text:
|Publication number
|Publication type
|Application number
|Publication date
|3 Apr 1990
|Filing date
|3 Jun 1986
|Priority date
|3 Jun 1986
|Fee status
|Also published as
|Publication number
|George W. Pratt, Jr., Paul Duchnowski
|Original Assignee
|Analog Devices, Inc.
|Export Citation
|BiBTeX, EndNote, RefMan
|Patent Citations (5), Non-Patent Citations (53), Referenced by (154), Classifications (24), Legal Events (5)
|External Links: USPTO, USPTO Assignment, Espacenet
1. Field of the Invention
This invention deals generally with diagnostic methods for determining the condition of bones. In particular, it discloses a method for non-invasively, in vivo, determining the condition of certain bones in humans and animals. This information can be used to evaluate whether or not the subject has any disorders relating to variations in bone condition, such as osteoporosis (abnormally low bone density) or osteopetrosis (abnormally high bone density).
2. Discussion of the Problem and Objects of the Invention
This invention pertains to detecting bone disease and other abnormal bone conditions. The invention is intended specifically for evaluation and diagnosis of humans, but with obvious modification of the illustrative embodiments, the invention could be used to evaluate animal bones, also. The main object is to diagnose the presence of osteoporosis. However, other conditions may also be detected using this method, including bone condition variations following renal failure and periodontal disease due to bone deterioration The invention may also be useful both for detecting fractures and for assessing, quantitatively, the healing of fractures.
The human skeleton is composed of tubular (long and hard) and cancellous (spongy) bones, each of which is composed of, specific proportions of cortex (compact bone) and trabeculae (connective strands). Tubular bones, which are composed largely of cortex, dominate the appendicular skeleton that makes up the limbs; cancellous bones, which are composed primarily of trabecular bone, dominate the axial skeleton of the vertebral column and pelvis.
In both cortical and trabecular bone, the collagen fibrils extend throughout. The difference between the two is actually one of degree, depending upon the form the network of collagen fibrils takes. In general, the fibrils may be separated such that the network is a network of rods. They may also be more closely spread, so that the network appears as a network of plates connected by rods. In both cases, a certain volume of the bone will comprise mineralized collagen fibrils, and a certain volume will comprise fluid known as "marrow."
Whether or not a particular bone assumes a trabecular or cortical formation is thought to depend largely upon the function that bone serves. The method of bone formation is not well understood; however, it is believed that the process of bone accretion responds in some manner to stresses experienced by the bone. Therefore, that region of a bone that experiences relatively high stresses, such as the diaphysis of the tibia of the leg, tends more toward cortical bone Regions of a bone that experience low stress tend more to be trabecular. In most sites of trabecular bone, the trabecular mass is surrounded by a relatively thin layer of cortical bone The patella (kneecap) is mostly trabecular with a subcortical layer just beneath the anterior surface.
The principal target of the invention, osteoporosis, is a disease of unknown cause which afflicts people, generally, as they age. Osteoporosis afflicts women more often than men, and of women, more often after menopause. White women are more often stricken than women of other races Osteoporosis is manifest as an absolute decrease in bone tissue mass. The bone that remains is, however, normal A person suffering from osteoporosis loses a greater proportional amount of trabecular bone than cortical bone Common manifestations of osteoporosis are a hunched back, caused by crush fractures of the vertebrae, and fractures of the neck, the femur (upper thigh bone) and distal end of the radius (wrist bone).
Osteoporosis is a particularly insidious condition, because during its early phases physical deformity is not evident. Because osteoporosis develops progressively, early diagnosis and appropriate treatment may turn an otherwise serious onslaught Additionally, because of the mode by which bone is formed, an enhanced exercise regimen during the patient's younger years, coupled with an appropriate diet, has been thought to also minimize the effects of the condition. With women, it is appropriate to begin these programs prior to menopause. The diagnosis and treatment of osteoporosis is complicated by the fact that every patient has a different "normal" bone density; thus it is beneficial to generate a historical record of the changes in some property of the individual patient's bones (i.e., density or elasticity) and to make a diagnosis, at least in part, on the basis of historical trends.
Another target of the invention, periodontal disease, involves loss of bone in the mandible and maxilla, with consequential loosening of teeth. Heretofore, the progress of bone loss in the jaw has been monitored with X-rays, which can only reveal the presence of periodontal disease after substantial bone loss has already occurred.
