the Xw and Yw axis are controlled according to this command.

Numerical control apparatus with manual shift operation functionality


A method and apparatus for reducing scan time, eddy currents and image factors in dynamic magnetic resonance (MR) imaging associated with at least a portion a k-space. The method includes scanning at least a portion of the k-space with an Echo-Planar Imaging (EPI) pulse sequence technique, acquiring a randomly under-sampled k-space; and reconstructing the under-sampled k-space utilizing a constrained reconstruction technique. A dynamic image is constructed of the at least a portion of the k-space based on EPI and the randomly undersampled k-space techniques to each segment of the EPI pulse sequence technique.

1. Field of the Disclosure
The present disclosure relates to Magnetic Resonance Imaging (MRI) methods that provide imaging with reference to time. More particularly, the present disclosure relates to improvements in scan time for MR imaging, in particularly accelerated 4D flow imaging.
2. Description of the Related Art
Medical imaging devices provide images of certain internal portions of a patient's body, and provides a vitally important tool in the detection and treatment of various medical conditions. Various types of medical imaging devices exist and often having respective advantages associated with performing imaging of different areas of the body to be viewed, such as ultrasonic diagnostic equipment, x-ray tomography equipment, magnetic resonance imaging equipment, and medical diagnostic equipment.
In general, magnetic resonance (MR) imaging equipment functions provide superior contrast images of soft tissues of a human body, as well as provide various types of diagnostic information. Therefore (MR) imaging equipment is a critical resource for diagnostic technology using medical images.
Image reconstruction in an MRI apparatus involves decoding of measured signals in order to identify and map spatial frequency components to spatial locations. While conventional Fourier reconstruction methods have been improved upon in recent years, constrained reconstruction methods use a priori information in order to compensate for a lack of high frequency data in a reconstruction process. Thus, the additional information to restore information beyond a measurement cutoff can be derived.
In addition, k-space refers to a matrix of spatial frequencies that has a mathematical relationship to an image (whose Fourier transform is the MR image), and in the case of digitized MRI signal data, virtually every point in k-space represents a spatial frequency and is used to add to signal intensity.
Moreover, Echo Planar Imaging (EPI) is a methodology that is used in part to obtain medical images. With regard to EPI, rather than measuring a single echo subsequent to transmitting a pulse, EPI permits the acquisition of many echoes. EPI is used to acquire more signals from an excitation pulse.
The use of EPI is seen as one possible way to reduce scan time because multiple k-space lines can be acquired for each phase, which is beneficial to Phase Contrast (PC) imaging in which flow encoding gradients are applied after each RF excitation.
However, conventionally, there have been some issues with EPI. While the acquisition time per slice with EPI can be on order of 100 ms/slice, there is a rather limited spatial resolution.
Recent advances in both hardware and software MR technologies have permitted EPI to be used for faster, higher temporal and spatial resolution flow imaging. However the importance of k-space trajectories used in EPI sequences increases when using EPI for faster, higher temporal images.
In general, a magnetic resonance (MR) imaging device includes imaging equipment that diagnoses internal structures of a human body using the energy—already converted to a signal—induced from resonance reactions obtained by applying a constant rate of frequency and energy to nuclei of atoms of a patient while a predetermined magnetic field is applied to the patient.
MR imaging extends beyond conventional 2D imagery, for example, 3D MRI, in which two dimensional slices are joined together so as to permit a 3-dimensional model, and dynamic imaging such as flow sensitive 4D MRI, which provides ECG synchronized flow sensitive 3DMRI. Flow sensitive 4D MRI data permits a useful quantification if items being directly measured, show as flow rates, and permits the use of pressure difference maps, pulse wave velocity, etc. Flow sensitive 4D MRI can permit analysis of blood flow through peripheral blood vessels, carotid artery, intracranial arteries, artificial valves, etc.
The scan time associated with dynamic imaging can be significantly long, on upwards of 30 minutes. Not only does this extended time increase costs of operation, but also discourages the use of such scanning as the accuracy and validity of such resulting data. Patients do not like and/or are sometimes able to be still for such a length of time, particularly when enclosed within a confined scanning area of the MRI apparatus.
Image reconstruction in an MRI apparatus involves decoding of measured signals in order to identify and map spatial frequency components to spatial locations. While conventional Fourier reconstruction methods have been improved upon in recent years, constrained reconstruction methods use a priori information in order to compensate for a lack of high frequency data in a reconstruction process. Thus, the additional information to restore information beyond a measurement cutoff can be derived.
In addition, k-space refers to a matrix of spatial frequencies that has a mathematical relationship to an image (whose Fourier transform is the MR image), and in the case of digitized MRI signal data, virtually every point in k-space represents a spatial frequency and is used to add to signal intensity.
Moreover, Echo Planar Imaging (EPI) is a methodology that is used in part to obtain medical images. With regard to EPI, rather than measuring a single echo subsequent to transmitting a pulse, EPI permits the acquisition of many echoes. EPI is used to acquire more signals from an excitation pulse.
The use of EPI is seen as one possible way to reduce scan time because multiple k-space lines can be acquired for each phase, which is beneficial to Phase Contrast (PC) imaging in which flow encoding gradients are applied after each RF excitation.
However, conventionally, there have been some issues with EPI. While the acquisition time per slice with EPI can be on order of 100 ms/slice, there is a rather limited spatial resolution.
Recent advances in both hardware and software MR technologies have permitted EPI to be used for faster, higher temporal and spatial resolution flow imaging. However, the importance of k-space trajectories used in EPI sequences increases when using EPI for faster, higher temporal images.
There is difficulty in providing high-resolution MRI of an object when there is motion is involved, for example, an MRI of organs such as the coronary arteries, lungs, etc. associated with both cardiac and respiratory motion. While there can be temporal triggering as the motion tends to be generally repetitive motion, the amount of scan time that can be needed to obtain an acceptable image can be excessive.
Moreover, heretofore it has not been feasible to obtain dynamic image with a 4D cine phase contrast as part of a clinical cardiac MRI protocol, as such cardiac MRI protocol includes evaluations of items such as function, anatomy, and scar imaging.
Accordingly, there is a long-felt need in the art to decrease the scan time of EPI methodologies when utilizing MR imaging in dynamic imaging, including but in no way limited to, for example, a 4D-PC flow imaging.

Methods and apparatus for reducing scan time of phase contrast MRI

Beth Israel Deaconess Medical Center, Inc.


The present invention encompasses albumin fusion proteins. Nucleic acid molecules encoding the albumin fusion proteins of the invention are also encompassed by the invention, as are vectors containing these nucleic acids, host cells transformed with these nucleic acids vectors, and methods of making the albumin fusion proteins of the invention and using these nucleic acids, vectors, and/or host cells. Additionally the present invention encompasses pharmaceutical compositions comprising albumin fusion proteins and methods of treating, preventing, or ameliorating diseases, disorders or conditions using albumin fusion proteins of the invention.

The invention relates generally to Therapeutic proteins (including, but not limited to, at least one polypeptide, antibody, peptide, or fragment and variant thereof) fused to albumin or fragments or variants of albumin. The invention encompasses polynucleotides encoding therapeutic albumin fusion proteins, therapeutic albumin fusion proteins, compositions, pharmaceutical compositions, formulations and kits. Host cells transformed with the polynucleotides encoding therapeutic albumin fusion proteins are also encompassed by the invention, as are methods of making the albumin fusion proteins of the invention using these polynucleotides, and/or host cells.
Human serum albumin (HSA, or HA), a protein of 585 amino acids in its mature form (as shown in FIG. 1 (SEQ ID NO:1)), is responsible for a significant proportion of the osmotic pressure of serum and also functions as a carrier of endogenous and exogenous ligands. At present, HA for clinical use is produced by extraction from human blood. The production of recombinant HA (rHA) in microorganisms has been disclosed in EP 330 451 and EP 361 991.
Therapeutic proteins in their native state or when recombinantly produced, such as interferons and growth hormones, are typically labile molecules exhibiting short shelf-lives, particularly when formulated in aqueous solutions. The instability in these molecules when formulated for administration dictates that many of the molecules must be lyophilized and refrigerated at all times during storage, thereby rendering the molecules difficult to transport and/or store. Storage problems are particularly acute when pharmaceutical formulations must be stored and dispensed outside of the hospital environment.
Few practical solutions to the storage problems of labile protein molecules have been proposed. Accordingly, there is a need for stabilized, long lasting formulations of proteinaceous therapeutic molecules that are easily dispensed, preferably with a simple formulation requiring minimal post-storage manipulation.

