In a heat exchanger (10) for transferring heat from a first fluid to a second fluid, which heat exchanger (10) comprises one or more flow passages (12) for a first fluid, the outer wall (26) of these passages is in heat-transferring contact with a flow body (20) made from metal foam for a second fluid. This metal foam has a gradient of the volume density of the metal, so that it is possible to achieve a favorable equilibrium between heat transfer and conduction, on the one hand, and flow resistance, on the other hand.

EP-A-0 744 586 has disclosed a heat-transfer element, for example a plate or tube, with a large heat-transferring surface in the form of copper foam, for use in a heat exchanger, in order to improve the heat transfer. An element of this type is produced by using a vapour deposition process to deposit a powder of copper oxide on a plastic foam which has previously been provided with a suitable adhesive. The foam which has been prepared in this way is then arranged under slight pressure on a plate or tube, which has likewise previously been covered with a copper oxide powder, in order in this way to form a composite element by sintering. After pyrolysis of the plastic foam, the copper oxide is reduced to form copper.
A heat exchanger of the type described above is used, for example, in what are known as thermo-acoustic heat engines. In a heat exchanger of this type, a first heat circuit is formed by a flow of a first fluid, such as a gas or liquid, through generally a plurality of flow passages. A second heat circuit comprises a flow of a second fluid, generally a gas (air, argon), through the porous flow body, which flow body surrounds the flow passages over a certain area. The direction of flow of the second fluid through the flow body is generally virtually perpendicular to the direction of flow of the first fluid in the flow passages. The porous flow body is in heat-exchanging contact with the outer wall of the flow passages. Heat is transferred, for example, from the first fluid to the inner wall of the flow passages and is carried to the outer wall as a result of conduction in the wall material. At the outer wall, heat transfer to the porous flow body takes place through radiation and conduction. Heat conduction takes place in the porous flow body. When there is only a flow body made from metal foam, this heat conduction is limited, and consequently solid lamellae made from a material with good conductivity are sometimes provided in the metal foam in order to increase the heat conduction. Transfer of heat from the flow body to the second fluid likewise takes place by means of radiation and conduction. The efficiency of the heat transfer overall is dependent, inter alia, on all these transitions, the transfer from the flow body to the second fluid or vice versa—generally the heat transfer on the gas side—in particular possibly representing an inhibiting factor.
It has now been found that, although the use of a metal foam, optionally in combination with lamellae or fins, offers an enlarged heat-exchanging surface area and possibly increased conduction, the flow resistance is relatively high, so that the overall performance, expressed as the ratio between heat transfer and flow resistance, is inferior to that of a conventional heat exchanger with only fins or lamellae. In many cases, an increase in the heat transfer when using a metal foam goes hand-in-hand with a disproportionate increase in the flow resistance.
U.S. Pat. No. 4,245,469 has disclosed a heat exchanger in which a porous metal matrix is arranged in a flow passage through which a heat-transferring medium flows. It is stated that this metal matrix has a greater density in an area which is perpendicular to the direction of flow, so that the internal heat transfer coefficient is increased in this area, where the temperature of the environment is much higher than at the end of the passage. To minimize the reduction in volume of the heat-transfer medium which would be produced with a passage of constant diameter, the diameter is increased at the location of the said area. A design of this type aims to improve the internal heat transfer.
Furthermore, DE A1 39 06 446 has disclosed a heat exchanger in which a foam, for example of aluminium, is arranged in a flow passage. If desired, the pore size in this foam may be varied, i.e. the number of pores may vary.


An image processing device for processing images of background images and moving objects. A region specifying unit specifies a mixed region made up of a mixture of a foreground object component and a background object component, and a non-mixed region made up of one or the other of a foreground object component and a background object component, and outputs region information corresponding to the specifying results. A foreground/background separation unit separates the input image into foreground component images and background component images, corresponding to the region information. A separated image processing unit processes the foreground component images and background component images individually, corresponding to the results of separation.

One type of processing for generating images with higher resolution based on input images, is class classification adaptation processing. An example of class classification adaptation processing is processing wherein coefficients used in processing for generating images with higher resolution are generated beforehand, in the spatial direction, and images are generated with higher resolution in the spatial direction based on the generated coefficients.
FIG. 1 is a block diagram illustrating the configuration of a conventional image processing device for generating coefficients used in class classification adaptation processing for generating HD (High Definition) images from SD (Standard Definition) images.
Frame memory 11 stores input images, which are HD images, in increments of frames. The frame memory 11 supplies the stored HD images to a weighted averaging unit 12 and a corresponding pixel obtaining unit 16.
The weighted averaging unit 12 performs ¼ weighted averaging on the HD images stored in the frame memory 11, generates SD images, and supplies the generated SD images to the frame memory 13.
The frame memory 13 stores the SD images supplied from the weighted averaging unit 12 in increments of frames, and supplies the stored SD images to a class classification unit 14 and prediction tap obtaining unit 15.
The class classification unit 14 is configured of a class tap obtaining unit 21 and a waveform classification unit 22, and performs class classification of pixels of interest which are the pixel of interest in the SD images stored in the frame memory 13. The class tap obtaining unit 21 obtains a predetermined number of class taps which are pixels of the SD image corresponding to the pixel of interest from the frame memory 13, and supplies the obtained class taps to the waveform classification unit 22.
FIG. 2 is a diagram explaining the class taps obtained by the class tap obtaining unit 21. As shown in FIG. 2, the class tap obtaining unit 21 obtains eleven class taps at predetermined positions.
The waveform classification unit 22 classifies the pixel of interest into one class out of multiple classes, based on the class taps, and supplies a class No. corresponding to the classified class, to the prediction tap obtaining unit 15. The waveform classification unit 22 classifies the pixel of interest into one class out of 2048 classes, based on the eleven class taps.
The prediction tap obtaining unit 15 obtains a predetermined number of prediction taps which are pixels of the SD image, corresponding to the classified class from the frame memory 13, based on the class No., and supplies the obtained prediction taps and class Nos. to a corresponding pixel obtaining unit 16.
FIG. 3 is a diagram explaining prediction taps which the prediction tap obtaining unit 15 obtains. As shown in FIG. 3, the prediction tap obtaining unit 15 obtains nine prediction taps at predetermined locations.
The corresponding pixel obtaining unit 16 obtains, from the frame memory 11, pixels of the HD image corresponding to the pixel values to be predicted, based on the prediction taps and the class Nos., and supplies the prediction taps, class Nos., and the pixels of the HD image corresponding to the obtained pixel values to be predicted, to a normal equation generating unit 17.
The normal equation generating unit 17 generates normal equations corresponding to relationships between prediction taps and pixel values to be predicted, corresponding to the classes, based on the prediction taps, class Nos., and the obtained pixel values to be predicted, and supplies the generated normal equations corresponding to the classes, to a coefficient calculating unit 18.
The coefficient calculating unit 18 solves the normal equation supplied from the normal equation generating unit 17, calculates coefficient sets corresponding to each class, and supplies the calculated coefficient sets to coefficient set memory 19, along with the class Nos.
The coefficient set memory 19 stores the calculated coefficient sets corresponding to the classes, based on the class Nos.
FIG. 4 is a diagram explaining an overview of class classification adaptation processing. In class classification adaptation processing, a tutor image which is an HD image is used to generate a corresponding SD image, by ¼ weighted average processing. The generated SD image is called a student image.
Next, a coefficient set for generating an HD image from the SD image is generated, based on the tutor image which is the HD image and the student image which is the corresponding SD image. The coefficient set is configured of coefficients for generating an HD image from an SD image, by linear prediction and the like.
A quadruple-density image is generated from the coefficients set thus generated and the SD image, by linear prediction and the like. The processing for generating an image or the like with higher density, from a coefficient set and an input image, is also called mapping.
SNR comparison, or visual qualitative evaluation is performed, based on the generated quadruple-density image and a corresponding HD image.
A coefficient set generated from a particular tutor image and corresponding student image is called a self coefficient set of the particular tutor image and corresponding student image. Mapping using the self coefficient set is called self mapping. A coefficient set generated from multiple other tutor images and corresponding student images is called a cross coefficient set.
On the other hand, with images obtained by a video camera taking a foreground subject which moves across a predetermined stationary background, movement blurring occurs in the event that the speed of movement of the object is relatively fast, and mixing of the foreground and background occurs.
With conventional class classification adaptation processing, one set of coefficients is generated for all of the foreground, background, and portions where mixing between the foreground and background occurs, by learning processing such as described above, and mapping processing is executed based on the coefficient set.
The conventional learning processing for generating coefficients used in the processing for generating HD images from SD images will be described, with reference to the flowchart shown in FIG. 6. In Step S11, an image processing device judges whether or not there are unprocessed pixels in the student image, and in the event that judgment is made that there are unprocessed pixels in the student image, the flow proceeds to Step S12, and pixels of interest are obtained from the student image, in order of raster scan.
In Step S13, the class tap obtaining unit 21 of the class classification unit 14 obtains a class tap corresponding to the pixel of interest, from the student image stored in the frame memory 13. In Step S14, the waveform classification unit 22 of the class classification unit 14 performs class classification of the pixel of interest, based on the class tap. In Step S15, the prediction tap obtaining unit 15 obtains a prediction tap corresponding to the pixel of interest from the student image stored in the frame memory 13, based on the class into which classification has been made.
In Step S16, the corresponding pixel obtaining unit 16 obtains a pixel corresponding to a pixel value to be predicted, from tutor data stored in the frame memory 11, based on the class into which classification has been made.
In Step S17, the normal equation generating unit 17 adds a pixel value of a pixel corresponding to the prediction tap and pixel value to be predicted to the matrix for each class, based on the class into which classification has been made, the flow returns to Step S11, and the image processing device repeats judgment regarding whether or not there are unprocessed pixels. The matrixes for each class to which the pixel value of a pixel corresponding to the prediction tap and pixel value to be predicted are added, correspond to the normal equation for calculating coefficients for each class.
In the event that judgment is made in Step S11 that there are no unprocessed pixels in the student image, the flow proceeds to Step S18, wherein the normal equation generating unit 17 supplies the matrix for each class wherein a pixel value of a pixel corresponding to the prediction tap and pixel value to be predicted has been set, to the coefficient calculating unit 18. The coefficient calculating unit 18 solves the matrix for each class wherein a pixel value of a pixel corresponding to the prediction tap and pixel value to be predicted has been set, and calculates a coefficient set for each class.
In Step S19, the coefficient calculating unit 18 outputs the coefficient for each class that has been calculated, to the coefficient set memory 19. The coefficient set memory 19 stores a coefficient set for each class, and the processing ends.
FIG. 7 is a block diagram illustrating the configuration of a conventional image processing device for generating HD images from SD images, by class classification adaptation processing.
Frame memory 31 stores input images which are SD images, in increments of frames. The frame memory 31 supplies the stored SD images to a mapping unit 32.
The SD images input to the mapping unit 32 are supplied to a class classification unit 41 and a prediction tap obtaining unit 42.
The class classification unit 41 is configured of a class tap obtaining unit 51 and a waveform classification unit 52, and performs class classification of pixels of interest which are the pixel of interest in the SD images stored in the frame memory 31. The class tap obtaining unit 51 obtains from the frame memory 31 a predetermined number of class taps corresponding to the pixel of interest, and supplies the obtained class taps to the waveform classification unit 52.
The waveform classification unit 52 classifies the pixel of interest into one class out of multiple classes, based on the class taps, and supplies a class No. corresponding to the classified class, to the prediction tap obtaining unit 42.
The prediction tap obtaining unit 42 obtains from the input image stored in the frame memory 31 a predetermined number of prediction taps corresponding to the classified class, based on the class No., and supplies the obtained prediction taps and class Nos. to a prediction computation unit 43.
The prediction computation unit 43 obtains coefficient sets corresponding to classes from the coefficient sets stored in coefficient set memory 33, based on the class No. The prediction computation unit 43 predicts pixel values of predicted images by linear prediction, based on coefficient sets corresponding to classes, and prediction taps. The prediction computation unit 43 supplies the predicted pixel values to frame memory 34.
The frame memory 34 stores-predicted pixel values supplied from the prediction computation unit 43, and outputs an HD image wherein the predicted pixel values have been set.
FIG. 8 is a diagram illustrating the pixel values of the input image, and the pixel values of the output image generated by class classification adaptation processing. In FIG. 8, the white squares indicate input signals, and the solid circles indicate output signals. As shown in FIG. 8, the image generated by the class classification adaptation processing contains waveforms lost in the bandwidth restriction of the SD image. In this sense, it can be said that processing for generating an image with higher resolution by the class classification adaptation processing creates resolution.
The conventional processing for creating images, for generating HD images from SD image with an image processing device which executes processing for creating resolution by class classification adaptation processing, will be described with reference to the flowchart in FIG. 9.
In Step S31, the image processing device judges whether or not there are unprocessed pixels in the input image, and in the event that judgment is made that there are unprocessed pixels in the input image, the flow proceeds to Step S32, where the mapping unit 32 obtains a coefficient set stored in the coefficient set memory 33. In Step S33, the image processing device obtains pixels of interest from the input image in raster scan order.
In Step S34, the class tap obtaining unit 51 of the class classification unit 41 obtains a class tap corresponding to the pixel of interest, from the input image stored in the frame memory 31. In Step S35, the waveform classification unit 52 of the class classification unit 41 performs class classification of the pixel of interest into one class, based on the class tap.
In Step S36, the prediction tap obtaining unit 42 obtains a prediction tap corresponding to the pixel of interest from the input image stored in the frame memory 31, based on the class into which classification has been made.
In Step S37, the prediction computation unit 43 obtains a pixel value of a predicted image by linear prediction, based on the coefficient set corresponding to the class into which classification has been made, and the prediction tap.
In Step S38, the prediction computation unit 43 outputs the predicted pixel value to the frame memory 34. The frame memory 34 stores the pixel value supplied from the prediction computation unit 43. The procedures return to Step S31, and repeats judgement regarding whether or not there are unprocessed pixels.
In the event that judgment is made in Step S31 that there are no unprocessed pixels in an input image, the flow proceeds to Step S39, where the frame memory 34 outputs the stored predicted image wherein predicted values are set, and the processing ends.
Also, edge enhancing processing is used for converting the input image into an image with the sense-of-resolution enhanced even further. As with the class classification adaptation processing described above, the same processing is executed for the entire screen with the edge enhancement processing as well.
However, in the event that objects move in front of still backgrounds, movement blurring occurs not only due to mixture of the moving object images itself, but also due to mixture of the moving object images and the background images. Conventionally, processing images corresponding to the mixing of the background image and the image of the moving object had not been given thought.