Consequently, it is highly desirable to provide a means for detecting changes of bone condition (including, but not limited to the loss of bone material and attendant decrease in bone density and elasticity). Optimally, such means is non-invasive, accurate, sensitive, easy to use and can be made generally available. This is not, however, true of the prior art techniques, in general.
Recently, several methods have been proposed for the early diagnosis of osteoporosis. These methods include Neutron Activation Analysis of Total Body Calcium (TBC), single photon absorptiometry (of the wrist and oscalcus) and dual photon absorptiometry (of the spine and neck of the femur), Computer Aided Tomography (CAT scanning) and methods of ultrasound analysis.
The TBC method, briefly described, is as follows: TBC requires a source of fast neutrons, having energy of approximately 14 MeV. A beam of neutrons is directed at the subject. Depending upon the energy of the incident neutron beam, the nuclei of certain atoms capture the neutrons and become excited. The excited isotopes revert to a stable condition by emitting one or more gamma rays, either immediately (on the order of 10-12 seconds) or after a decay period characteristic of the activation product. The energy of the emitted gamma ray characterizes the target element. Calcium emits gamma rays at an energy of 3.1 MeV. The intensity of the gamma rays, i.e., a count rate per unit volume, indicates the amount of the subject element present. A disadvantage of TBC is that it convenienty measures only the total body calcium, thus, localized change in bone mass, as may be present in early stages of osteoporosis, will not be discernible. Further, TBC facilities require a neutron source, such as a nuclear reactor, a cyclotron or a radioactive material. They also include a large and sophisticated machine, and thus are relatively expensive, and rare. Thus, they are not available for most patients. As can be expected, this method is relatively expensive. Finally, a large radioactive dose of 0.3-0.5 rem is required, inhibiting repeat testing.
Photon absorptiometry is a technique that depends upon the absorption by a material, of discreet energy photons. In single photon absorptiometry, a single energy source emits a beam of monochromatic photons. The intensity of transmitted photons attenuates exponentially with respect to the mass of the substance in the path of the photons. Knowing the distance travelled, the density of the intervening substance can be determined. The problem with single energy photon devices is that they cannot resolve the effect of multiple attenuating layers, such as soft tissue surrounding bone.
Thus, dual photon absorptiometry is used According to this method, a single source having photons of two discreet energies, such as 153 Gd, or two discreet energy sources such as 125 I and 241 Am are used. Two equations, each in two unknowns, result, relating the unattenuated and the attenuated photon intensities to the densities of the two substances. The two equations can be solved, and the two densities can be determined As is the case with respect to TBC, the equipment is relatively expensive and rare. Further, because soft tissue is made up of different components of skin, fat and muscle, a "fat/lean" adjustment factor must be used.
Density of bones can also be determined by using a CAT scan. A CAT scanner is a device which computes an image from multiple incidents of X-ray transmission. The patient is placed in a hollow cyclinder having X-ray sensitive receivers around the entire circumference. An X-ray source revolves around the patient, sending individual beams of X-rays through the patient to be received by the receiver at the opposite end of a diameter of the cylinder. This transmission is repeated for the entire circumference of the cylinder. The intensity of X-rays received by the receiving sensor is related to the total density of the path through the patient's body. A large number of these readings are taken as the transmitter circumnavigates the patient Sophisticated computerized analysis collates the readings received at each receiver, and generates a map of the density of a thin slice of the patient's body taken parallel to the plane defined by the many transmitted beams.
The output of the CAT scan is a density map. A CAT scan through bony areas will provide information relative to the density of the bones. The asserted advantages of the CAT scan are that it is a reproducible and reliable device, that it has been well tested in other related fields. Further, it quantifies the trabecular and cortical density separately. Thus, the exact density of the cancellous bone may be determined, without any averaging effect caused by the presence of the surrounding compact cortical bone.
Drawbacks to the CAT scanning technique are that the equipment is expensive and that it is not available in many communities. Further, it is not portable and may be regarded as traumatic for certain patients. Administration of CAT scans must be done by licensed doctors of radiology or technicians associated with radiologists, thereby further increasing the cost. Finally, CAT scans involve X-ray exposure to the patient, which is seen as undesirable by some doctors and patients. "Patient", as used herein, refers to both human and animal subjects.