This patent is subject to a terminal disclaimer.


Systems and apparatuses are provided for placing interconnects or connector modules into stacked arrangements, wherein individual interconnects or connector modules can be readily accessed and repaired without disrupting the stacked arrangement. In one embodiment, the electrical connector system has a plurality of interconnects mounted together in a stacked arrangement. Each of the interconnects comprises a connector body and a backshell removably coupled to the connector body, wherein the backshell is configured to receive and retain a overbraid. Each backshell is designed to be uncoupled from the connector body while retaining the plurality of interconnects in the stacked arrangement, thereby making is possible to repair single a interconnect without disrupting the others.

1. Field of the Invention
The present invention is directed towards connection systems for communicating electrical signals, and more particularly, to systems and apparatuses with stacked arrangements of interconnects that can be easily accessed and repaired.
2. Description of Related Art
With the increasing demand and complexity of modern electronic systems in high reliability applications such as military and aerospace, there is a continuing need to incorporate electronic equipment into a confined space while ensuring reliability in harsh environments. In such applications, connection systems provide a critical communication link between physically separated electronic devices. These connection systems have to satisfy many competing requirements. They should be capable of withstanding a rugged environment that includes vibration, wide temperature swings, moisture, and exposure to hazardous materials and chemical contaminants. Components of the connection systems should also be both compact and easily accessible to permit repair or replacement of damaged components while limiting disruption or removal of other undamaged components.
Such connection systems typically frequently utilize connector devices or interconnects that interface with the leading ends of cables, overbraids, or the like. Such interconnects typically comprise pins or connectors on a first end, as well as a backshell on a second end for interfacing with the overbraids or the like. While such interconnects are designed to withstand rugged environments, some inevitably become damaged or non-functional during operation, and need to repaired or replaced. Design demands of electronics systems often require that the components of a system fit into a compact space. As such, interconnects are frequently placed into close proximity with each other, and are often stacked relative to each other. Such interconnects are frequently modular in design, and frequently are placed into stacked arrangements.
Placing interconnects into a stacked arrangement, however, makes it difficult to access and repair any one of the interconnects, particularly when the damaged interconnect is located in the middle or toward the bottom of the stack. As such, stacked interconnects are typically disassembled in order to access the particular interconnects that require repair or need to be replaced. This increases the number of parts that need to removed from the system, which in turn increases the amount of time needed to reassemble the system, thereby increasing the time and costs associated with repairing such systems.
Accordingly, it would be desirable to provide a connection system with stacked components, such as interconnects or the like, that can be more easily accessed and repaired.

Modular interconnect system and apparatus

Deutsch Engineered Connecting Devices, Inc.


Systems and methods for signaling information related to wireless device positioning in a cellular communications network are disclosed. In some embodiments, a method of operation of a first network node for signaling information related to wireless device positioning in a cellular communications network comprises signaling, from the first network node to a second node, information comprising information that relates to a new vertical surface model for a plurality of cells in a cellular communications network. The new vertical surface model is a translated and scaled version of an initial vertical surface model.