Image processing apparatus and method, and image pickup apparatus


Methods automatically and comprehensively self-test the operation, hardware, and programs of a robotic system to reveal problems in a robotic system. The system preferably evaluates repeatability of measurement by each distance sensor, an accuracy of measurement by each distance sensor, an accuracy of movement of any positioning joints used to position the robot arm, and an accuracy of at least one routine of the system control programs. The positioning joints may include one or more rotational joints or one or more translational joints. In some embodiments, the robotic system is a robotic pulse/echo layer thickness (PELT) system. When a robotic system has passed all of the tests, then the system performance has been verified. The inclusion of these self-tests allows a robotic PELT system owner to determine whether or not the robotic portion of a system is performing correctly.

Field of the Invention
The invention pertains to the fields of hardware and program testing. More particularly, the invention pertains to methods for automatically testing the hardware and programs of robotic systems.
Description of Related Art
A robotic system typically includes one or more robots, tools wielded by the robot, sensors that enable the position of the robot to be sensed or stepper motors that move the positioning joints in steps to discrete angles or locations, firmware built into a robot controller that causes the robot to move in response to commands delivered to the controller, and software that sends commands to the robot controller so as to cause the robot to perform desired operations.
Robotic systems are employed in automated manufacturing operations in many situations, for example in factories. Of these robotic systems, some are dedicated to a particular task that is performed repetitively to objects without any alteration in robot motion from object to object. Other robotic systems require alteration of the motion of a robot based on variations in object size, orientation, color, or other object characteristics.
When a robotic system is designed to perform a particular task on objects whose characteristics vary from object to object, software is required to control the robotic system to perform the task. This software can be complex, and it is often difficult to completely test the software to ensure that the robotic system performs exactly as required on all possible objects. To compound the problem, the designer and installer of the robotic system may be a third-party system-integrator who has only partial knowledge of the complexity of each of the components of the robotic system. Consequently, the integrator may not possess sufficient knowledge to test the system so as to guarantee proper system performance. As a result, system performance issues can occur that are difficult to associate with a particular element of the robotic system. If the robotic system fails to perform its tasks correctly, it can be difficult and expensive to determine and correct the cause of the failure.
In addition to problems related to initial development of the robotic system, as the robotic system ages, its accuracy may decline and eventually reach a point where it no longer performs as required, and it can be difficult to localize which element of the system is causing the degradation.
A pulse/echo layer thickness (PELT) gauge is a measurement device that makes accurate measurements of the thicknesses of coatings applied to manufactured materials. A robotic PELT system is a robotic system to which a PELT gauge is added. The PELT gauge is thus the tool that is manipulated by the robotic system for the purpose of measuring coatings on materials. The entire robotic PELT system thus includes of one or more industrial robots, a distance measurement sensor mounted to the end of the arm of each robot, computer programs that control the robots, and a PELT 'tool' mounted to the end of each robot arm.
The PELT tool held by each robot includes an ultrasonic transducer. A primary objective of the robotic system is to ensure that the transducer is placed onto the surface of a test material with the front face of the transducer flat against the surface. In order for this to occur:
1. The robot needs to move accurately through three-dimensional space,
2. The distance sensor needs to be properly calibrated, and
3. The computer programs that control the robots need to be proper for the task and free of bugs.
U.S. Pat. No. 4,815,006, entitled "Method and Device for Calibrating a Sensor on an Industrial Robot" and issued to Andersson et al. on Mar. 21, 1989, describes a welding robot that uses a sensor for detecting a weld joint. The patent discloses a method for determining the relationship between the sensor coordinate system and the robot coordinate system in a manner that requires minimal manual operations. A calibration test object is used, and a calibration software program moves the sensor about the calibration object in order to determine the relationship between the sensor coordinates and the robot coordinates.
U.S. Pat. No. 4,967,370, entitled "Robot and Sensor Error Determination System" and issued to Stern et al. on Oct. 30, 1990, is similar to U.S. Pat. No. 4,815,006 in that both describe sensors on a robot, in this case a "vision" sensor, and the need to relate the sensor coordinate space to the robot coordinate space. The patent describes a test process that compares current sensor data with previously stored baseline or reference data. When differences are detected in the relationship between the sensor apparatus and the robot, the patent describes how to determine the source of the differences/error, such as robot positioning error or a change in orientation of the sensing apparatus mounted to the robot.
U.S. Pat. No. 6,571,148, entitled "System for Automatically Certifying the Accuracy of a Manufacturing Machine and Associated Methods" and issued to Wunder on May 27, 2003, discloses certifying, or checking the accuracy of, a computer-controlled manufacturing machine. This patent teaches making comparisons of successive outputs of a manufacturing machine. The accuracy and performance of the manufacturing machine is evaluated by monitoring and comparing the successive outputs of the manufacturing machine.
U.S. Pat. No. 7,050,937, entitled "Performance Measurement System" and issued to Lee on May 23, 2006, describes a software program for assessing the performance of a robotic semiconductor wafer handling system. The software requires a large amount of operator input and is thus neither automatic nor autonomous.
The above references are hereby incorporated by reference herein.

Automated testing and verification of a robotic system


A pump jack for a scaffold in a system to support a work platform and move the platform up and down a pole to access a vertical work surface. The pump jack includes an L-shaped framework having a horizontal frame member which supports the work platform and a vertical frame member. The vertical frame member having laterally opposing Z-shaped channels, each having a leg that bends about the pole and extends inward toward the pole. The pump jack includes an upper shackle supported by the framework. The pump jack includes a lower shackle supported by the framework, which with the upper shackle applies a coupling force for gripping the pole. The pump jack includes a pump arm lever pivotably coupled to the vertical frame member to step upwardly the pump jack relative to the pole. The pump jack includes a crank mechanism coupled to the vertical frame member. A method for supporting and moving a work platform up and down a pole to access a vertical work surface.