For in vivo, non-invasive analysis of bones in humans and other animals, measurement by use of ultrasound also has been performed. Such measurement is complicated, though, by the presence of soft tissue surrounding most bones. The speed of an ultrasound signal injected transdermally is affected by passage through the soft tissue surrounding the bones, as well as by passage through the bone(s) of interest It is possible to minimize the effect of the soft tissue; however, prior attempts to do so have been encumbered by requirements for rather sophisticated echo analysis and careful measurement. See, for example, U.S. Pat. No. 4,361,154, "Method for Establishing, In Vivo, Bone Strength."
Thus, the several objects of this invention are: (1) to evaluate bone condition in patients with a non-invasive, in vivo technique; (2) to evaluate bone condition without subjecting patients to substantial doses of X-rays; (3) to evaluate bone condition in patients economically and quickly; (4) to provide a method or methods of evaluating bone condition that may be performed safely and economically many times over the course of several years; and (5) to provide a method or methods of evaluating bone condition that may be performed by a technician without the need for expensive equipment, especially careful measurement or complex analysis.
As used herein, "patella" refers to the thick, flat triangular bone that forms the anterior part of the knee; "kneecap" refers to the patella and surrounding soft tissue; "tibia" refers to the anterior bone of the lower leg; "shin" refers to the tibia and surrounding soft tissue.
According to the present invention, bone condition is determined by sending an ultrasound signal through a portion of bone, and analyzing the signal that is received. The ultrasound signal preferably contains at least two components of distinguishable waveshape or frequency content. These components may be in either pulse or continuous-wave format, or some combination thereof. Hereinafter, except as expressly appears otherwise, where the term "pulse" is employed, it is intended to include both finite duration and continuous-wave signals. If narrow band signals are used, they may be transmitted at the same time (e.g., as part of a composite waveform) or at different times Alternatively, a broadband signal may be employed. This may, for example, be a signal containing energy over a large frequency range, such as from about 100 kHz to about 3 MHz. The differences in the propagation of the two (or more) components contains information on the condition of the bone.
The invention is believed to operate on the principle that the speed of transmission of an ultrasound signal through a medium is related to the density and elasticity of the medium. It further relies on the observation that the attenuation is frequency-dependent. Due to the varied nature of bone, ranging from cortical bone to trabecular bone, it is not possible to exactly state the relationship between the velocity of any ultrasound signal and the density and/or elasticity of the medium. However, models have been proposed for both cortical and trabecular bone that correlate well with results from experiments performed on bone that is mostly cortical and mostly trabecular, respectively. Thus, the relative speed of ultrasound signal propagation may be used as an indicator of susceptibility of bone to breakage A pair of transducers is used, for sending and receiving the pulse. These transducers are connected to an ultrasound pulse generator and to a signal receiving and processing system, respectively. The transducers are positioned at two different locations adjacent the bone such that the ultrasound signal is launched into and through the bone and soft tissue, and intercepted by the receiving transducer.
The bone to be measured preferably is surrounded by only minimal soft tissue and its surface preferably has opposing portions, such that sound energy may be coupled into and out of these portions by faces of sending and receiving transducers arranged substantially in parallel. The sound path of the first arriving portion of the ultrasound signal thus begins at the face of the sending transducer, travels though the soft tissue covering the bone, through the bone to and through the soft tissue separating the bone from the receiving transducer, and finally to the receiving transducer. (Portions of the ultrasound signal may propagate over other, acoustically longer paths and will therefore arrive later).
Various bone sites may be used for test purposes, but the kneecap has been found to be a favorable location due, in part, to the fact that (a) the distance through the soft tissue layers surrounding the patella is much less than the distance through the bone and (b) there exists an acoustic propagation path through the soft tissue overlaying the patella which is approximately parallel to, and nearly the same distance as, the propagation path through the patella and soft tissue layers. Other useful sites are, for example, the tibia, the maxilla and the mandible. Examination at the two latter bones may, it is hoped, provide a way to detect periodontal disease.
In a first embodiment of the invention, the received signal is processed to filter out noise, thereby permitting more precise determination of the duration of ultrasound propagation delay. The distance between the sending face and the receiving face of the transducers is measured automatically by digital caliper, and the velocity through the bone is calculated. In calculating such velocity, it is preferable to first correct the measured propagation delay for error introduced by the finite thickness of the soft tissue cover surrounding the bone.