Since the standardization of Fifth Generation (5G) positioning technology has not yet been finalized, the Long Term Evolution (LTE) system is used to describe the conventional technology and some of the solutions. The solutions for 5G are expected to be similar, and the present description should therefore not be seen as a limitation to the Fourth Generation (4G) LTE systems.
I. New Federal Communications Commission (FCC) Requirements and Need for Time Difference of Arrival (TDOA) Positioning
To understand the background of the present disclosure, the new E-911 positioning requirements mandated by the US FCC needs to be reviewed. The FCC E-911 emergency positioning requirements mandate the positioning performance that must be met by cellular operators in the US. To account for the increased amount of cellular indoor traffic, the FCC tightened its requirements in February 2015 to specify:                A 50 meter horizontal accuracy must be provided for 40%, 50%, 70%, and 80% of all emergency calls within two, three, five, and six years, respectively.        For vertical positioning performance, operators should propose an accuracy metric within three years to be approved by the FCC. Operators need to comply with the metric within six years. To facilitate an enhanced vertical accuracy, all services must make uncompensated barometric data available from any handset that has the capability to deliver barometric sensor data.        The response time shall be less than 30 seconds after the E-911 call is placed for 90% of all calls.
Support for barometric measurement reporting was introduced in the LTE 4G cellular system, Release 14. It needs to be kept in mind that originally the vertical accuracy requirement discussions driven by the FCC called for a vertical inaccuracy of less than three meters for the majority of the E-911 positioning attempts. Since the final values are yet unknown, the three meter requirement is kept here as a working assumption. The underlying reason for the three meter requirement is the need to point out the floor of the user when inside tall buildings.
One may ask why there is a need for TDOA positioning, due to the wide-spread availability of Global Positioning System (GPS) receivers in cell phones today. The reasons include, e.g., the fact that satellite based positioning like GPS and Assisted GPS (A-GPS) has very poor availability indoors; then, e.g., E-911 positioning requires other high precision methods. Only TDOA based positioning methods have this high precision potential. Secondly, in case of lawful intercept, terrorists and other criminal elements may very well turn off satellite based positioning services to avoid interception. However, when their phones stay on, the cellular network may obtain their positions by application of TDOA based positioning.
II. Positioning Technology Overview
A. Positioning Architecture of LTE
Since 5G positioning standardization is not close to finalization at the time of writing of the present disclosure, the positioning architecture of the LTE system is briefly reviewed here. The positioning architecture is believed to become similar in the 5G cellular systems that are currently being standardized.
The three important network elements in any positioning architecture are the Location Service (LCS) client, the LCS target, and the LCS server. The LOS server is a physical or logical entity managing positioning for a LOS target device by obtaining measurements and other location information, providing assistance data to assist User Equipment devices (UEs) in measurements, and computing or verifying the final position estimate. A LOS client is a software and/or hardware entity that interacts with a LOS server for the purpose of obtaining location information for one or more LCS targets, i.e. the entities being positioned. LOS clients may reside in the LCS targets themselves. LOS clients subscribe to LOS to obtain location information, and LOS servers process and serve the received requests and send the positioning result, e.g., to the LOS target. Depending on the positioning method, a location may be obtained based on radio signals received by and/or transmitted from the LOS target. The radio signals transmitted from the LOS target are typically received by enhanced or evolved Node Bs (eNBs), and the radio signals received by the LOS target are typically transmitted from eNBs or satellites. However, to further enhance the positioning methods based on radio signals received by the LOS target, an additional Terrestrial Beacon System (TBS) may be deployed. The TBS consists of a network of ground-based transmitters, broadcasting signals only for positioning purposes. The signals comprise the non-LTE Metropolitan Beacon System (MBS) signals, as well as the LTE Positioning Reference Signals (PRSs), these signals corresponding to two different beacon types. To enhance positioning methods based on radio signals transmitted from the LOS target, additional Location Measurement Units (LMUs) may be deployed in a standalone manner. The LMUs may also be co-located with or integrated into eNBs. The purpose of the LMUs is to perform measurements on uplink radio signals transmitted by the LOS target and to report the measurements to the LOS server.
In LTE Release 9, two new protocols were standardized specifically to support positioning, the LTE Positioning Protocol (LPP) and the LTE Positioning Protocol Annex (LPPa). The LPP is a point-to-point protocol between a LOS server and a LOS target device, used in order to position the target device. The following transactions have been specified: capability transfer procedure (request/provide messages), assistance data transfer procedure (request/provide messages), and a location information transfer procedure (request/provide messages). Multiple LPP procedures of any of the aforementioned types can be used in series and/or in parallel. LPP is used both by control plane and user plane positioning solutions. LPPa is specified only for control plane positioning procedures. However, with the user plane and the control plane interworking, LPPa can also assist the user plane solution by querying eNBs for information and eNB measurements not related to a UE connection. Another positioning protocol, SLmAP, over the SLm interface between the LMU and the LOS server was introduced in LTE Release 11 to support Uplink TDOA (U-TDOA).
To support LOS, at least two functional nodes must be present in the LTE control plane architecture: the Evolved Serving Mobile Location Center (E-SMLC), which controls the coordination and scheduling of the resources required to locate the mobile device, and the Gateway Mobile Location Center (GMLC), which controls the delivery of position data, user authorization, charging, and more. The LPP messages are transmitted transparently to the Mobility Management Entity (MME), using Radio Resource Control (RHO) as a transport over the LTE-Uu interface between the UE and the E-SMLC, using S1-AP over the S1-MME interface, and using LOS Application Protocol (AP) over the SLs interface between the eNB and the E-SMLC. LPPa conducts the LPPa location.
Information transfer procedures for positioning-related information. LPPa is also transparent to the MME which routes the LPPa packets transparently over the S1-MME and SLs interfaces without knowledge of the involved LPPa transaction. The LTE positioning architecture for the control plane is shown in FIG. 1. To describe the operation of the architecture, consider the case where the MME receives a positioning request for some LCS associated with a particular LCS target (e.g., a UE). The MME then sends a LCS request in a LCS-AP Location Request message to an E-SMLC. The E-SMLC processes the location services request to perform a positioning of the target UE. The E-SMLC then returns the result of the location service back to the MME.
In general, Secure User Plane Location (SUPL) supports and complements control plane protocols to enable Location Based Services (LBS) support with the least possible impact on the control plane and the deployed network. The LTE user plane positioning architecture is shown in FIG. 2. SUPL uses established data-bearing channels (i.e., the LTE user plane) and positioning protocols (i.e., LPP) for exchanging the positioning-related data between a LOS target and a LOS server. In the general user plane protocol stack, SUPL occupies the application layer with LPP transported as another layer above SUPL. After establishing a Transmission Control Protocol (TOP)/Internet Protocol (IP) connection and initiating the SUPL and then LPP sessions, the flow of LPP messages can be the same as in the control plane version of LPP, just with the SUPL Enabled Terminal (SET) as the LOS target and the SUPL Location Platform (SLP) as the LOS server. The SLP implements the SUPL Location Center (SLC) and the SUPL Positioning Center (SPO) functions with the latter either being integrated in the E-SMLC or attached to it with a proprietary interface. The SLC system coordinates the operations of SUPL in the network and implements the following SUPL functions as it interacts with the SET over the user plane bearer: privacy function, initiation function, security function, roaming support, charging function, service management, and position calculation. The SPC supports the following SUPL functions: security function, assistance delivery function, SUPL reference retrieval function (e.g., retrieving data from a GPS reference network), and SUPL position calculation function.
B. Air Interface Resource Grid and Positioning Reference Signals
The 4G and 5G air interfaces both employ variants of so called Orthogonal Frequency Division Multiplexing (OFDM) Access (OFDMA) transmission schemes. These schemes operate on a time-frequency grid. In the frequency domain, the bandwidth is divided in so called subcarriers. In the 4G LTE system and at low carrier frequencies (15 kilohertz (kHz) and possibly 30 kHz), subcarrier spacing is used. At the high millimeter wave (mmw) carrier frequencies, the subcarrier spacing may typically be 120 kHz or 240 kHz. In the time domain, the transmission is organized in so called OFDMA symbols. In LTE, there are 14 OFDM symbols in each millisecond (ms), while sub-ms time intervals in the 5G standard also occupy 14 OFDMA symbols. An example part of the time frequency grid of the LTE downlink is depicted in FIG. 3.
FIG. 3 depicts the locations of the PRSs. These signals are known pilot signals upon which the receiver can measure, e.g., Time Of Arrival (TOA). This is of central importance for the present disclosure since the TOAs are the measurements behind the disclosed new positioning methods.
In the LTE uplink, these TOA measurements are instead done on transmitted Sounding Reference Signals (SRSs).
In the 5G system, the definitions of the PRSs are not yet finally defined; however, they will need to be based on similar considerations as in the LTE 4G system.
C. Signaling of Positioning Information
A positioning result is a result of processing of obtained measurements, including cell Identifiers (IDs), power levels, received signal strengths, etc., and it may be exchanged among nodes in one of the predefined formats. The signaled positioning result is represented in a predefined format corresponding to one of the so called Geographical Area Description (GAD) shapes. Other formats, e.g. string address format, are also known.
In LTE, the positioning result may be signaled between:                LCS target and LCS server, e.g. over LPP protocol,        Positioning servers (e.g., E-SMLC and SLP) over standardized or proprietary interfaces,        Positioning server and other network nodes (e.g., E-SMLC and MME/Mobile Switching Center (MSC)/GMLC/Operation and Maintenance (O&M)/Self-Organizing Network (SON)),        Positioning node and LCS client (e.g., between E-SMLC and Public Safety Answering Point (PSAP) or between SLP and external LCS client or between E-SMLC and UE).
There are seven GAD shapes. The polygon shape is discussed in the next subsection where the Cell Identifier (CID) positioning method is described. The other six formats are:                Ellipsoid arc: The ellipsoid arc is described by a center point (eNB antenna position), encoded as latitude, longitude in World Geodetic System (WGS) 84 coordinates. Furthermore, the format contains an inner radius of the arc, a thickness of the arc, as well as the offset angle (clockwise from north) and the included angle (opening angle). Together, these parameters define a circular sector, with a thickness and with left and right angles. The ellipsoid arc carries confidence information. This format is, for example, produced by cell ID+Timing Advance (TA) positioning in LTE        Ellipsoid point: The ellipsoid point format is described by a center point, encoded as latitude, longitude in WGS 84 coordinates. The format neither carries uncertainty nor confidence information.        Ellipsoid point with uncertainty circle: The ellipsoid point with uncertainty circle format consists of a center point, encoded as latitude, longitude in WGS 84 coordinates, in combination with a radial uncertainty radius. The format does not carry confidence information. This is addressed by the present disclosure.        Ellipsoid point with uncertainty ellipse: The ellipsoid point with uncertainty ellipse format consists of a center point, encoded as latitude, longitude in WGS 84 coordinates. The uncertainty ellipse is encoded as a semi-major axis, a semi-minor axis, and an angle relative to north, counted clockwise from the semi-major axis. The format carries confidence information. This format is typically produced by Observed TDOA (OTDOA) and A-GPS positioning in LTE.        Ellipsoid point with altitude: The ellipsoid point with altitude format is encoded as an ellipsoid point, together with an encoded altitude. The format neither carries uncertainty nor confidence information.        Ellipsoid point with altitude and uncertainty ellipsoid: This is the format commonly received from A-GPS capable terminals. It consists of an ellipsoid point with altitude and an uncertainty ellipsoid, the latter encoded with a semi-major axis, a semi-minor axis, an angle relative to north, counted clockwise from the semi-major axis, together with an uncertainty altitude. The format carries confidence information. This format is typically produced by A-GPS positioning in LTE.
D. CID Positioning
All cellular systems are divided into cells, served by one specific base station. Each base station may serve more than one cell. The important point from a positioning and navigation perspective is that the cell where a specific UE is located is known in the cellular system. Hence, after determination of the geographical area covered by a specific cell, it can be stated that the UE is located somewhere within said geographical area, as long as it is connected and the reported cell identity of the serving cell is equal to the cell identity of the particular geographical area.
In several systems, the preferred representation of the geographical extension of the cell is given by the cell polygon format. The extension of a cell is described by 3-15 corners of a closed polygon which does not intersect itself. The format is two-dimensional and the corners are determined as pairs of longitudes and latitudes in the WGS 84 geographical reference system, see FIG. 4 and FIG. 5 for details. The polygon format is at the focal point of the present disclosure.
E. Enhanced CID (E-CID) Positioning