The application of a work platform forces to the pump jack "L" frame result in significant stresses in the material and fasteners located at the connection of the vertical and horizontal members. FIG. 2 shows that the "L" frame design currently employed by pump jack manufacturers utilizes outwardly opened, laterally opposing, "C" shaped channels for both the vertical 10 and horizontal 11 frame members. At the connection of the vertical and horizontal members, the flange of the vertical member 10 must be notched 12, or removed as shown in FIG. 3, to facilitate the connection of the horizontal member 11. The notching 12, or removal, of the flange in this area weakens the frameworks at its most structurally critical location in two ways:                1. The removal of flange material in the area local to the most significant stresses.        2. The notching process generates a point where stresses are concentrated. This point 13 is located at the corner of the notch 12. This point 13 of concentrated stress is commonly referred to as a stress riser.
As a result, under test loads, the "L" frame vertical member 10 will fail in this structurally critical area.


The prior art lacks a formulation, application or product of D-Ala7-Angiotensin-(1-7) (A-779) and analogues and derivatives, D-Pro7-Angiotensin-(1-7) and analogues or derivatives or of Ang-(1-7) analogues or derivatives using cyclodextrins, liposomes, biodegradable polymers and its derivatives for the study or treatment of arterial hypertension and other cardiovascular diseases, wounds, burns, arrhythmia, tumors, diabetes mellitus, sperm mobility, nephropathy, gastrointestinal and gynaecologicalgynecological disorders, angiogenesis, angioplatsy, alopecia and blood diseases in warm blooded animals, or as ligands for de G-protein-coupled receptor MAS. This characterizes the present invention as a more effective option for the study and treatment of pathologies associated or not to this receptor. A combination of two different technologies are provided: the molecular encapsulation of the peptide angiotensin-(1-7) and its analogues and derivates in cyclodextrin and the microencapsulation in biodegradable polymers and liposomes. It is also characterized by the increase of this peptides and its analogues and derivatives using the formulation.