The velocity measured through the bone and soft tissue, or the velocity corrected for soft tissue, may be compared to various data compilations. First, over time, a history of the patient under examination may be created, so that changes in velocity, indicating changes in bone density and/or elasticity, can be noted. This type of comparison charts the development of the disease or the rehabilitation of the patient. Additionally, a data base comprised of bone density, elasticity and/or velocity may be compiled for a wide cross-section of the population, including in that cross-section both healthy and diseased individuals of all relevant ages. A patient's bone density, elasticity and/or velocity measurements may be compared with the information in this data base automatically, based on selected threshold criteria, to predict within clinically useful confidence levels whether the patient's bone is healthy or not, or to assess the probability that the patient is suffering from a bone disease.
In a second embodiment of the invention, measurement of the distance between the sending and receiving transducer faces is not required. The ultrasound signal emitted by the sending transducer has at least two separate frequency components in the range from about 100 kHz to about 3 MHz. after propagating through the patient's soft tissue and bone, a low frequency component of this signal arrives at the receiving transducer first, followed by a later arriving high frequency component. It has been found that the ratio of the arrival times of the two components is a good predictor of bone condition. Other measurements also appear to be good predictors, such as the ratio (as a function of frequency) of the power spectra of the received low frequency (i.e., below 1 MHz) components to the applied excitation in the same range. This ratio is referred to as a "gain function." The peak amplitude and the area under such a gain function can also be used as a predictor.
Moreover, these different predictors can be used in tandem, to achieve a predictor of even greater reliability.
The foregoing, and other as yet unstated, objects, advantages and features of the invention will become more apparent from the following detailed description and the claims appended thereto, all of which should be read in conjunction with the accompanying drawing.
In the drawing,
FIG. 1 is a flow chart outlining in general the steps of the method of the present invention;
FIG. 2 is an illustration of the spectrum of the ultrasound signal emitted from a transducer useful in the apparatus of FIG. 4;
FIG. 3 is a flow chart outlining in greater detail the implementation of step 7 of FIG. 1 as a sequence of more specific steps according to a first embodiment of the method of the present invention;
FIG. 4 shows a schematic representation of an apparatus that may be used to practice the method of both embodiments of the invention, though the caliper is unnecessary for the second embodiment;
FIG. 5 shows a schematic representation of a typical plotting of the amplitude of the received excitation versus time, for one ultrasound pulse;
FIG. 6 schematically shows the method of "matched filtering;"
FIG. 7 shows schematically the first arriving waveform after passing through healthy bone;
FIG. 8 shows schematically the first arriving waveform after passing through osteoporotic bone;
FIG. 9 is a flow chart outlining in greater detail the implementation of step 7 of FIG. 1 as a sequence of more specific steps according to a second embodiment of the method of the present invention;
FIGS. 10A and 10B are schematic illustrations of a time-domain high frequency waveform and a time-domain low frequency waveform produced by the method of FIG. 9; and
FIG. 11 is a table listing exemplary data obtained by the method of FIG. 9.
Turning to FIG. 1, a schematic flow chart illustrates the basic steps of the method. The first step, of course, labeled with the numeral 2, entails providing an appropriate apparatus to conduct the generation, administration and measurement of ultrasonic signals. The apparatus, which will be discussed more fully below in connection with FIG. 4, consists generally of an ultrasonic signal (e g., pulse) generator, a pair of transducers and a signal detection and analysis unit.
As indicated in block 4, a broad band waveform generator is provided to launch from one of the transducers a pulse of sound containing energy components from about 100 kHz to about 3 MHz, for a duration of approximately 2�10-6 seconds. The spectrum of the excitation from an exemplary apparatus (discussed below) is shown in FIG. 2; note that the signal amplitude and power may vary widely over that spectrum. (For this reason, as stated above, separate narrow band signals at about 250 kHz and 2.5 MHz could alternatively be used.) The launching of the pulse is recorded by a data acquisition system, which stores it on a magnetic disk or other archivable medium. It may also be displayed on a cathode ray tube or other suitable display device. The next step, 6, includes monitoring acoustic excitations at the receiving transducer. These excitations include background noise, the first arriving signal transmitted through the bone and soft tissue, and subsequent arriving signals transmitted through the bone and soft tissue. Step 6 also includes generating electronic signals corresponding to the acoustic excitation, storing the record of receipt of those excitation signals by means of the data acquisition system, and displaying the record of receipt of the signals on the same cathode ray tube display. In step 7, the received signals obtained from steps 4 and 6 are processed (by a variety of techniques, which may include analog or digital filtering and a variety of computations) to produce one or more derived measurements. These derived measurements are then compared with a data base of information correlating received signal characteristics against patient-categorizing factors such as (but not limited to) age, sex, race and the patient's bone condition.