E-CID methods exploit four sources of position information: the CID and the corresponding geographical description of the serving cell, the TA of the serving cell, the CIDs and the corresponding signal measurements of the cells (up to 32 cells in LTE, including the serving cell), as well as Angle of Arrival (AoA) measurements. The following techniques are commonly used for E-CID:                CID+TA (combining of the geographical cell description, the eNB position, and the distance between the eNB and the UE obtained from a time measurement, where the timing measurement is TA in LTE),        Signal strength (distance measures are derived from signal strengths measured in the UE and combined with cell polygons as for CID and TA),        AoA (e.g., defining the angle of a UE with respect to a reference direction which is the geographical North).
In 5G systems, large antenna arrays are expected to become common. This implies that the accuracy of AoA will improve dramatically, as compared to present systems. In addition, the improved resolution will be available both in azimuth and elevation. This means that for small 5G cells it will be possible to find a very accurate direction from the base station to the UE. In 5G, the radio bandwidth will also increase, the consequence of which is an increased time resolution. This improvement carries over to a correspondingly better range inaccuracy. When AoA and TA information is combined in 5G, it will hence become possible to determine a small volume where the UE is located, perhaps with only a few meters inaccuracy in all dimensions. This means that E-911 requirements are likely to be met in small 5G cells, indoor and outdoor. However, for large rural cells this is no longer true since the inaccuracy of AoA scales linearly with the distance from the base station to the UE.
F. Adaptive E-CID Fingerprinting
Fingerprinting positioning algorithms operate by creating a radio fingerprint for each point of a fine coordinate grid that covers the Radio Access Network (RAN). Fingerprinting methods are typically not standardized and rely on measurements collected, e.g., for E-CID, OTDOA, etc. or even measurements originally collected for other purposes than positioning.
In LTE the fingerprint may, e.g., consist of:                The cell IDs that are detected by the terminal, in each grid point.        Quantized path loss or signal strength measurements, with respect to multiple eNBs, performed by the terminal, in each grid point. Note: an associated ID of the eNB may also be needed.        Quantized TA, in each grid point. Note: an associated ID of the eNB may also be needed.        AoA measurements performed in one or several eNBs.
Whenever a position request arrives to the positioning method, a radio fingerprint is first measured, after which the corresponding grid point is looked up and reported. This of course requires that the point is unique.
The database of fingerprinted positions (the radio map) can be generated in several ways. A first alternative would be to perform an extensive surveying operation that performs fingerprinting radio measurements repeatedly for all coordinate grid points of the RAN. The disadvantages of this approach include:                The surveying required becomes substantial also for small cellular networks.        The radio fingerprints are in some instants (e.g., signal strength) sensitive to the orientation of the terminal, a fact that is particularly troublesome for handheld terminals. For fine grids, the accuracies of the fingerprinted positions therefore become highly uncertain. This is unfortunately seldom reflected in the accuracy of the reported geographical result.
Another approach is to replace the fine grid by high precision position measurements of opportunity, and to provide fingerprinting radio measurements for said points. This avoids the above drawbacks, however:                Algorithms for clustering of high precision position measurements of opportunity needs to be defined.        Algorithms for computation of geographical descriptions of the clusters need to be defined.
The above two problems are addressed by previous patents on the Adaptive E-CID (AECID) positioning method. This is further described below.
Of particular importance for the present disclosure is the augmentation of AECID with altitude information. U.S. Pat. No. 8,892,124 discloses how the AECID algorithm can be used to provide polygons with altitude information augmented to each corner. This is a starting point for the present disclosure. In addition, U.S. Pat. No. 8,170,582 discloses reporting format details and signaling aspects for a polygon with augmented altitudes.
G. Assisted Global Navigation Satellite System (A-GNSS)
A-GPS positioning is an enhancement of the GPS. A-GPS is a subset of the A-GNSS positioning method supported in LTE for UEs that are equipped with radio receivers capable of receiving Global Navigation Satellite System (GNSS) signals. Examples of satellite systems of A-GNSS include GPS, modernized GPS, Galileo, Global Navigation Satellite System (GLONASS), and Beidu. The operation of satellite based systems like A-GPS is well known today and can be studied in many textbooks.
H. TDOA Positioning
TDOA positioning is the principle used for the present disclosure, and a more extensive description of TDOA positioning is therefore provided below.
III. TDOA Positioning
A. OTDOA
The downlink OTDOA method relies on measurements, typically on PRSs in LTE, see above, from multiple base stations. The measurement is performed by means of correlation with the known signals of the base stations measured upon. The situation is depicted in FIG. 6.
Assuming that the measurements are successful for a number of cells, three of which are depicted in FIG. 6, the following relations between the measured TOAs in the terminal, the transmission times from the base stations (eNBs in LTE), and the distances between the terminals and the base stations follow:
                                                           t                                                T                                    O                                    A                                ,                1                                      +                          b              clock                                =                                    T              1                        +                                                                                                r                    1                                    -                                      r                    Terminal                                                                                                            /                                          c                                                          ⋮                                                                t                                                T                                    O                                    A                                ,                n                                      +                          b              clock                                =                                    T              n                        +                                                                                                r                    n                                    -                                      r                    Terminal                                                                                                            /                                                          c                .
Here tTOA,i,i=1, . . . , n denotes the measured TOAs in the terminal, Ti, i=1, n denotes the transmission times from the eNBs, and c is the speed of light. The boldface quantities are the (vector) locations of the base stations and the terminal. bclock denotes the unknown clock bias of the terminal with respect to cellular system time. Now, in TDOA positioning, TOA differences with respect to the own site are formed according to:
                              t                      TDOA            ,            2                          =                                            t                                                T                                    O                                    A                                ,                2                                      -                          t                                                T                                    O                                    A                                ,                1                                              =                                    T              2                        -                          T              1                        +                                                                                                r                    2                                    -                                      r                    Terminal                                                                                                            /                                          c                        -                                                                                                r                    1                                    -                                      r                    Terminal                                                                                                            /                                          c                                                      ⋮                                    t                                    T                            D                            O                            A                        ,            n                          =                                            t                                                T                                    O                                    A                                ,                n                                      -                          t                                                T                                    O                                    A                                ,                1                                              =                                    T              n                        -                          T              1                        +                                                                                                r                    n                                    -                                      r                    Terminal                                                                                                            /                                          c                        -                                                                                                r                    1                                    -                                      r                    Terminal                                                                                                            /                                                          c                .
Note that the formation of differences eliminates bclock. In the above n−1 equations, the left hand sides are known (with some additional measurement error), provided that the time of transmission differences (denoted the real time differences) can be measured. This is normally achieved with dedicated LMUs, see above, or by other procedures. Further, the locations of the base stations, ri, i=1, . . . , n, can be surveyed to within a few meters and so they are known as well. What remains unknown is the terminal location, i.e.rTerminal=(xTerminalyTerminalzTerminal)T.In the more common case, a two dimensional positioning is performed the unknown position is insteadrTerminal=(xTerminalyTerminal)T.
It then follows that at least three TOA differences are needed in order to find a three dimensional (3D) terminal position and that at least two TOA differences are needed in order to find a two dimensional (2D) terminal position. This, in turn, means that at least four sites need to be detected for 3D terminal positioning and at least three sites need to be detected for 2D terminal positioning. In practice, accuracy can be improved if more measurements are collected and a maximum likelihood solution is introduced. There may also be multiple (false) solutions in cases where only a minimum number of sites are detected.
The OTDOA method belongs to the set of high precision methods, the inaccuracy is however significantly larger than that of A-GNSS. The main advantage of OTDOA is that it provides high precision positioning also indoors, a situation where the availability of A-GNSS is very limited.
B. U-TDOA
The U-TDOA method differs from the OTDOA method in the sense that pilot signals are transmitted by the UE, with TOA measurements being performed in multiple base stations. Typically, SRSs are used as pilot signals. The position calculation is performed in the same way as the OTDOA method. Therefore OTDOA and U-TDOA are both handled by the present disclosure.
C. Hybrid Positioning
The present disclosure discloses a new method for hybrid positioning; therefore, the state of the art of TDOA hybrid positioning methods is discussed below.
IV. Hybrid TDOA Positioning
A. TDOA Positioning Aspects
In many rural positioning topographies, the landscape is relatively flat. This means that the base stations are located in almost the same horizontal plane. This horizontal geometry makes it difficult to estimate the vertical position coordinate of a UE, leading to large vertical inaccuracy for TDOA positioning methods.
Another aspect is that a dense deployment of base stations is often not economical in rural areas. As a consequence, the inter-site distance becomes large. This affects the possibility for mobiles to detect neighbor base station transmissions, and it affects the possibility for neighbor base stations to receive UE transmission. As a consequence, OTDOA and U-TDOA both experience problems in that few TDOAs can be used for the position calculation. Sometimes this number is only two, in which case only a horizontal position calculation is possible.
B. Hybrid TDOA Positioning
The hybrid TDOA positioning method that is of interest was disclosed in U.S. Pat. No. 7,203,499. In that patent, a method is disclosed that replaces the unknown vertical position of the TDOA equations with a predetermined function of the lateral coordinates, thereby reducing the TDOA equations to dependency only of the two lateral unknown UE coordinates. After these unknowns have been determined, the predetermined function is evaluated to obtain the vertical coordinate. It is stressed that U.S. Pat. No. 7,203,499 does not specify the function, it states that Geographical Information System (GIS), i.e. typically maps, is used to define the function of the lateral coordinates.
C. Vertical Surface Modeling
The vertical surface modeling that is of interest also needs to be discussed. The relevant disclosure is U.S. Pat. No. 7,676,232, which discloses a surface modeling method where a polygon format is the starting point. Map data is then used to extract the altitude for each corner point, said altitudes can then be encoded as Third Generation Partnership Project (3GPP) points and augmented with the polygon. This information is then signaled over an interface. At the other end of the interface, a vertical function, like the one discussed in the previous section, is then computed, e.g., with least squares techniques.