In most countries of the world 15% to 25% of the adult population presents high arterial blood pressure (MacMahon S. et. al. Blood pressure, stroke, and coronary heart disease. Lancet 335:765-774, 1990). The cardiovascular risk increases with the level of arterial pressure. The more high the arterial pressure bigger are the risk of cerebral vascular accidents and coronary events. Hypertension, considered the main responsible cause for coronary, cerebral and renal vascular diseases, is the main cause of death and incapability among adults.
The heart failure is worldwide the main cause of hospitalization of patients in the age group of 60 to 80 years old. The aging of the population is already an important factor for the increase in the incidence of heart failure: while 1% of the individuals in the age range of 25 to 54 years old present heart failure, among the more seniors the incidence is very larger, reaching about 10% in those individuals with more than 75 years (Kaannel W. B. et. al. Changing epidemiological features of cardiac failure. Br. Heart J 1994; 72 (suppl): S3-S9).
The heart failure by its clinical characteristic is a restrictive disease, that reduces the quality of the patients' life with its worsening and, in the advanced forms, is characterized as a malign disease with mortality rate above 60% in the first year, even nowadays (Oliveira, M. T. Clinical characteristics and patients' prognostic with advanced congestive heart failure. Faculty of Medicine, USP 1999). It is estimated that these days there are more than 15 million of individuals affected only in the industrialized world and that only in the USA, for example, the number of cases has increased 450% among 1973-1990 (Kannel, W. B. et al. Changing epidemiological features of cardiac failure, Br. Hear J 1994; 72 (suppl 3): S3-S9).
Hypertension is a complex, multifactorial, of high prevalence disease responsible for countless deleterious effects and high morbidity (Kaplan, N. M. Blood pressure the cardiovascular risk factor: prevention ant treatment. JAMA. 275:1571-1576, 1996). Several studies aimed for the evaluation of the effectiveness of its control in the population in general and in special groups have been developed, in order to better understand its course. The control of the normal level of blood pressure without wide intervention with no pharmaceutical drugs of the associated risk factors (such as, diabetes, obesity, smoke) can reduce or even avoid the benefits of the long term treatment of arterial hypertension in the reduction of the mortality, in general, as for coronary disease (Wilson, P. W. et. al. Hypertension, the risk factors and the risk of cardiovascular disease. Raven Press. 94-114).
Hypertension is the pathology that more contributes to the cardiovascular atherosclerosis (The fifth Report of the Joint National Committee on detection, evaluation, and treatment of High Blood Pressure. National Institute of Health (VJNC). Arch. Intern. Med. 153:154-181, 1994). According to statistics, of each four Americans, one is, or will be, hypertensive, and it is estimated 4.78 million people with heart failure. Every year 400 thousand new cases are diagnosed, provoking 800 thousand hospitalizations, with an expense of US$ 17.8 billion of dollars in the treatment.
In Brazil, data from the National System of Health (SUS) show that, in 1997, heart failure was the main cause of hospitalizations among the heart diseases, costing about R$ 150 million for the government in the treatment, corresponding to 4.6% of the whole expense with health (Filho, Albanesi F. Heart failure in Brazil. Arq. Bras. Cardiol, 71:561-562, 1998).
The renin-angiotensin system (RAS) is responsible for the regulation of the arterial pressure, cardiovascular homeostase and hydroelectrolite balance, as in physiological as in pathological conditions (Krieger, E. M.; Santos, R. A. S. Angiotensins—physiologic aspects. Hypertension, 1:7-10, 1998). Angiotensin II (Ang II) is the main peptide of RAS, possessing several actions: vasopressor, stimulator of the synthesis of adrenal steroids, proliferative effect (fibroblasts, smooth muscle of the vasculature) and hypertrophic (cardiomyocytes). Its formation pathways involve the production of angiotensinogen from the liver and renin production in the juxtaglomerular apparatus. Those substances are released in the blood where, the angiotensinogen is hydrolysed by renin, forming Ang I, that, is converted to Ang II, mainly the lung circulation, by the angiotensin converting enzyme (ACE) and it will originate Ang II. This last peptide will act in target-organs distant from the place of its production (Krieger, E. M.; Santos, R. A. S. Angiotensins—physiologic aspects. Hypertension, 1:7-10, 1998).
Recently it was discovered that in parallel to the circulating RAS, that generate Ang II in the circulation, there are independent systems that generates Ang II in different tissues probably for a local action. All the components of the RAS are found in the walls of the blood vessels, in the uterus, in the exocrine portion of the pancreas, eyes, heart, adrenal cortex, testicle, ovaries, anterior and median lobes of the hypophise, pineal and brain. The function of those tissue RAS are not very well understood. (Ardaillou, R.; Michel, J. B. The relative roles of circulating and tissue renin-angiotensin systems. Nephrol. Dial. Transplant., 14:283-286, 1999). The local actions of RAS can occur at the level of the cell that produces the peptide (as an autocrine or intracrine function), or on adjacent cells (as a paracrine function), or in distant sites from the production area (endocrine function).
Recent observations indicate that important peripheral and cerebral actions of the RAS can be mediated by smaller sequences of the angiotensinergic peptides, including Angiotensin-III [Ang-(2-8)], Angiotensin-IV [Ang-(3-8)] and Angiotensin-(1-7). We can consider that both Angiotensin-I [(Ang-(1-10)] and Angiotensin-II [Ang-1-8)] can suffer a biotransformation process, generating a whole "family" of biological active angiotensin peptides. (Santos, R. A. S.; Campagnole-Santos, M. J.; Andrade, S. P. Angiotensin-(1-7): an update. Regulatory Peptides, 91:45-62, 2000).
Angiotensin-(1-7) is a biologically active peptides of the angiotensin "family", being formed by a pathway independent of the ACE. Ang I processing by endopeptidases or Ang II by prolyl-peptidases or carboxy-peptidases can generate the heptapeptide, Ang-(1-7). Ang-(1-7) can be hydrolysed by amino-peptidases generating Ang-(2-7) and Ang-(3-7). The hydrolysis of Ang-(1-7) by ACE originates Ang-(1-5) (Santos, R. A. S.; Campagnole-Santos, M. J.; Andrade, S. P. Angiotensin-(1-7): an update. Regulatory Peptides, 91:45-62, 2000).
Ang-(1-7) and Ang II are the main efectors of the RAS. However, two important characteristics differentiate Ang-(1-7) from Ang II: the first one possesses highly specific biological actions and its formation pathway is independent of ACE (Santos, R. A. S.; Campagnole-Santos, M. J.; Andrade, S. P. Angiotensin-(1-7): an update. Regulatory Peptides, 91:45-62, 2000).
The primary objective of hypertension treatment not only seeks for the fall expenses, but as well as the prevention of end-organ damages, through modifications of life quality and the use of medications, when necessary (The Fifth Report of The Joint National Committee on detection, evaluation, and treatment of High Blood Pressure. National Institute of Health (VJNC). Arch. Intern. Med. 153:154-181, 1994).
The use of anti-hypertensive drugs is indicated when patients do not respond to the alterations in lifestyle for a period of three to six months, and in the presence of end-organs damage (left ventricular hypertrophy, myocardic ischemia, stroke, or hypertensive retinopathy). All patients with systolic arterial pressure above 180 mmHg or diastolic arterial pressure above 110 mmHg should be submitted to pharmacological treatment, independent of the presence of another (Report the Canadian Hypertension Society. Consensus Conference. 3. Pharmacological treatment of essential hypertension. Xan. Med. Assoc. J. 149 (3): 575-584, 1993).
During the years 70 and 80, however, the anti-hypertensives became an important tool for the treatment of the high arterial pressure (Ménard, J. Anthology of renin-angiotensin system: The one hundred reference approach to angiotensin antagonist II. J. Hypertension 11 (suppl 3): S3-S11, 1993). During the last four decades, the pharmacological research produced new classes of drugs to treat the hypertension: the diuretics in the sixties, the beta-blockers in the seventies, the calcium channel blockers, the angiotensin II antagonists and the ACE in inhibitors.
The diuretics can be divided in three categories: thazidics, loop diuretics and the potassium savers. The thazidics and analogues include chlorothiazides and hydroclorotiazidehydroclorotiazide, which induce in the first days of treatment a 10-15% of decrease in the arterial pressure mainly due to a decrease in the extracellular volume and an increase in the diuresis and natriuresis. After six months, the blood volume and cardiac output return to baseline levels and the decrease in arterial pressure is maintained by a decrease in peripheral vascular resistance (Frolich, E. Current Approaches in the treatment of Hypertension, 405-469). These drugs are habitually used as monotherapy and the give best results in black patients and, at low doses, in the old patients. They have as collateral effects: increase in peripheral resistance to insulin, increase in triglicerides levels, increase in LDL, hypocalcemia, hyperucemia. Among the loop diuretics are furosemide, bumetamide and trianterene, and they are much more potent than the thiazides. They act predominantly in the medullar and cortical portions of the Henle loop. They present the same collateral effects of the thiazides. The potassium savers, however, which include amolonide, trianterene and speronolactones are drugs with weak diuretic action and rarely used alone.
The betablockers, such as Atenolol and Nadolol, are classified in beta-1 and beta-2 and the mechanism of action are not completely defined. They present as collateral effects: alteration in the response to insulin, prolongation of the hypoglicemichypoglycemic coma, increase in triglicerides levels and increase in creatinine due to a decrease in renal flow.
The calcium channel blockers are being used for at least 25 years (Frolich, E. D. Current Approaches in the Treatment of Hypertension, 405-469, 1994). They can be classified in two major groups, according to its pharmacological actions: those that have larger action in the conduction of the stimulus, such as Verapamil and Diltiazem, and those that present a predominant vasodilator action, as those derived from diidropirinicos (Nifedipine and others) (Frolich, E. D., Hypertension. Adult Clinical Cardiology Self Assessment Program (ACCSAP), 6: 3-19, 1995). They present as collateral effects edema of inferior members and tachycardia.
The main action of the ACE inhibitors is to inhibit the conversion of angiotensin I in to angiotensin II. Thus, the essentially vasoconstrictor actions of angiotensin II are minimized. Teprotide, the first ACE inhibitor clinically used, exerted its anti-hypertensive action only when it was administered by intravenous route, because it was inactive when given orally, what have limited its employment. It is known now that ACE is an enzyme with multiple actions, i.e., that it acts in several substrate. Besides acting as a dipeptidase in the angiotensin I and in the bradykinin, it is also capable of hydrolysing peptidic chains of the natriuretic peptide, indicating that the enzyme can act in several tissues. ACE has an important role in the inactivation of circulating and tissue Ang-(1-7). The circulating concentration of this peptide is similar to Ang II concentration and it has been shown that it increases after inhibition of ACE. This increase can be due to both the increase in its precursor (Ang I) and the decrease in its degradation by ACE (Santos, R. A. S.; Campagnole-Santos, M. J.; Andrade, S. P. Angiotensin-(1-7): an update. Regulatory Peptides, 91:45-62, 2000). The ACE inhibitors are excellent when administered as monotherapy, since they induce a relatively fast fall in arterial pressure in 60 to 70% hypertensive patients. (Ganong, W. Neuropeptides in cardiovascular control. J. Hypertens 2 (suppl 3): 15-22, 1984). In addition, they are in general well tolerated, but its use can cause collateral effects and adverse reactions, some of which are relatively serious, among them angiodema, cutaneous eruptions and dry coughs (8 to 10%).