It is good practice, although not essential, to reduce error due to random noise by repeating steps 4 and 6 several times and averaging the results.
The patient's soft tissue and bone act, in part, like a complex network with transmission properties varying as a function of frequency. The resulting alteration of the ultrasound input excitation as it passes through the patient provides, at the receiving transducer, a very much altered spectrum. This spectrum contains at least two separate pulses, or signals, which arrive at different times. An evaluation of the characteristics of these pulses by either analog or digital processing means, both compared with each other and against the original, transmitted ultrasound signal, yields information about the condition of the patient's bone. Characteristics to be evaluated include, without limitation, frequency, amplitude and phase.
The complicated transformation of the ultrasound excitation which occurs as it propagates through the patient is not yet fully understood. Present indications are that for the patella, within the frequency spectrum of interest, the higher frequency components travel as a leakage mode through the soft tissue covering of the bone and that the lower frequency components propagate along a parallel path in the relatively dense bone. More particularly, with respect to the patella, the lower frequency signals appear to propagate in the relatively dense subcortical bone layer just beneath the anterior surface. This bone path sharply attenuates the high frequency content of the applied ultrasound pulse. For other bones, the transformation is not so well understood.
In the first embodiment of the invention (see FIGS. 3 and 4), the transducers are mounted on a digital caliper device, 38. The calipers are closed about the bony member to be evaluated, with the transducers in contact with the patient's surrounding skin. The coupling of ultrasound energy between the transducers and the tissue is facilitated by an impedance matching gell or other such material. As the excitation is being launched and received, the caliper automatically measures the distance travelled by the pulse (i.e., the separation between the opposing faces of the transducers), as indicated by block 8. After the transmission and excitation data have been recorded, a template signal is provided as indicated at 10, which is matched through a cross-correlation function to the signal corresponding to the excitation at the receiving transducer. Evaluation of the cross-correlation function permits filtering out the noise making up the baseline signal, thereby facilitating pinpointing the exact time of arrival of the pulse, block 12. Now, knowing both the elapsed time of pulse travel, from 12, and the distance travelled, from 8, the average velocity of the ultrasound pulse through the bone and minimal surrounding soft tissue may be computed, block 14.
Even at the kneecap, a normally bony area, some patients exhibit non-trivial amounts of soft tissue; therefore, it is beneficial to correct or adjust the velocity measurements to eliminate the effect of soft tissue, 16. According to the invention, a factor related to the patient's height and weight ratio can be used.
The velocity measurement may alternatively be adjusted, or corrected, with respect to the patient's soft tissue content according to a more sophisticated echo technique, described more fully in U.S. Pat. No. 4,361,154, identified above, the disclosure of which is incorporated herein by reference. This method takes advantage of the fact that a portion of the ultrasound energy reflects from the bone, as the signal crosses the interface between the soft tissue and the bone. It is possible to measure the thickness of the soft tissue covering the bone on each end of the ultrasound signal path by launching an ultrasound pulse from each transducer, and measuring the time until receiving a reflected echo pulse. This technique requires equipment capable of launching an ultrasound pulse from both transducers and of monitoring the excitation at both transducers. The speed of an ultrasound pulse travelling through soft tissue is known and is approximately 1,550 m/sec. Thus, examination of the record of the ultrasound echo transmission will give the time period during which the ultrasound pulse travelled through the soft tissue, reflected from the bone and came back to the launching transducer, for each transducer. Knowing the velocity during this travel, the path length may also be determined. This path length through the soft tissue may be subtracted from the total distance between the transducers, thus arriving at the distance travelled through the bone. Further, the time of transmission through the bone may also be computed, by subtracting from the time measured the period spent during transit through the soft tissue, as determined above.