Signaling of scaled 3D position information


A data access arrangement circuit (60) for supplying electrical isolation between a telephone line (11) and a data device, such as a data terminal or a computer, connected to a modem (10). An isolation circuit (17) connected between a first modem circuit (15) having a transmitter (19), a receiver (20), and a controller (18), and a second modem circuit (16) connected to the telephone line (11), couples signals between the first modem circuit (15) and the second modem circuit (16), thereby electrically isolating the first modem circuit (15) from the second modem circuit (16). The second modem circuit (16) conditions an incoming analog telephone signal received via the telephone line (11) to supply an incoming digital data signal to the receiver (20). The second modem circuit (16) further conditions an outgoing digital data signal received from the transmitter (19) to supply an outgoing analog telephone signal for transmission over the telephone line (11). The isolation circuit (17) couples the incoming data signal, the outgoing data signal, and control signals between the second modem circuit (16) and the first modem circuit (15) while electrically isolating the second modem circuit (16) from the first modem circuit (15) A first power source (21) supplies operating power to the first modem circuit (15) and a second power source (22) draws power only from the telephone line (11) to supply operating power to the second modem circuit (16). Electrical isolation between the first modem circuit (15) and the second modem circuit (16) is maintained by the use of these separate power sources.

The Federal Communications Commission (FCC) has issued a stringent set of regulations and specifications that must be satisfied by equipment intended for connection to a telephone line to prevent such equipment from degrading the operation of the network. This equipment, such as a modem, must satisfy these regulations and specifications before the equipment is connected to the telephone network. Generally, some form of electrical isolation circuitry is required to prevent voltage transients or surges generated by the equipment from reaching the telephone line and thereby degrading telephone network operation. Further, the connected equipment must not provide a path from the telephone line to ground.
The use of a transformer within a modem to electrically isolate the telephone line is well known. Typically, a directly coupled or capacitively coupled isolation transformer is connected between the two wire telephone line and the analog front end of the modem circuit to provide the necessary electrical isolation.
Although a transformer supplies a high degree of electrical isolation, the transformer is also one of the physically largest and heaviest electrical components in a typical modem circuit. The placement of the transformer on a modem printed circuit board having limited board layout space is a challenging design task because the transformer is much larger than the other electrical components of the remaining modem circuitry. Furthermore, the overall weight of a modem is typically significantly increased by the use of the isolation transformer in a modem design. Consequently, the physical size and weight of the modem, as well as the appearance of the packaging or housing for a modem, is often constrained by the physical characteristics of the isolation transformer.
A modem is often utilized with a portable computer system for communicating data between a remote site and a central computer location. Portable personal computers, such as laptop and notebook personal computers, are of small size and low weight and generally require peripheral devices of proportional small size and low weight. The portability of a laptop or a notebook computer is limited if a necessary peripheral device, such as a modem, is of significant size or weight when compared with the computer. Therefore, the users of such small size portable computers require a reduced sized modem package that is thinner and lighter than modems intended for use with larger personal computers employed in a stationary location, such as desktop personal computers.
The Personal Computer Memory Card International Association (PCMCIA) has established an industry standard for connecting a peripheral device to a small sized personal computer, such as a laptop or a notebook computer. To date, the small sized modems compatible with this industry standard, often described as thin modems, utilize an external "plug-in" or outboard isolation transformer to supply the proper voltage levels to the modem and to electrically isolate the telephone line from the computer. The transformer, which connects to a power outlet during modem operation, is physically separated from the remaining modem circuitry by a cable, thereby enabling the thin modem to be conveniently installed within or adjacent to the housing of the small sized computer. However, the portability of a small sized computer connected to a thin modem having an external isolation transformer remains limited by the bulky size and weight of the outboard transformer.
To reduce the size and weight of the isolation transformer, it is well known to provide one signal path for coupling certain telephone line signals, such as incoming ringing signals, to the modem circuitry and another signal path which couples the data signals to the modem circuitry via a capacitively coupled isolation transformer. This capacitive coupling design enables the use of a smaller and lighter isolation transformer by preventing saturation of the small core of the transformer. Nevertheless, a transformer is still required by this prior art design to provide the necessary isolation between the telephone line and the modem circuitry.
Alternative prior art modems utilize electro-optical isolators to isolate the telephone line from the data device. Electro-optical isolators typically employ an emitter, such as a light emitting diode (LED), which supplies a light signal in response to an input electrical signal, and a photodetector that supplies a corresponding electrical output signal in response to the the received light signal. The use of electro-optical isolators for electrically isolating an input circuit from an output circuit is well known.
U.S. Pat. Nos. 4,373,117, 4,417,099, and 4,578,533, all to Pierce, and U.S. Pat. No. 4,395,590 to Pierce et al. describe a line powered modem that derives its operating power entirely from the telephone line and uses electro-optical isolators within receiver and transmitter data buffers located between the telephone line and an RS-232 serial interface to electrically isolate the telephone line. However, the Pierce line powered modem also includes a DC-to-DC converter that utilizes a two-winding transformer to supply the proper voltage levels for the RS-232 interface and to provide additional electrical isolation between the telephone line.
U.S. Pat. No. 4,592,069 to Redding describes a line powered modem that obtains its entire operating power from the telephone line and uses an electro-optical isolator located at each of the data input terminals and the data output terminals of the modem. The electro-optical isolators electrically isolate the terminals from the remaining modem circuitry to provide the required isolation for the telephone line. The Redding line powered modem further uses an inductance simulation circuit to prevent the power supply from loading down the AC signal on the telephone line, thereby assisting the construction of the modem circuit as a single integrated circuit. However, the power consumption of the Redding line powered modem is limited because the modem does not have a power source separate from the telephone line and FCC regulations limit the amount of power that can be drawn from the telephone line. Also, the Redding modem is a relatively simple modem having only a frequency shift keying (FSK) mode and does not support other high level or advanced communications modes, such as phase shift keying (PSK) or PSK combined with pulse amplitude modulation (PAM).
Therefore, there is a need for a small sized, advanced modem that has sufficient power capability to support high level communications modes and does not use a transformer for electrically isolating the telephone line from the data device. The present invention uses electro-optical isolators for coupling signals between a first modem circuit including a transmitter, a receiver and a controller, and a second modem circuit connected to the telephone line, thereby electrically isolating the telephone line. Electro-optical isolator devices, which are typically packaged within a dual in-line package, are sufficiently small to allow the construction of a thin modem. The present invention further uses separate power sources to power the first and second modem circuits, thereby supplying the necessary power to support advanced communications modes, and to maintain the electrical isolation provided by the electro-optical isolator devices connected between these modem circuits.

Apparatus for electrically isolating a telephone line from a data device


Amorphous silicas suitable for use as abrasives in transparent toothpastes can be prepared by a precipitation route. These silicas are distinguished by having a BET surface area of 420 to 550 m.sup.2 /g, a weight mean particle size of 5 to 20 micron, a perspex abrasion value of 15 to 28, a mean pore diameter from 3 to 8 nm and a transmission of at least 70% in the R1 range from 1.444 to 1.460.