The first attempts to develop Ang II antagonists are from the beginning of the 70's decade and they were concentrated on the development of peptides similar to Ang II. The first antagonist was saralasina, 1-sarcosina, 8-isoleucina angiotensin II, that was followed by others. However, they did not have clinical acceptance, because they presented partial agonist activity. In 1982 were developed the first two selective antagonists for the AT1 receptor of non-peptidic characteristic (S-8307 and S8308). However, eventhough they were highly specific and without agonist activity, they presented a weak bind to Ang II'S receptors. With a series of modifications in the molecular structure of those two precursors, to improve the potency and to retain the selectivity and to reach the pharmacokinetis properties, a new product of orally active, potent and of high specificity was developed, Losartan. Starting from then, many other antagonists of non-peptidic origin were developed, such as Candesartan, Irbesartan, Valsartan, Telmisartan, Eprosartan, Tasosartan and Zolasartan.
Angiotensin-(1-7), (Asp-Arg-Val-Tyr-Ile-His-Pro) (SEQ ID NO:1) and its derivative one [Sar1]-Ang-(1-7) antagonize Ang II pressor effect in man (Ueda S, Masumori-Maemoto S, Ashino K, Nagahara T, Gotoh and, Umemura S, Ishii M. Angiotensin-(1-7) attenuates vasoconstriction evoked by angiotensin II but not by noradrenaline in man. Hypertension 2000; 35:998-1001) and mice (Bovy P R, Trapani A J, McMahon E G, Palomo M. The carboxy-terminus truncated analogue of angiotensin II [Sar1]-angiotensin II-(1-7)-amide, provides an entry to the new class of angiotensin II antagonists. J Med Chem. 1989; 32:520-522). The contraction produced by Ang II in isolated arteries of rabbits and humans is also reduced by angiotensin-(1-7) (Bovy P R, Trapani A J, McMahon E G, Palomo M. The carboxy-terminus truncated analogue of angiotensin II [Sar1] angiotensin II-(1-7)-amide, provides an entry to the new class of angiotensin II antagonists. J Med Chem. 1989; 32:520-522. Roks A J, Van-Geel P P, Pinto Y M, Buikema H, Henning R H, of Zeeuw D, van-Gust W H. Angiotensin-(1-7) is a modulator of the human renin-angiotensin system. Hypertension 1999; 34(2): 296-301).
Until very recently, the receptor(s) responsible for the transduction of the Ang-(1-7) response had not been identified and many possibilities were raised regarding Ang-(17) signal transduction. The first evidence for the existence of different receptors and/or different mechanisms of signal transduction for Ang-(1-7) effects was based on the demonstration that several Ang-(1-7) actions are different and even opposite from those ascribed for Ang II. Recently, the heptapeptide D-[Ala7]-Ang-(1-7) (A-779) was characterized as a potent antagonist for Ang-(1-7) effects (Santos R A S, Campagnole-Santos M J, Baracho N C V, Fontes M A P, Silva L C S, Neves L A A, Oliveira D R, Caligiorne S M, Rodrigues A R V, Gropen Jr. C, Carvalho W S, Silva A C S, Khosla M C. Characterization of the new angiotensin antagonist selective goes angiotensin-(1-7): Evidence that the actions of angiotensin-(1-7) it plows mediated by specific angiotensin receptors. Brain Res. Bull. 1994; 35:293-299). The results of that study indicated that this analogue is a selective antagonist of Ang-(1-7) without demonstrating agonist activity in several biological preparations. A-779 was shown to potently antagonize the antidiuretic effect of Ang-(1-7) in rats with water overload. The vasodilatation produced by Ang-(1-7) in the afferent arterioles of rabbits, the Ang-(1-7) pressor effect in the RVLM, the vasodilation produced in the mesenteric microcirculation in vivo are completely blocked by the administration of A-779, and are not affected by the selective Ang II antagonists. Other studies using bovine endothelial cells, dog coronary arteries, SHR aorta, human epithelial fibroblasts, human heart fibroblasts and kidney slices have supported the evidences for the existence of specific receptors of Ang-(1-7) that can be blocked by the A-779. (Santos, R A S; Campagnole-Santos, M J.; Andrade, S P. Angiotensin-(1-7): an update. Regulatory Peptides, 91:45-62, 2000).
A-779 and its analogues such as Sar1-D-Ala 7-Ang-(1-7) (Bovy P R, Trapani A J, McMahon E G, Palomo M. THE carboxy-terminus truncated analogue of angiotensin II [Sar1] angiotensin II-(1-7)-amide, provides an entry to the new class of angiotensin II antagonists. J Med Chem. 1989; 32:520-522.), and the D-Pro7-Ang-(1-7) (Naves-Santos, V., Khosla, M. C., Oliveira, R. C., Campagnole-Santos, M. J., Lima, D. X., Santos, R A S. Selective inhibition of the effect central pressor of angiotensin-(1-7) for its similar one [D-Pro7]-angiotensin-(1-7). XI Reunião Annual of the Federation of Society of Experimental Biology, 1996, Caxambu, M G) and others can serve extremely as tools to elucidate biological effects of Ang-(1-7).
It has been demonstrated that Ang-(1-7) acts inside the RAS as a contraregulatory peptide of this system, acting at multiple points (Ferrario C M, Chappell M C, Dean R H, Iyer S N. Novel angiotensin peptides regulate blood pressure, endothelial function, and natriuresis. J Am Soc Nephrol. 1998; 9: 1716-1722. Santos, R. Campagnole-Santos, M J, Andrade, S P. Angiotensin-(1-7): an update. Regulatory Peptides, 91:45-62, 2000. Heringer-Walther S, Batista E N, Walther T, Khosla M C, Santos R A S, Campagnole-Santos M J. Baroreflex improvement in SHR after ACE inhibitors involves angiotensin-(1-7). Hypertension, 37: 1309-1313, 2001).
Ang-(1-7) decreases angiogenesis and cellular proliferation (Machado, R D P, Santos, R A S, Andrade, S P. Mechanisms of angiotensin-(1-7) induced inhibition of angiogenesis. Am J Physiol, 280: 994-1000, 2001. Rodgers K, Xiong S, Félix J, Rotates N, Espinoza T, Maldonado S, Dizerega G. Development of angiotensin-(1-7) the in the agent to acelerate dermal repair. Wound Repair Regen, 9: 238-247, 2001) presenting therefore a potential for the treatment of lesions. Ang-(1-7) can act as an ACE inhibitor in the amino-terminal domain of the enzyme, in which it acts as substrate, as well in the c-terminal domain in which it acts as an inhibitor (Deddish P A, Marcic B, Jackman H L, Wang H Z, Skidgel R A, Erdös E G. N-domain-specific substrate and C-domain inhibitors of angiotensin-converting enzyme: angiotensin-(1-7) and keto-ACE. Hypertension. 1998; 31:912-917. Tom B, Of Vries R, Saxena P R, Danser A H J. Bradykinin potentiation by angiotensin-(1-7) and ACE inhibitors correlates with ACE C- and N-domain blockade. Hypertension, 38: 95-99, 2001). Its IC50 for inhibition of ACE is approximately 1 micromolar (Chappell M C, Pirro N T, Sykes T H E, Ferrario C M. Metabolism of angiotensin-(1-7) by angiotensin-converting enzyme. Hypertension. 1998; 31(part 2): 362-367. Paula, R D, Lima, C V, Britto, R R, Campagnole-Santos, M J, Khosla, M C, Santos, R A S. Potentiation of the hypotensive effect of bradykinin by angiotensin-(1-7)-related peptides. Peptides, 20:493-500, 1999. Deddish P A, Marcic B, Jackman H L, Wang H Z, Skidgel R A, Erdos E G. N-domain-specific substrate and C-domain inhibitors of angiotensin-converting enzyme: angiotensin-(1-7) and keto-ACE. Hypertension, 31:912-917, 1998).
In addition to the ACE inhibitory activity, Ang-(1-7) inhibits the Ang II actions by two different mechanisms: 1) competing for the ligation on AT1 receptors (Bovy P R, Trapani A J, McMahon E G, Palomo M. The carboxy-terminus truncated analogue of angiotensin II [Sar1]-agiotensin II-(1-7)-amide, provides an entry to the new class of angiotensin II antagonists. J Med Chem. 1989; 32:520-522.—Ueda S, Masumori-Maemoto S, Ashino K, Nagahara T, Gotoh A N D, Umemura S, Ishii M. Angiotensin-(1-7) attenuates vasoconstriction evoked by angiotensin II but not by noradrenaline in man. Hypertension 2000; 35:998-1001. Roks A J, Van-Geel P P, Pinto Y M, Buikema H, Henning R H, deZeeuw D, van-Gilst W H. Angiotensin-(1-7) is a modulator of the human renin-angiotensin system. Hypertension 1999; 34(2): 296-301. Rowe B P, Saylor D L, Speth R C, Absher D R. Angiotensin-(1-7) binding at angiotensin II receptors in the rat brain. Regul Pep. 1995; 56(2): 139-146. Mahon J M, Carrr R D, Nicol A K, Hendersn I W. Angiotensin-(1-7) is an antagonist at the type 1 angiotensin II receptor. J Hypertension 1994; 12:1377-1381), and 2) altering the signalling mechanisms of Ang II effects, possibly by altering the availability of intracellular calcium (Chansel D, Vandermeerch S, Andrzej T, Curat C, Ardaillou R. Effects of angiotensin IV and angiotensin-(1-7) on basal angiotensin II-stimulated cytosolic Ca+2 in mesangial cells. Eur J Pharmacol. 2001; 414:165-175). A third mechanism for which Ang-(1-7) can antagonize the Ang II deleterious effects on the cardiovascular system are the potentiation of the bradykinin effects (Paula, R D; It Rasps, C V, Khosla, M C, Santos, R A S. Angiotensin-(1-7) potentiates the hypotensive effect of bradykinin in concious rats. Hypertension, 26: 1154-1159, 1995. Li P, Chappell M C, Ferrario C M, Brosnihan K B. Angiotensin-(1-7) augments bradykinin-induced vasodilation by competing with ACE and releasing nitric oxide. Hypertension. 1997; 29 (part 2): 394-400).
Bradykinin is an endogenous peptide with potent vasodilatatory action (Rocha and Silva, M, Beraldo, W T, Rosenfeld, G. Bradykinin, the hypotensive and smooth muscle stimulating factor releases from shapes globulin by snake venoms and by trypsin. Am. J. Physiol. 156, 261-273, 1949). It has also been described beneficial actions of bradykinin in the heart (Linz W, Wohlfart P, Scholkens B A, Malinski T, Wiemer G. Interactions among ACE, kinins and NO. Cardiovasc Res. 1999; 43:549-561). Ang-(1-7) potentiate the effects of bradykinin, in vessels (Paula, R. D.; Lima, C. V.; Khosla, M. C.; Santos, R. A. S. Angiotensin-(1-7) potentiates the hypotensive ffect of bradykinin in concious rats. Hypertension, 26: 1154-1159, 1995. Li P, Chappell M C, Ferrario C M, Brosnihan K B. Angiotensin-(1-7) augments bradykinin-induced vasodilation by competing with ACE and releasing nitric oxide. Hypertension. 1997; 29 (part 2): 394-400), in the heart (Almeida, A P, Frábregas, B C, Madureira, M M, Santos, R J S, Campagnole-Santos, M J, Santos, R A S. Angiotensin-(1-7) potentiates the coronary vasodilatory effect of bradykinin in the isolated rat heart. Braz. J. of Medical and Biological Research, 33: 709-713, 2000).
A particular drug could be chemically modified in order to alter its properties such as biodistribution, pharmacokinetics and solubility. Various methods have been used to increase the solubility and stability of drugs, among them the use of organic solvents, their incorporation within emulsions or liposomes, the adjustment of pH, their chemical modifications and their complexation with the cyclodextrins.
The cyclodextrins are oligosaccharides cyclic family, which include six, seven or eight units of glucopyranose. Due to sterics interactions, the cyclodextrins, CD's, form a cycle structure in the shape of a (cone truncado) with an internal cavity apolar. Those are compounds chemically stable that can be modified in a regioselective way. The cyclodextrins hosts form complexes with various hydrophobic guests in their cavity. The CD's have been used for the solubilization and encapsulation of the drugs, perfumes and fragrances as described by Szejtli, J., Chemical Reviews, (1998), 98, 1743-1753. Szejtli, J., J. Mater. Chem., (1997), 7, 575-587.
According to detailed studies of toxicity, mutagenecity, teratogenecity and carcinogenecity about the cyclodextrins, described in [Rajewski, R. A., Stella, V., J. Pharmaceutical Sciences, (1996), 85, 1142-1169], these are presented with low toxicity specially of the (hydroxypropyl-β-cyclodextrin, as reported in Szejtli, J. Cyclodextrins: properties and applications. Drug investing., 2(suppl. 4): 11-21, 1990. Except for some high concentrations of some derivates which cause harm to the erythrocytes, these products in general are not harmful to the health. The use of cyclodextrins as additives in foods has already been authorized in countries such as Japan and Hungary, and for more specific applications, in France and Denmark. Besides this, they are obtained from a renewable source of degradation of the amide. All these characteristics are a high motivation for the research findings of new applications. The structure of the molecule of CD is similar to a cone truncate one, of Cn approximately symmetry. The primary hydroxilas are located in the narrowest side of the cone by the intramolecular hydrogen bonds, this element is flexible enough to allow a considerable deviance in the regular shape.
The known cyclodextrin derivatives can be classified according to their polarity, size, biological activity, etc. As for their practical uses are classified as follows: 1. Carriers (solubilizers, stabilizers) for biologically active substances; 2. Enzyme models; 3. Separating agents (for chromatography or batch-processes); 4. Catalysts and additives (as detergents, viscosity modifiers, etc), L. Szente and J. Szejtli, Adv. Drug Deliv. Rev. 36 (1999), 17. The CD's are moderately soluble in water, methanol and ethanol and readily soluble in polar solvents, such as the dimethyl sulfoxide, dimethyl formamide, N,N-dimethyl acetamide e piridine.
Numerous research works exist in the literature about the effects of the increase of solubility in water of the guests little soluble in water, using the cyclodextrins through the using compounds of inclusion were describe in Szejtli, J., Chemical Reviews, (1998), 98, 1743-1753. Szejtli, J., J. Mater. Chem., (1997), 7, 575-587.