The velocity measured between the two transducers may also be normalized with respect to the patient's soft tissue characteristics, by means of a factor produced by a standard "skin fold" test. According to the skin fold test, measurements with calipers are taken at several designated spots of a patient's body, to measure the amount of skin the soft tissue at the spots. Large amounts of data have been collected from the general populace, ranking persons according to a general "fleshiness" based on the skin fold tests. An index based on this test could also be used to normalize the velocity measured through the bone and soft tissue.
The adjustment for soft tissue, however generated, whether by height/weight or skin-fold reference, or echo technique, will be referred to in the following as a "soft tissue adjustment factor." Thus, from the absolute velocity measured, and the soft tissue adjusted factor, a soft tissue adjusted velocity is determined, step 18.
The soft tissue adjusted velocity may be used in a number of ways, two of which are indicated in FIG. 3. First, the adjusted velocity may be compared (22) to entries in a data compilation of adjusted velocities gathered from a wide cross-section of the population (20). This data bank may be organized according to ranges of ages and other patient characterisitics (e.g, sex, race, ethnic group, etc ), and also according to known skeletal conditions. Thus, if the adjusted velocity of a 40-year-old woman falls within the standard range of known velocities for 40-year-old women in the population at large, it can be said with a reasonable certainty that this person has healthy bones. Conversely, if the adjusted velocity falls within the range normally associated with healthy 60-year-old women, there is a substantial probability of an abnormal condition and it would be wise to begin preventative and rehabilitative treatment.
An adjusted velocity may also be compared to previous and future measurements made with respect to the patient under examination, step 26. Under this scheme, measurements will be made for an individual over the course of years, step 24. Thus, significant change in ultrasound velocity will indicate a significant change in bone condition. Depending upon the direction of the change in bone condition, it will be possible to determine whether the patient's health is improving or deteriorating, step 28.
With reference now to FIG. 4, a suitable apparatus for practice of this method will be described in detail. A sending transducer 40 and a receiving transducer 42 are provided. Each transducer (40 and 42) is capable of launching a broad band high frequency ultrasound pulse. Transducers manufactured by Panametrics Inc., 221 Crescent Street, Waltham, Mass. 02254, such as the Panametrics model A533S transducer, have been used with good results. The latter is represented as a 2.25 MHz transducer. 2.25 MHz is a desirable base frequency for several reasons. First, transducers capable of transmitting and receiving ultrasound at this frequency are relatively small, measuring approximately one-third of an inch in diameter Thus, they may conveniently engage parts of the patient's body. Secondly, the frequency must be high enough so that the sensitivity of the device will be able to resolve measurements of time at least as small as about 1�10-6 seconds. This requires a frequency of at least 1 MHz. A higher frequency device has more ability to resolve time measurements than a lower frequency device. Unfortunately, if the frequency is too high, the amplitude of the signal received at the receiving transducer will be attenuated seriously due to reflection at boundary surfaces surrounding and within the bone. We have found that a base frequency of about 2.25 MHz provides a reasonable compromise between the competing concerns of sensitivity and transmitted amplitude. With reference to FIG. 2, the spectrum of the signal emitted by the above-described transducer is shown. It will be seen that the spectrum contains substantial energy components from about 100 kHz to about 3 MHz. This broad spectrum is desirable, as the signal transmitted through the bone has significant energy at frequencies in the neighborhood of 300 kHz, while the signal transmitted through soft tissue has significant energy at frequencies in the neighborhood of 2.5 MHz; thus, the transducer and signal generator 52 must be operable in both frequency ranges. Since these two transmissions (i.e., bone and soft tissue) are substantially independent, similar results may be achieved with narrow band transducers excited either by narrow band sources operating at separate frequencies or by a wide band source.
The transducers are mounted on an automatic electronic digital vernier caliper 38, manufactured by Fred V. Fowler Co., Inc., 66 Rowe Street, Newton, Mass. 02166, model name "Ultra-Cal." The vernier caliper has a stationary arm 44 and a movable arm 46. As the movable arm 46 moves along the support arm 48, the distance between the transducer faces 44' and 46' are displayed on the display 50. The workings of this caliper are unimportant to the disclosed invention, and an ordinary vernier caliper also could be used. However, in that case, manual reading and recording of the distance would have to be taken, and the distance would have to be read into the data processing equipment by hand.