Toothpaste compositions are well characterized in the literature and many compositions are disclosed in patent specifications and other literature. Toothpaste compositions contain a number of specific components for example abrasive agents, fluoride sources, binders, preservatives, humectants, anti plaque agents, colouring agents, water, flavour and other optional ingredients. Of these components the abrasive agent is required to provide the appropriate cleaning and plaque removal without subjecting the tooth itself to excessive abrasion. Typically a toothpaste composition will contain from about 5% to about 50% preferably up to about 30% by weight of abrasive. Commonly used abrasives are aluminas, calcium carbonates and calcium phosphates. More recently synthetic silicas have been adopted because of their efficient cleaning, compatibility with other ingredients and their physical properties. An important property of a silica for use in transparent toothpaste formulations is refractive index, and it has been shown that this property can be controlled by careful selection of process conditions in the preparation of the silica.


The toner of the present invention contains: a toner base particle, and a silica particle and a fatty acid metal salt particle adhering to a surface of the toner base particle. The toner base particle contains a crystalline polyester resin and an amorphous polyester resin. The toner particle has an average circularity of 0.945 to 0.965. The silica particle has a volume average particle size of 70 to 300 nm, and has an average circularity of 0.5 to 0.9. The fatty acid metal salt particle has a median diameter based on a volume of 0.50 to 2.00 μm.

1. Field of the Invention
The present invention relates to a toner.
2. Description of Related Art
Recently, for purposes of increasing a printing speed, increasing the number of usable types of paper, and reducing environmental load, there is a demand for reduction of thermal energy applied in fixing a toner image. In order to meet the demand, a technique to improve the low-temperature fixability of a toner is required, and as one of methods for achieving the technique, a crystalline resin having an excellent sharp melt property, such as crystalline polyester, is used as a binder resin.
For example, an electrostatic image developing toner using a binder resin containing a crystalline polyester resin and an amorphous resin is known. If a mixture of a crystalline polyester resin and an amorphous resin is used, a crystal portion of a toner particle is melted when the temperature of the toner particle exceeds the melting point of the crystalline polyester resin during heat fixing, and hence the crystalline polyester resin and the amorphous resin are compatibilized with each other. As a result, low-temperature fixability can be attained (see, for example, Japanese Patent Application Laid-Open No. 2006-251564).
On the other hand, there is also a demand for high image quality in recent years, and in order to meet with the demand for high image quality, examinations have been made on size reduction and spheroidization of a toner particle. The size reduction of a toner particle can improve the reproducibility of dots of a toner image formed on a surface of a photoconductor. Besides, the spheroidization of a toner particle can improve developability and transferability. As a result, fine-line reproducibility and printing performance can be improved.
Besides, there are known techniques to attain long-term stability in high image quality of a toner by focusing on an external additive adhering to a toner base particle. For example, a toner containing, as an external additive, deformed colloidal silica and a fatty acid metal salt particle is known. It is described that the toner can form high quality images for a long period of time and inhibit occurrence of cleaning failure (see, for example, Japanese Patent Application Laid-Open No. 2010-128216).
For supplying a toner to an image forming apparatus, a configuration in which a resin toner bottle containing a toner is loaded to replenish the toner is known. The toner reduced in size or spheroidized is, however, liable to be degraded in dischargeability from the toner bottle (hereinafter referred to as the bottle dischargeability). In particular, the toner using a polyester resin is liable to adsorb a water component, and hence the adhesion to the toner bottle is further enhanced, resulting in much more degrading the bottle dischargeability.


The present invention concerns to recombinant influenza viruses and modified Vaccinia Ankara viruses (MVA), and to a process for construction of recombinant influenza viruses and modified vaccinia Ankara viruses (MVA) with genes that encode for the T. gondii parasite SAGI (MVA) and SAG2 (MVA and influenza) proteins, by means of a homologous recombination technique between two transfer vectors (for construction of MVA virus) and reverse genetics (for construction of influenza virus). Additionally, the present invention describes a vaccine composition using recombinant influenza viruses and modified vaccinia Ankara viruses (MVA), or recombinant adenoviruses and modified vaccinia Ankara viruses (MVA), for immunization against infections caused by the T. gondii parasite.