In order to design a drug delivery system (DDS) various kinds of high performance carrier materials are being developed to deliver the necessary amount of drug to the targeted site for a necessary period of time, both efficiently and precisely. Cyclodextrins, biodegradable or non biodegradable polymers, liposomes, emulsions, multiple emulsions are potential candidates for such a role, because of their ability to alter physical, chemical, and biological properties of guest molecules
Besides the cyclodextrins, a number of drug delivery systems have been investigated, including polymer microcapsules, microparticles, liposomes and emulsion. Many of these are prepared from synthetic biodegradable polymers such as polyanhydrides and poly(hydroxy acids). In these systems the drugs incorporate in a polymeric microspheres, which release the drug inside the organism, in small and controlled daily doses, during days, months or until years.
Several polymers already were tested in controlled release systems. Such as: polyuretans for its elasticity, polysiloxans or silicons for being a good one insulating, polymethyl-methacrilate for its physical force, polyvinyl alcohol for its hydrophobicity and resistance, polyethylene for its hardness and impermeability (Gilding, D. K. Biodegradable polymers. Biocompat. Clin. Impl. Mater. 2:209-232, 1981). Biodegradable polymers and biocompatible polymers, hve been extensively investigated as vehicle for controlled release systems due to their ability to undergo surface degradation. These kind of polymers can be chose from: poly(hydroxy-ethylmethacrylate), polyacrylamide, polymer from lactic acid (PLA), from glicolic acid (PGA), and the respective ones co-polymers, (PLGA) and the poly(anidridesanhydrides), as described by Tamada and Langer, J. Biomater. Sci. Polym. Edn, 3(4): 315-353.
A formulation of the present invention can also include other components such as a pharmaceutical acceptable excipient. For example, formulation of the present invention can be formulated in an excipient that the animal to be protected can tolerate. Excipients can also contain minor amounts of additives, such as substances that enhance isotonicity and chemical stability of buffers. Standard formulation can either be liquid injectables or solids which can be taken up in a suitable liquid as a suspension or solution for injection or oral formulation. Suitable controlled release vehicles include, but are not limited to, biocompatible polymers, other polymeric matrices, capsules, microcapsules, nanocapsules, microparticles, nanoparticles, bolus preparations, osmotic pumps, diffusion devices, liposomes, lipospheres and transdermal delivery systems, implantable or not.
In the last years, several systems of drugs delivery systems have been studied to improve the drug absorption, to increase the drug stability and target it to a certain cell population. These studies led to the development of several products based on cyclodextrins, emulsions, liposomes and polymers for drug carrying and delivering. These formulations can be administered through intramuscular, intravenous, subcutaneous injection, oral application, inhalation or devices that can be implanted.
Liposomes are lipid vesicles that include aqueous internal compartments in which molecules, for example drugs, are encapsulated with the objective of reaching a controlled release of the drug after administration in individuals.
Many different techniques have been proposed for the preparation of liposomes [U.S. Pat. No. 4,552,803, Lenk; U.S. Pat. No. 4,310,506, Baldeschwieler; U.S. Pat. No. 4,235,871, Papahadjopoulos; U.S. Pat. No. 4,224,179, Schneider; U.S. Pat. No. 4,078,052, Papahadjopoulos; U.S. Pat. No. 4,394,372, Tailor; U.S. Pat. No. 4,308,166, Marchetti; U.S. Pat. No. 4,485,054, Mezei; and U.S. Pat. No. 4,508,703, Redziniak; Woodle and Papahadjopoulos, Methods Enzymol. 171:193-215 (1989)]. Unilamellar vesicles display a single membrane [Huang, Biochemistry 8:334-352 (1969)] while multilamellar vesicles (MLVs) have numerous concentric membranes [Bangham et al., J. Mol. Biol. 13:238-252 (1965)]. The procedure of Bangham [J. Mol. Biol. 13:238-252 (1965)] produces "ordinary MLVs", that present unequal solute distributions among the aqueous compartments and, consequently, differences of osmotic pressure. Lenk et al. (U.S. Pat. No. 4,522,803; U.S. Pat. No. 5,030,453 and U.S. Pat. No. 5,169,637), Fountain et al. (U.S. Pat. No. 4,588,578), Cullis et al. (U.S. Pat. No. 4,975,282) and Gregoriadis et al. (Pat. W.O. 99/65465) introduced methods for the preparation of MLVs that present substantially equal solute distributions among the compartments. Similar solute distributions among the different compartments mean a larger drug encapsulation efficiency as well as smaller differences of osmotic pressure that turns these MLVs more stable than ordinary MLVs. Unilamellar vesicles can be produced by sonication of MLVs [Papahadjopoulos et al. (1968)] or by extrusion through polycarbonate membranes [Cullis et al. (U.S. Pat. No. 5,008,050) and Loughrey et al. (U.S. Pat. No. 5,059,421)].
Satisfactory lipids include for example, phosphatidylcholine, phosphatidylserine, phosphatidylglycerol, cardiolipin, cholesterol, phosphatidic acid, sphingolipids, glycolipids, fatty acids, sterols, phosphatidylethanolamine, polymerizable lipids in their polymerized or non-polymerized form, mixture of these lipids.
The composition of the liposomes can be manipulated such as to turn them specific for an organ or a cell type. The targeting of liposomes has been classified either on the basis of anatomical factors or on the basis of the mechanism of their interaction with the environment. The anatomical classification is based on their level of selectivity, for example, organ-specific or cell-specific. From the point of view of the mechanisms, the targeting can be considered as passive or active.
The passive targeting exploits the natural tendency of conventional liposomes to be captured by the cells of the reticulo-endothelial system, i.e. mainly the fixed macrophages in the liver, spleen and bone marrow. Sterically stabilized liposomes (also well-known as "PEG-liposomes") are characterized by a reduced rate of elimination from the blood circulation [Lasic and Martin, Stealth Liposomes, CRC Press, Inc., Boca Raton, Fla. (1995)]. PEG-liposomes present a polyethylene glycol polymer conjugated to the head group of some phospholipid that reduces their interaction with plasma proteins, such as opsonins, and reduces the rate of their uptake by cells. The resulting steric barrier allows these liposomes to remain for a longer period of time within the circulation than conventional liposomes [Lasic and Martin, Stealth Liposomes, CRC Press, Inc., Boca Raton, Fla. (1995); Woodle et al., Biochim. Biophys. Acta 1105:193-200 (1992); Litzinger et al., Biochim. Biophys. Acta 1190:99-107 (1994); Bedu Addo, et al., Pharm. Res. 13:718-724 (1996)]. The drug encapsulation within PEG-liposomes has resulted in the improvement of the effectiveness of many chemotherapeutic agents [Lasic and Martin, Stealth liposomes, CRC Press, Inc., Boca Raton, Fla. (1995)] and bioactive peptides [Allen T. M. In: Liposomes, New Systems, New Trends in their Applications (F. Puisieux, P. Couvreur, J. Delattre, J. -P. Devissaguet Ed.), Editions de la Santé, France, 1995, pp. 125].
Studies in this area demonstrated that different factors affect the effectiveness of PEG-liposomes. Ideally, the diameter of the vesicles should be below 200 nm, the number of units in PEG of approximately 2.000 and the proportion of Pegylated lipid from 3 to 5 mol % [Lasic and Martin, Stealth Liposomes, CRC Press, Inc., Boca Raton, Fla. (1995); Woodle et al., Biochim. Biophys. Acta 1105:193-200 (1992); Litzinger et al., Biochim. Biophys. Acta 1190:99-107 (1994); Bedu Addo et al., Pharm. Res. 13:718-724 (1996)].
The active targeting involves alteration of liposomes through their association with a ligand, such as a monoclonal antibody, a sugar, a glycolipid, protein, a polymer or by changing the lipid composition or the liposome size to target them to organs and cells different from those which accumulate conventional liposomes.
Liposome-based vehicles have been proposed for a large variety of pharmacologically active substances, including antibiotics, hormones and antitumoral agents [Medical applications of liposomes (D. D. Lasic, D. Papahadjopoulos Ed.), Elsevier Science B. V., Holland, 1998].
Ang-(1-7) and its analogues have great potential for study and treatment of several diseases including cardiovascular disorders. Another important aspect related RAS is related to the clear need of amplification of the knowledge about its physiologic actions that can propitiate the development of new therapeutic strategies. However, the conventional way of administration of most of the drugs anti-hypertensive especially biologically active peptides, as the angiotensins and derivatives, suffers limitations due to the short half-life of peptides.
In that sense, the present invention is characterized by the use of liposomes, cyclodextrins and biodegradable polymers as controlled release systems of the angiotensins and derivatives to increase their bioavailability, the duration and intensity of their biological effects.
The formulation of the present invention is characterized by the use of the mixture of excipients pharmaceutically acceptable for Ang-(1-7) and/or analogues. Excipients examples include water, saline solution, buffered phosphate solutions, the solution of Ringer, dextrose solution, the solution of Hank, biocompatible saline solutions with or without polyethylene glycol. Non aqueous vehicles, as fixed oils, sesame oil, ethyl-oleate, or triglicerides can also be used. Other useful formulations include agents capable to increase the viscosity, as carboxymetilcelulose of sodium, sorbitol, or dextran
The excipients can also contain smaller amounts of additives, such as substances that increase isotonicity and chemical stability of substance or buffers. Examples of buffers include phosphate buffer, bicarbonate buffer and Tris buffer, while examples of preservatives include timerosal, m- or o-cresol, formalin and benzyl-alcohol. The formulation state can be liquid or solid. In the case of a non-liquid formulation, the excipients can include dextrose, human serum albumin, preservatives, etc. for which water or sterile saline solution can be added before the administration.
The present invention is also characterized by the preparation of controlled release systems containings Ang-(1-7) and/or its analogues for interaction ligand-receptor with the G Protein-coupled receptor, MAS. Satisfactory systems of controlled release include, but are not limited to, the ciclodextrinescyclodextrins, biocompatible polymers, biodegradable polymers, other polymeric matrixes, capsules, micro-capsules, microparticles, bolus preparations, osmotic pumps, diffusion devices, liposomes, lipospheres, and systems of transdermic administration. Other compositions of controlled release of the present invention include liquids that, when submitted the temperature changes, form a solid or a gel in situ.
The MAS receptor (Young, D., Waitches, G., Birchmeier, C., Fasano, O., and Wigler, M. (1986). Isolation and characterization of a new cellular oncogene encoding a protein with multiple potential transmembrane domains. Cell 45: 711-719) was initially described as an angiotensin II receptor (Jackson, T. R., Blair, A. C., Marshall, J., Goedert, M. & Hanley, M. R. The MAS oncogene encodes an angiotensin receptor. Nature 335, 437-440 (1988)), however subsequent studies showed that this hypothesis was not right (Ambroz, C., Clark, A. J. L. & Catt, K. J. The MAS oncogene enhances angiotensin-induced [Ca2+]i responses in cells with pre-existing angiotensin II receptors. Biochem. Biophys. Acta 1133, 107-111 (1991)). This protein is expressed in the brain (Bunnemann, B., Fuxe, K., Metzger, R., Mullins, J., Jackson, T. R., Hanley, M. R. & Ganten, D. Autoradiographic localization of MAS proto-oncogene mRNA in adult rat brain using in situ hybridization. Neurosci. Lett. 114, 147-153 (1990)) and in other tissues. There is no description in the literature of an interaction of MAS with angiotensin-(1-7) or its analogues.
The present invention is characterized by the obtention of systems of controlled release of the heptapeptide Angiotensin-(1-7) and/or its derivatives, using the cyclodextrins and/or its derivatives , that decrease the degradation of the peptide in the treatment gastrointestinal (TGI), meaning larger biodisponibility of the peptide in the biological system. The present invention it is characterized by the obtention of controlled release systems of the heptapeptide Angiotensin-(1-7) and/or of its analogues, using biodegradable polymers, liposomes or mixtures of those systems with cyclodextrins, which increase the biodisponibility of the peptides.
Until the present, any application using the heptapeptide Angiotensin-(1-7) or its analogues, agonists and antagonists associated to the cyclodextrins or theirs derivatives, to biodegradable polymers or to liposomes, was not described.
The present invention can be understood better through the following examples:

Systems for delivery and release of angiotensin-(1-7)

Universidade Federal De Minas Gerais—UFMG


An antenna structure includes a dipole antenna element, a closed-loop conductor, and a reflection plane. The dipole antenna element is configured to transmit an electromagnetic signal. The closed-loop conductor is disposed adjacent to the dipole antenna element. The dipole antenna element is substantially between the closed-loop conductor and the reflection plane, or the closed-loop conductor is substantially between the dipole antenna element and the reflection plane. The reflection plane is configured to reflect the electromagnetic signal from the dipole antenna element so as to enhance the total gain of the antenna structure. The mutual coupling effect between the closed-loop conductor and the dipole antenna element effectively causes the distance between the dipole antenna element and the reflection plane to be shorter.

1. Field of the Invention
The disclosure generally relates to an antenna structure, and more particularly, to a directional antenna structure with a dipole antenna element.
2. Description of the Related Art
With the progress of mobile communication technology, portable electronic devices, such as portable computers, mobile phones, tablet computers, multimedia players, and other hybrid functional mobile devices, have become more common. To satisfy user demand, portable electronic devices can usually perform wireless communication functions. Some functions cover a large wireless communication area, for example, mobile phones using 2G, 3G, and LTE (Long Term Evolution) systems and using frequency bands of 700 MHz, 850 MHz, 900 MHz, 1800 MHz, 1900 MHz, 2100 MHz, 2300 MHz, and 2500 MHz. Some functions cover a small wireless communication area, for example, mobile phones using Wi-Fi, Bluetooth, and WiMAX (Worldwide Interoperability for Microwave Access) systems and using frequency bands of 2.4 GHz, 3.5 GHz, 5.2 GHz, and 5.8 GHz.
Since the interior space of a mobile device is limited, its antenna structure for wireless communication should have as small a size as possible. A conventional high directional antenna structure is often limited by a long distance from a radiation element to the reflection plane thereof, and cannot be applied to a variety of small mobile devices.

Directional antenna structure with dipole antenna element


A fastener assembly is shown including a cylindrical support structure with a bore provided partially therein, the bore having a wall surface with a slot, and a bushing, disposed within the bore of the cylindrical support structure, having an end and an outer surface with a slot therein. The bushing further includes a bore with a first portion having a first diameter and a second portion having a second different diameter, the bushing also having a pair of tangs extending from the end. The fastener assembly further includes a nut, partially disposed within the second portion of the bore of the bushing, the nut having an outer surface with a pair of lugs disposed on the outer surface to engage the pair of tangs of the bushing and a pin disposed juxtapositional the slot of the wall surface of the cylindrical support structure and juxtapositional the slot of the bushing. The fastener assembly still further includes a pin disposed juxtapositional the slot of the wall surface of the cylindrical support structure and juxtapositional the slot of the bushing. With such an arrangement, a fastener assembly is provided in which a forward shell section and an aft shell can be interconnected independent of the cylindrical support structure, thus maintaining circularity of airframe components and minimizing circular distortion.

This invention pertains generally to fasteners and particularly to a thermally compensating insert fastener for interconnecting two sections of a missile.
It should be appreciated in an apparatus such as a missile it is often desirable to construct a missile in sections. Typically the missile includes a radome, a guidance section, a warhead section, a flight control section and a rocket motor section. In a missile, the guidance section can be pressurized to prevent high voltage arcing during operation at high altitudes. Numerous seals are employed to maintain guidance section pressure during passive captive carry flight and during active operational free flight. Loss of pressure during flight can cause the guidance section which houses a target seeker to operate incorrectly.
One known cause of loss of pressure in the guidance section during flight is from an improper seal at an interconnection of two sections of the missile. One type of interconnection for connecting a forward titanium shell with an aft titanium shell includes an inner titanium support structure which is mutually interconnected with the forward and aft titanium shells with a set of eleven fasteners. Each of the fasteners include an external countersunk screw and a "Keensert", which is an externally threaded bushing having an internally mounted nut, affixed within the internal support structure.
With such an arrangement, when the fasteners are tightened, deformation of the forward and aft shells will occur as the forward and aft shells are drawn toward the internal support structure. Since the inner diameter of the forward shell will not exactly match the outer diameter of the aft shell and the inner diameter of the aft shell will not exactly match the outer diameter of the internal support structure due to manufacturing tolerances, varying radial gaps will exist. As the fasteners are tightened, scalloping of the forward and aft shells will occur. Typically, visible measurable shell scalloping between fastener locations can be observed with the forward shell being the most deformed. The interconnection also includes two seals using butyl O-rings. One O-ring seals the forward shell to the support structure. The other O-ring seals the aft shell to the support structure. When the forward shell and the aft shell are interconnected with the support structure, the seals are uniformly compressed. As the fasteners are tightened, mechanical deformation is induced and the seals are no longer uniformly compressed. Cold temperatures inhibit the seal response to changes in compression which occur during rapid airframe heating. The latter can induce seal failure and pressure loss during flight.


A glow plug energization control apparatus is provided which includes a power supply working to supply electric power to a glow plug mounted in an internal combustion engine, an on-off switch working to produce a control trigger signal when turned on, and a controller including a microcomputer. The microcomputer is responsive to the control trigger signal to control supply of the electric power from the power supply to energize the glow plug. The microcomputer works to monitor an off-on interval from turning off to turning on of the on-off switch and control an amount of energization of the glow plug as a function of the off-on interval, thereby avoiding overheating of the glow plug.

1. Technical Field of the Invention
The present invention relates generally to a glow plug energization controlling apparatus which may be employed in automotive vehicle to control energization of a glow plug working to assist in starting an internal combustion engine, and more particularly to such an apparatus equipped with a microcomputer designed to control an operation of a glow plug for avoiding overheating thereof.
2. Background Art
Usually, typical diesel automotive vehicles are equipped with a glow plug working to assist in heating inside a cylinder of a diesel engine up to an ignition temperature of an air-fuel mixture, especially when the outside air temperature is low, and the engine is cold.
In recent years, in order to meet requirements to improve the startability of the engine, engine control systems have been employed which are designed to apply a dc voltage to the glow plug to heat the glow plug to a target temperature quickly. Rough control of an on-duration for which the dc voltage is applied to the glow plug will, thus, result in increase in physical load on the glow plug. For instance, too long the on-duration of the glow plug will result in overheating of the glow plug, which may lead to wire breakage in the glow plug.
In recent years, for the purpose of increasing the accuracy in controlling the energization of the glow plug, glow plug energization control systems have been in widespread use which are equipped with a microcomputer designed to control power supply to the glow plug as well as other controls for the engine. When a key switch of the automotive vehicle is turned on, the electric power is supplied to the microcomputer. The microcomputer applies an effective voltage of 11V to the glow plug in the form of a PWM signal for a given initial energiation duration and then also applies an effective voltage of 7V to keep the glow plug at a target temperature of, for example, 900° C., for a given period of time (will also be referred to as a temperature-holding time below).
The above glow plug energization control systems, however, encounter a drawback in the following situation.
When the key switch is turned off by an operator in the course of energization of the glow plug and then turned on again immediately to reenergize the glow plug, the glow plug starts to be heated from a relatively high temperature. When the glow plug continues to be energized over the initial energization duration and the temperature-holding time, it may cause the glow plug to overheat.
In order to avoid the above problem, Japanese Patent First Publication No. 2004-108189 teaches a glow plug energization control system designed to keep the microcomputer activated after the key switch is turned off until the temperature of the glow plug decreases to a given lower level to calculate an optimum amount of energization of the glow plug which will not result in the overheating of the glow plug when the key switch is turned on immediately. This system, however, requires an electrical circuit which measures the voltage and current given to the glow plug to determine the optimum amount of energization, thus resulting in complexity and increase in production cost of the system.

Glow plug energization control to avoid overheating


Systems and methods for, inter alia, allowing a remote user to access content, such as data or an executable program, on demand from a remoter server. When accessed the content can be delivered on demand to the user's remote workstation for use by the user. As network resources may vary, the systems described herein further include systems that will monitor network resources, and other factors, versus the transfer demands for the content requested by the user. The systems may then determine a schedule, or load map, for transferring blocks of the content in a way that efficiently employs the available resources, and in a way that provides the user with a user-experience that is similar, or substantially similar, to the user-experience that the user would have if the content were stored locally on the user's workstation.

Today, interconnectivity over data networks continues to expand. Most companies today have an internal network, many of which provide high speed data delivery to terminals on the network. Additionally, the Internet provides interconnectivity between networks, and terminals that are located across the globe.
With the interconnectivity provided by the Internet and other networks, systems have been proposed that would allow users to license, on a per use or per hour basis, access to a software title such as Microsoft PowerPoint, games or a patent docketing software package. In these systems, once the user has been granted access to the title, the user can execute the title and employ the software as needed. Typically, the application service providers have employed a telnet type architecture that has directed the user to employ the user workstation as a terminal, while computing takes place on a remote processor that has execution access to the selected title. Alternatively, systems have employed an NFS kind of architecture that joins a remote file system into the file systems of the local user.
Other systems have been proposed that would provide access to executable programs that have a distributable component architecture. These titles, commonly written in Java, may be downloaded piecemeal to the remote user, for execution by that user on the user's local terminal.
Although such component systems can work well, they require that applications familiar to the user be re-written into a distributable architecture that allows for easy download over the Internet. Moreover, systems based on telnet technologies or on NFS technologies create problems with burdening the processing resources of the remote machine and of security.

Systems and methods for delivering content over a computer network


The field of the invention is that of producing 3D electronic modules, compatible with components operating beyond 1 GHz. The invention relates to a 3D electronic module featuring an interconnection between a horizontal conductor and a vertical conductor to which it is connected exhibits, in a vertical plane, a non-zero curvature. It also relates to the associated production process.