Toxoplasmosis is one of the most common zoonoses in various regions of the world, being caused by the T. gondii protozoa. It is estimated that nearly one third of the world's population has been exposed to this pathogen. In Brazil, the prevalence of infection by T. gondii varies from 50 to 80%, with the highest rates occurring in some of the Northern and Southern states, and the lowest values in the Southeast states [Orefice, F. & Bonfioli, A. A. (2000). Uveìte Clìnica e Cir ùrgica(Uveitis and Surgical Clinic). In toxoplasmosis), pp. 619-680. Edited by E. C. Médica, Rio de Janeiro].
The T. gondii has three infectious forms: the tachyzoites, which multiply rapidly inside the cells throughout the body, the bradyzoites, which have a slower multiplication rate and are found in intracellular cysts in various tissues, and the sporozoites, which are present in the oocysts released in feces of the definitive hosts [Rey, L. (1991). Toxoplasma gondii e toxoplasmosis. In Parasitologia Humana. (Toxoplasma gondii and toxoplasmosis. In Human Parasitology.), pp. 274-285. Rio de Janeiro: Guanabara Koogan.]
An important characteristic of the T. gondii infection is the tissue cysts formation, during the chronic phase of disease. Cysts are rounded intracellular structures, bounded by an elastic wall formed by material derived from the host cell and the parasite. The cysts develop with higher frequency in the brain, eyes, cardiac and skeletal striated muscle, although its distribution and quantity vary between different species of hosts [Dubey, J. (1997). Tissue cyst tropism in Toxoplasma gondii: a comparison of tissue cyst formation in organs of cats, and rodents fed oocysts. Parasitology 115.]
T. gondii has an asexual reproduction stage and a sexual reproduction stage. The latter occurs only in Felidae, which leads to description of these mammals as the parasite's definitive hosts. [Tenter, A. M., Heckreroth, A. R. & Weiss, L. M. (2000). Toxoplasma gondii: from animals to humans. International Journal of Parasitology 30, 1217-1258.] The infection of intermediate and definitive hosts can occur through ingestion of tissue cysts in meat or viscera, by ingestion of oocysts sporulated from environmental contamination by feces of definitive hosts or also by transplacental transmission of tachyzoites [Tenter et. al., 2000].
Most of the toxoplasmosis cases in humans are asymptomatic. However, the acute infections in prenatal stage or during pregnancy can result in major complications. At pregnancy beginning, toxoplasmosis can cause abortion, neonatal death and fetal abnormalities. In the last three decades, the incidence of prenatal infection has been estimated in the range of 1 to 100 per 10,000 births, in different countries.
Regarding chronic infections in immunocompromised individuals, a reactivation can occur, triggering a pathological picture of great seriousness. For example, we can mention encephalitis, pulmonary toxoplasmosis, and disseminated toxoplasmosis, which have been observed in patients with immunodeficiencies related to various diseases such as Hodgkin's disease and AIDS. It is estimated that 40% of AIDS patients develop encephalitis caused by Toxoplasma, being that 10 to 30% die as result of this infection [Ferreira, M. S. & Borges, A. S. (2002). Some aspects of protozoan infections in immunocompromised patients—a review. Memórias do Instituto Oswaldo Cruz 97, 443-457] [Tenter et al., 2000]
The disseminated toxoplasmosis can also be a complication arising from organs and bone marrow transplant. This may arise from both the transplant of organs from donors infected with T. gondii to a susceptible recipient, as from reactivation of latent infection in recipients, due to immunosuppressive therapy [Tenter et al, 2000].
Considerable effort has been applied for developing a vaccine that prevents the transmission of T. gondii within human and animal populations. The main objective of a vaccine against T. gondii is to generate an immune response in different hosts, controlling the parasite's replication and its transmission within the population. The induction of an immune response, prior to infection with the parasite, would prevent the release of oocysts by definitive hosts, preventing the formation of tissue cysts in intermediate hosts, and their oral transmission via meat, and would prevent the development of a state of asymptomatic carriers subject to a recall in humans. A vaccine could also prevent the acute toxoplasmosis in pregnant women and the transplacental transmission [A lexander, J., Jebbari, H., Bluethmann, H., Satoskar, A. & Roberts, C. W. (1996). Immunological control of Toxoplasma gondii and appropriate vaccine design. Current Topics in Microbiology and Immunology: Toxoplasma gondii., 183-195].
Initial studies showed that it is possible to induce protective immunity, with activation of T CD4+, T CD8+ cells and production of IFN-γ, using attenuated forms of the parasite. However, vaccines produced this way are not suitable for application in humans, considering the risk of reversion of the vaccine samples to a pathogenic state [Gazzinelli, R. T., Hakim, F. T., Hieny, S., Shearer, G. M. & Sher, A. (1991). Synergistic role of CD4+ and CD8+ T lymphocytes in IFN-gamma production and protective immunity induced by an attenuated Toxoplasma gondii vaccine. Journal of Immunology 146, 286-292] [Hiramoto, R. M., Galisteo, A. J., Nascimento, N. & Andrade Jr, H. F. (2002). 200Gy sterilized Toxoplasma gondii tachyzoites maintain metabolic functions and mammalian cell invasion, eliciting cellular immunity and cytokine response similar to natural infection in mice. Vaccine 20, 2072-2081] [Rodrigues, M. M., Boscardin, S. B., Vasconcelos, J. R., Hiyane, M. I., Salay, G. & Soares, I. S. (2003). Importance of CD8 T cell-mediated immune response during intracellular parasitic infections and its implications for the development of effective vaccines. Annals of the Brazilian Academy of Sciences 75, 443-468] [Sayles, P. & Johnson, L. L. (1996). Intact immune defenses are required for mice to resist the ts-4 vaccine strain of Toxoplasma gondii. Infection & Immunity 64, 3088-3092]. To bypass this problem, molecular biology techniques that allow the parasite genes cloning and expression has been used to develop the named subunit vaccine, containing only T. gondii immunogenic components. (Biemans et al., 1998, Büllow & Boothroyd, 1991). (Biemans et al., 1998, Bulow & Boothroyd, 1991).
Recently, significant progress has been made in identifying T. gondii antigens that can induce protective immune response. Most of the work has been focused on surface antigens expressed in tachyzoites, with particular interest in SAG1, SAG2 and SAGS, which act in the host cell invasion process [Lekutis, C., Fergunson, D. J. P., Grigg, M. E., Camps, M. & Boothroyd, J. C. (2001). Surface antigens of Toxoplasma gondii: variations on a theme. International Journal of Parasitology 67, 5869-5876]. The SAGs sequence are maintained within different strains of T. gondii and, moreover, these antigens stimulate cellular and humoral response, which makes these proteins good candidates for development of vaccines.
Amongst vectors for expression of these antigens, both in humans as in other animals, the recombinant viruses deserve mention [Rocha, C., Caetano, B., Machado, A. & Bruna-Romero, O. (2004). Recombinant viruses as tools to induce protective cellular immunity against infectious diseases. International Microbiology 7, 89-94] [Rodrigues et al., 2003]. Studies using different recombinant virus (vaccinia, adenovirus, Sindbis and influenza) expressing the Plasmodium yoelii antigens, showed that such viruses are capable of inducing a protective immunity in BALB/c mice exposed to an experimental infection by P. yoelii sporozoites [Li, S., Rodrigues, M., Rodriguez, D., Rodriguez, J. R., Esteban, M., Palese, P., Nussenzweig, R. S., Zavala, F. & Alexander, D. J. (1993b). Priming with recombinant influenza virus followed by administration of recombinant vaccinia virus induces CD8+ T-cell-mediated protective immunity against malaria. Proceedings of the National Academy of Sciences of the United States of America 90, 5214-8] [Rodrigues, M., Li, S., Murata, K., Rodriguez, D., Rodriguez, J. R., Bacik, I., Bennink, J. R., Yewdell, J. W., Garcia-Sastre, A. & Nussenzweig, R. S. (1994). Influenza and vaccinia viruses expressing malaria CD8+ T and B cell epitopes. Comparison of their immunogenicity and capacity to induce protective immunity. Journal of Immunology 153, 4636-48] [Tsuji, M., Bergmann, C., Takita-Sonoda, Y., Murata, K., Rodrigues, E., Nussenzweig, R. & Zavala, F. (1998). Recombinant Sindbis viruses expressing a cytotoxic T-lymphocyte epitope of a malaria parasite or of influenza virus elicit protection against the corresponding pathogen in mice. Journal of Virology 72, 6907-6910].
Most of the experimental data obtained so far showed that, when the viral vectors are used alone, the protection level achieved was significantly lower than that observed when two different viral vectors expressing the same antigen were used for prime and boost immunization. [Gherardi, M. M., Najera, J. L., Perez-Jimenez, E., Guerra, S., Garcia-Sastre, A. & Esteban, M. (2003). Prime-boost immunization schedules based on influenza virus and vaccinia virus vectors potentiate cellular immune responses against human immunodeficiency virus Env protein systemically and in the genitorectal draining lymph nodes. Journal of Virology 77, 7048-7057] [Li, S., Polonis, V., Isobe, H., Zaghouani, H., Guinea, R., Moran, T., Bona, C. & Palese, P. (1993a). Chimeric influenza virus induces neutralizing antibodies and cytotoxic T cells against human immunodeficiency virus type 1. Journal of Virology 67, 6659-66] [Murata, K., Garcia-Sastre, A., Tsuji, M., Rodrigues, M., Rodriguez, D., Rodriguez, J. R., Nussenzweig, R. S., Palese, P., Esteban, M. & Zavala, F. (1996). Characterization of in vivo primary and secondary CD8+ T cell responses induced by recombinant influenza and vaccinia viruses. Cellular Immunology 173, 96-107] [Shiver, J. W., Fu, T. M., Chen, L., Casimiro, D. R., Davies, M. E., Evans, R. K., Zhang, Z. Q., Simon, A. J., Trigona, W. L., Dubey, S. A., Huang, L., Harris, V. A., Long, R. S., Liang, X., Handt, L., Schleif, W. A., Zhu, L., Freed, D. C., Persaud, N. V., Guan, L., Punt, K. S., Tang, A., Chen, M., Wilson, K. A., Collins, K. B., Heidecker, G. J., Fernandez, V. R., Perry, H. C., Joyce, J. G., Grimm, K. M., Cook, J. C., Keller, P. M., Kresock, D. S., Mach, H., Troutman, R. D., Isopi, L. A., Williams, D. M., Xu, Z., Bohannon, K. E., Volkin, D. B., Montefiori, D. C., Miura, A., Krivulka, G. R., Lifton, M. A., Kuroda, M. J., Schmitz, J. E., Letvin, N. L., Caulfield, M. J., Bett, A. J., Youil, R., Kaslow, D. C. & Emini, E. A. (2002). Replication-incompetent adenoviral vaccine vector elicits effective anti-immunodeficiency-virus immunity. Nature 415, 331-5].
This kind of immunization strategy is known as heterologous system for priming and boosting the immune response. As an example on the effectiveness of this strategy, we could mention the total inhibition of development of hepatic forms and 100% protection against malaria, in mice that were first immunized with recombinant adenovirus expressing the P. yoelii or P. berghei CS protein and boosted with a vaccinia virus expressing this same protein [Bruna-Romero, O., Gonzalez-Aseguinolaza, G., Hafalla, J. C., Tsuji, M. & Nussenzweig, R. S. (2001). Complete, long-lasting protection against malaria of mice primed and boosted with two distinct viral vectors expressing the same plasmodial antigen. Proceeding of National Academy of Sciences of United States of America 98, 11491-11496] [Gilbert, S. C., Schneider, J., Hannan, C. M., Hu, J. T., Plebanski, M., Sinden, R. & Hill, A. V. (2002). Enhanced CD8 T cell immunogenicity and protective efficacy in a mouse malaria model using a recombinant adenoviral vaccine in heterologous prime-boost immunization regimes. Vaccine 20, 1039-1045].
Amongst viruses potentially usable as antigens delivery vectors, the adenoviruses, the modified vaccinia Ankara viruses (MVA) and the influenza viruses have some characteristics making them interesting candidates for use in induction of a heterospecific immune response against T. gondii and other pathogens [Garcia-Sastre, A. (2000). Transfectant influenza viruses as antigen delivery vectors. Advances in Virus Research 55, 579-97] [Rocha et al., 2004] [Tatsis, N. & Ertl, H. C. (2004). Adenoviruses as vaccine vectors. Molecular Therapy 10, 616-629].
Amongst advantages of using the influenza virus, we could mention the fact that it does not integrate in the host genome and does not persist in the body. Furthermore, the existence of different influenza virus variants and subtypes enables the execution of sequential immunizations using two subtypes or variants of this virus [Ferko, B., Stasakova, J., Sereinig, S., Romanova, J., Katinger, D., Niebler, B., Katinger, H. & Egorov, A. (2001). Hyperattenuated recombinant influenza A virus nonstructural-protein-encoding vectors induce human immunodeficiency virus type 1 Nef-specific systemic and mucosal immune responses in mice. Journal of Virology 75, 8899-908]. Another favorable argument for choosing the influenza virus as vector for expression of heterologous sequences consists in that currently the molecular biology techniques for genetic manipulation of this virus are already well developed [Neumann, G. & Kawaoka, Y. (2002). Generation of influenza A virus from cloned cDNAs—historical perspective and outlook for the new millennium. Reviews in Medical Virology 12, 13-30] [Neumann, G. & Kawaoka, Y. (2004). Reverse genetics systems for the generation of segmented negative-sense RNA viruses entirely from cloned cDNA. Current Topics in Microbiology and Immunology 283, 43-60] and different strategies already exist for expression of heterologous proteins using recombinant influenza viruses. [Garcia-Sastre et al., 1994] [Machado, A., Naffakh, N., van der Werf, S. & Escriou, N. (2003). Expression of a foreign gene by stable recombinant influenza viruses harboring a dicistronic genomic segment with an internal promoter. Virology 313, 235-249] [Percy, N., Barclay, W. S., Garcia Sastre, A. & Palese, P. (1994). Expression of a foreign protein by influenza A virus. Journal of Virology 68, 4486-4492] [Takasuda, N., Enami, S., Itamura, T. & Takemori (2002). Intranasal inoculation of a recombinant influenza virus containing exogenous nucleotides in the NS segment induces mucosal immune response against the exogenous gene product in mice. Vaccine 20, 1579-1585] [Watanabe, T., Watanabe, S., Noda, T., Fujii, Y. & Kawaoka, Y. (2003). Exploitation of nucleic acid packaging signals to generate a novel influenza virus-based vector stably expressing two foreign genes. Journal of Virology 77, 10575-83].
Additional to the advantages above mentioned, is the ability of this of vector type to induce an heterospecific immune response, both local as systemic [Garulli, B., Kawaoka, Y. & Castrucci, M., R. (2004). Mucosal and systemic immune responses to a human immunodeficiency virus type 1 epitope induced upon vaginal infection with a recombinant influenza A virus. Journal of Virology 78, 1020-1025] [Gherardi, M. M., Najera, J. L., Perez-Jimenez, E., Guerra, S., Garcia-Sastre, A. & Esteban, M. (2003). Prime-boost immunization schedules based on influenza virus and vaccinia virus vectors potentiate cellular immune responses against human immunodeficiency virus Env protein systemically and in the genitorectal draining lymph nodes. Journal of Virology 77, 7048-7057]. The existence of a well-developed technology for influenza virus industrial scale production and the existence of attenuated viral strains are additional favorable points in using this vector. Regarding the attenuated strains, their use in humans has been authorized in the United States and they could then be used to construct recombinant live vaccines, able to immunize simultaneously against the influenza virus and some other pathogen [Izurieta, H. S., Haber, P., Wise, R. P., Iskander, J., Pratt, D., Mink, C., Chang, S., Braun, M. M. & Ball, R. (2005). Adverse events reported following live, cold-adapted, intranasal influenza vaccine. Jama 294, 2720-5] [Subbarao, K. & Katz, J. M. (2004). Influenza vaccines generated by reverse genetics. Curr Top Microbiol Immunol 283, 313-42].
Adenoviruses, in turn, are genetically stable, easy to handle and possess a remarkable capacity for heterologous sequences expression. Adenoviruses are still characterized by multiplying well in cellular culture and having broad tropism, being able to infect a wide range of cell types (replicating and non-replicating ones) and tissues. Moreover, they can be inoculated both by systemic and mucous routes.
Another favorable aspect of adenoviral vectors consists in that they are relatively safe, since they do not integrate in the host cells chromosomes [Tatsis & Ertl, 2004], and in that diseases caused by serotypes that normally infect humans are of little significance. Moreover, it is possible deleting significant portions of the viral genome, resulting in defective vectors for replication. This contributes not only to further enhance the security of this type of vector, but also to allow a better heterologous antigen expression [Xiang, Z. & Ertl, H. C. (1999). Induction of mucosal immunity with a replication-defective adenoviral recombinant. Vaccine 17, 2003-2008] [Xiang, Z. Q., Yang, Y., Wilson, J. M. & Ertl, H. C. (1996). A replication-defective human adenovirus recombinant serves as a highly efficacious vaccine carrier. Virology 219, 220-227].
Another interesting aspect of adenoviruses is the ability to change their cellular tropism by modifying the protein responsible for the virus adherence to host cells [Tatsis & Ertl, 2004]. Finally, it is possible using adenoviral vectors based on serotypes of low circulation in human population, or even non-human serotypes [Barouch, D. H., Pau, M. G., Custers, J. H., Koudstaal, W., Kostense, S., Havenga, M. J., Truitt, D. M., Sumida, S. M., Kishko, M. G., Arthur, J. C., Korioth-Schmitz, B., Newberg, M. H., Gorgone, D. A., Lifton, M. A., Panicali, D. L., Nabel, G. J., Letvin, N. L. & Goudsmit, J. (2004). Immunogenicity of recombinant adenovirus serotype 35 vaccine in the presence of pre-existing anti-Ad5 immunity. Journal Immunology 172, 6290-6297] [Farina, S. F., Gao, G. P., Xiang, Z. Q., Rux, J. J., Burnett, R. M., Alvira, M. R., Marsh, J., Ertl, H. C. & Wilson, J. M. (2001). Replication-defective vector based on a chimpanzee adenovirus. Journal of Virology 75, 11603-11613] [Fitzgerald, J., Gao, G., Reyes-Sandoval, A., Pavlakis, G., Xiang, Z., Wlazlo, A., Giles-Davis, W., Wilson, J. & Ertl, H. (2003). A simian replication-defective adenoviral recombinant vaccine to HIV-1 gag. Journal Immunology 170, 1416-1422] [Reyes-Sandoval, A., Fitzgerald, J. C., Grant, R., Roy, S., Xiang, Z. Q., Li, Y., Gao, G. P., Wilson, J. M. & Ertl, H. C. (2004). Human immunodeficiency virus type 1-specific immune responses in primates upon sequential immunization with adenoviral vaccine carriers of human and simian serotypes. Journal of Virology 78, 7392-7399], thus, allowing to bypass potential problems related to occurrence of a pre-existing immune response against the adenoviral vector.
Historically, the MVA (from "modified vaccinia virus Ankara) was created to serve as a safe vaccine against smallpox. This virus was attenuated after more than 570 passages on primary chicken embryo fibroblasts (CEF) cultures, during which occurred the deletion of several of the vaccinia virus genes responsible for virulence, rendering them unable to generate productive infections in mammals cells [Sutter, G. & Staib, C. (2003). Vaccinia vectors as candidate vaccines: the development of modified vaccinia virus Ankara for antigen delivery. Curr Drug Targets Infect Disord 3, 263-71]. The MVA viruses have the following advantages concerning its use as vaccine vectors:                (1) Ability to receive the insertion of large exogenous DNA sequences (up to 25 kb).        (2) Stability to freezing and freeze-drying.        (3) Lack of integration in the host genome due to the fact that this virus multiplies in the infected cells cytoplasm.        (4) Ability to induce cellular and humoral immune response against the heterologous antigen [Rocha et al., 2004].

Utilization of recombinant influenza viruses and modified vaccinia ankara virus (MVA) with genes that encode for the