In a 3D electronic module, there are multiple levels of components stacked on top of one another. A 3D module or printed circuit board (PCB) comprises multiple horizontal levels comprising electrical conductors and components.
3D interconnections may be categorized according to three groups:                a. the stacking of bare chips or of packages with interconnection by means of a metal bus;        b. the stacking of bare chips interconnected by holes through the silicon, also called TSVs for through-silicon vias;        c. the stacking of bare chips interconnected by connecting wires, one level after the next.
For the first group, in order to interconnect chips that are stacked on top of one another, the vertical faces of the stack, which are metallized, are used to form the electrical connections between chips. As a result, the current technology is based on a "T"-shaped interconnection. Each stacked level contains conductors etched into a PCB which are connected vertically by a metal bus. In other words, the interconnections between the 2D (plane of a level) and 3D (stacking of the various levels) levels are made perpendicularly, i.e. at 90°.
For the second group, generally, these electronic modules are provided with holes pierced vertically, i.e. in the direction of the thickness of the module. The metallized holes, often called vias, pass through these levels and thus allow these conductors to be connected to one another vertically through contact between the metallized holes and the sections of these conductors level with the holes. Hereinafter, "hole" refers to a blind hole (a hole that does not pass all the way through) or a through-hole. Of course, an electronic module may comprise blind holes and through-holes. In this case too, the conductors located on the various stacked planes orthogonally intercept the holes.
For the third group, the superposed layers of connecting wires lead to substantial variations in impedance and inductive interference. They cannot be used beyond 1 GHz.
For the first and second groups, the 3D interconnection is orthogonal as mentioned, although TSVs are much smaller in size than an interconnection using a metal bus.
For components operating beyond 1 GHz, the orthogonal interconnection, or "T"-shaped interconnection, leads to reflections that negatively affect signal integrity. For a 3D electronic module in the radiofrequency domain, since the connections are vertical on the faces of the stack, the "T"-shaped interconnections between electrical conductors (for example conductors from chips and vertical conductors) are arranged at right angles. Electrons are reflected at the site of the connection, which interferes with the electrical connection and weakens it.
Consequently, there is still a need for a method for interconnecting stacked chips that allows the integrity of signals to be ensured at radiofrequencies.

Process for producing a high-frequency-compatible electronic module


A new Verbena plant particularly distinguished by large pink and white flowers having good color contrast, good branching and an early flowering time, is disclosed.

The present invention comprises a new and distinct variety of Verbena, botanically known as Verbena sp., and hereinafter referred to by the variety name 'KLEVP14463'. 'KLEVP 14463' originated from a cross-pollination conducted in April 2010 in Sydney, Australia between the proprietary female Verbena variety '001.1.42' (unpatented), and the proprietary male Verbena variety derived from the cross of 'V9120' (unpatented).
The seeds from the cross were sown and plants were grown for evaluation, where an individual plant designated 'KLEVP14463' was selected from the group of plants in Cobitty, NSW, Australia in September 2011.
In September 2011, 'KLEVP14463' was first vegetatively propagated by vegetative cuttings in Cobitty, NSW, Australia. 'KLEVP14463' was found to reproduce true to type in successive generations of asexual propagation via vegetative cuttings in Stuttgart, Germany.


A system, comprising of an engine having a cylinder therein, a fuel injector coupled to said cylinder and configured to directly inject fuel into said cylinder, a fuel system coupled to said injector, and a controller configured to control engine starting operation, wherein during a start, said fuel injector performs a first fuel injection at least partially during an exhaust stroke of said cylinder, where fuel from said first fuel injection is mixed with air inducted at least during an intake stroke following said exhaust stroke, said fuel injector performing a second fuel injection after said first fuel injection, and combusting fuel from said first and second fuel injections to perform a combustion event in said cylinder.

Strategies have been developed in order to reduce the tailpipe hydrocarbon emissions produced during vehicle startup while simultaneously obtaining reliable combustion and increasing exhaust heat for catalyst heating. In one example, intake port fuel injection can be used to provide a selected air-fuel ratio for combustion. In another example, direct fuel injection may be used to improve control over fuel delivery during a cold start.
One approach to facilitating fuel injection control in a direct injection engine during startup is described in U.S. Pat. No. 5,794,586. In this approach, a fuel injection control system provides a means of delivering fuel in a single low pressure injection during startup. In particular, the approach relies on a single injection of fuel initiated late in the exhaust stroke that persists throughout the intake stroke in order to facilitate the vaporization of the fuel during cold start applications. In this manner, the fuel may be pre-heated by the exhaust residuals remaining in the combustion chamber from the subsequent operating cycle.
The inventors herein have recognized a disadvantage with such an approach. Specifically, a single injection occurring late in the exhaust stroke and continuing into the intake stroke may cause excessive piston wetting. For example, some of the fuel that is injected at or near top dead center may form a film on the piston that can decrease air and fuel mixing and thus increase hydrocarbon emissions, at least under some conditions such as engine cold starting.
In one approach, the above issues may be addressed by a system, comprising of an engine having a cylinder therein; a fuel injector coupled to said cylinder and configured to directly inject fuel into said cylinder; a fuel system coupled to said injector; and a controller configured to control engine starting operation, wherein during said start, said fuel injector performs a first fuel injection at least partially during an exhaust stroke of said cylinder, where fuel from said first fuel injection is mixed with air inducted at least during an intake stroke following said exhaust stroke, said fuel injector performing a second fuel injection after said first fuel injection, and combusting fuel from said first and second fuel injections to perform a combustion event in said cylinder.
In this way, it may be possible to achieve improved vaporization via the first injection at least partially during the exhaust stroke. Further, it may be possible to achieve this vaporization while reducing piston wetting by using at least a second injection event during engine cold starting. In other words, the combination of the first and second separate injection can enable less fuel injection near top dead center, thereby reducing piston wetting. Finally, by utilizing at least two injections, it may be possible to deliver the desired fuel to meet the desired combustion torque to start the engine.
Also, note that there are various forms of direct fuel injectors that may be used, such as a cylinder side-wall located injector, or an injector mounted in a cylinder head above the piston. Further, the piston may be configured in various ways to direct the fuel into the cylinder. In some embodiments, low pressure fuel system having a single fuel pump located in or near the fuel tank or located near the engine may be used among others. In some embodiments, dual stage fuel injection systems may be also be used. Further, engine start may include various types of starting, such as starting from rest, starting from a crank speed, engine run-up, engine idle operation following run-up, and various others or combinations thereof.

Fuel injection strategy for reduced cold start emission from direct injection gasoline engines


An apparatus for obtaining correlation by despreading a spread symbol with a spreading code is provided with a symbol storage section for storing symbol and a plurality of correlation calculators each of which executes a correlation calculation to obtain correlation by despreading the symbol data with a spreading code. The apparatus switches a spreading code to be provided to each of the plurality of correlation calculators individually so that each of the plurality of correlation calculators executes correlation calculation with a respective different spreading code and holds a same spreading code until correlation calculations of a plurality of symbols are finished.

1. Field of the Invention
The present invention relates to a correlation detection apparatus used in detecting the correlation of a spread spectrum signal in a CDMA (Code Division Multiple Access) radio communication apparatus, and more particularly, to a correlation detection apparatus applicable to a digital matched filter.
2. Related Art
A matched filter is used at a receiving station to demodulate a spread spectrum signal that is generated by multiplying transmission data with a spreading code at a transmitting station.
FIG. 1 illustrates an example of a configuration of a conventional matched filter. The matched filter illustrated in FIG. 1 is a digital matched filter with 4 taps for spreading ratio 4 composed of FIR digital filters.
Digital signal IO is input to signal input terminal 1 of the digital matched filter. Digital signal IO is, for example, a digital signal generated by sampling a spread spectrum signal at a sampling frequency of 4,096 MHz. This digital signal IO is input to first flip-flop group 11 of shift register with taps 10 (hereinafter referred to as shift register 10), and then shifted sequentially to fourth flip-flop group 14 from first flip-flop group 11 in synchronization with clock CLK of 4,096 MHz input to clock input terminal 2.
Output Signals output from every tap and the flip-flop at the last stage of shift register 10 are respectively input to first to fourth multipliers 15 to 18. Corresponding despreading code C among from despreading code sequence C3C2C1C0 is provided to each of first to fourth multipliers 15 to 18. Accordingly, first multiplier 15 executes multiplication of an output signal from first flip-flop group 11 by despreading code Co (1 bit). Similarly, second to fourth multipliers 16 to 18 execute respectively multiplication of output signals from second to fourth flip-flop groups 12 to 14 respectively by despreading codes C1 to C3. First to fourth multiplies 15 to 18 respectively execute multiplication of respective output signals from first to fourth flip-flop groups by 1 when the despreading code indicates 0, and multiplication of output signals from first to fourth flip-flop groups by xe2x88x921 when the despreading code indicates 1.
First adder 19 adds outputs from first and second multipliers 15 and 16, second adder 20 adds outputs from third and fourth adders 17 and 18, and third multipliers 21 adds outputs from first and second adders 19 and 20. As a result, correlation value MFOUT of digital signal IO with despreading code sequence C3C2C1C0 is output to external through output terminal 3.
Conventionally, the digital matched filter described above rewrites despreading code sequence C3C2C1C0 on a basis of one symbol period to detect the correlation of each symbol. As a result, it is not possible to detect the correlation of delayed waves input after one symbol period passes.
Such a condition has remained the inconveniences that it is not possible to effectively utilize delayed waves input after one symbol period passes in the CDMA system that enables a plurality of delayed waves to be utilized. One of means of solving the inconveniences suggests a configuration having a plurality of parallel connected matched filters each of which is illustrated in FIG. 1. FIG. 2 illustrates the configuration having a plurality of parallel connected matched filters each of which is illustrated in FIG. 1. First to fourth digital matched filters M1 to M4 are provided in parallel.
However, the configuration with the plurality of parallel connected matched filters results in the problem that a circuit scale and power consumption are increased.
An object of the present invention is to provide a correlation detection apparatus capable of detecting the correlation of delayed waves arriving after one symbol period passes, and of decreasing a circuit scale and power consumption.
The correlation detection apparatus has a data storage section for storing symbol data, a plurality of correlation calculators connected to the data storage section in parallel, each for executing the correlation detection of the symbol data with a spreading code for despreading, and a code controller for rewriting the spreading code for each of the correlation calculators on a basis of a plurality of symbol periods individually.
According to the configuration, a plurality of correlation calculators are connected to the data storage section in parallel, and the spreading codes in respective correlation calculators are individually rewritten after a period corresponding to a plurality of symbols passes. Therefore, it is possible to detect the correlation of delayed waves arriving after one symbol period passes, and to decrease a circuit scale and power consumption largely compared with the case of arranging a plurality of digital matched filters in parallel to perform the processing.

Correlation detection apparatus and CDMA receiving apparatus

Matsushita Electric Industrial Co., Ltd.