In use, the sending transducer 40 and receiving transducer 42 are brought to bear upon opposite surfaces of a bony portion of the patient's body 60, preferably the kneecap. The pulse generator 52 generates a pulse of a duration of approximately 2�10-6 seconds. This pulse is transmitted along electrical connection 54 to the launching transducer 40. Simultaneously, along electrical connection 56, a launch signal is transmitted to the data acquisition system 58, indicating the departure of the launched pulse. This latter signal is used by the signal processor to record the time of launch. For the data acquisition system, a Data 6000, manufactured by the Data Precision division of Analogics Corporation, Peabody, Mass., has been used with good results.
The pulse travels through the member being measured 60 and is received by the receiving transducer 42. The receiving transducer 42 emits signals that are electrically transmitted along lead 62 to the data acquisition system 59. These signals correspond to the ultrasound pulse received by the transducer 42.
The data acquisition system 58 is capable of storing the amplitude of the signals received by it, and displaying the time-varying amplitude upon a standard CRT display 64. The data acquisition system includes data computing means 66, shown schematically in FIG. 4. A signal representing the distance measured by the caliper 38, between the transducer faces 44' and 46', has been transmitted along electrical connection 68 to the computer 66, for use at a later step as described below.
The next figure, FIG. 5, shows schematically a typical response received by the receiving transducer before the cross-correlation technique of "matched filtering," described below, has been applied. In FIG. 5, the display is represented by 64. The horizontal axis represents elapsed time. The time from the origin to the end of oval 644 is on the order of 15 to 20�10-6 seconds. The vertical axis represents the amplitude of the signal received.
The portion of the signal indicated within the circle identified as 642 shall be referred to as the "main bang" and constitutes the record of the launched pulse. The portion of the signal roughly circumscribed by oval 644 is the base line noise received by the receiving transducer. The portion of the signal indicated by oval 646 represents the initial receipt by the receiving transducer of any signal passing through the bone and soft tissue as a result of the launched pulse. This received signal consists of two distinguishable components: a first arriving low frequency signal followed by a later arriving high frequency signal (which may also be termed a "received first distinguishable component" and a "received second distinguishable component"). It is good practice to average the amplitude of the received signals from a number (e.g, 16 or more) of separate, initial pulses. Random signals, such as noise, tend to average to zero.
As can be seen from the schematic representation in FIG. 5, it is difficult to determine precisely the time at which the signal 646 emerges from the baseline noise 644. Errors in determining the time of arrival by as much as 1�10-6 seconds can result in an error in the velocity calculation of as much as 10 percent. Although measurements made with an error of this amount will be useful, it is, of course, highly desirable to eliminate (or, at least, minimize) this error to the extent possible.
Fortunately, an error correction method has been developed. This method is known as "matched filtering." It is described in full in various texts, such as Y. W. Lee, The Statistical Theory of Communication, published by Wiley in 1960. The error correction method is shown schematically in FIG. 6. In general, the baseline noise is filtered out of the display of the received signal, by signal averaging and cross-correlation. A template signal is provided that matches, to a significant degree, the shape of the averaged incoming first arrived signal received through the bone. As will be evident below, it is not necessary that the template be exactly identical to the leading edge of the received signal through the bone It must only be similar. The template may be obtained, for example, by taking an appropriate number of cycles (e.g., one-half a period) of the dominant "low-frequency" Fourier component received for that patient. Preferably, two template signals are used, one pertaining to transmission through the bone and the other pertaining to transmission through the soft tissue. The latter may be a standard signal since there is very little difference from one patient to another in the velocity of ultrasound through soft tissue or in the frequency response of the soft tissue It may be desirable to use different sampling intervals and/or sampling rates for the two different template signals in order to provide an appropriate number of sample points within the template.
Only a small portion of the signal, such as 180 degrees of one cycle, is retained. The cross-correlation function C(d) is defined as ##EQU1##
The function F(t) is the signal received by the receiving transducer as indicated in FIG. 6. The function G(t-d) is the template signal, which is non-zero only near the origin. In order to pinpoint the moment of arrival of the signal through the bone, the integral is performed as time ranges from zero to infinity. Then the first extremum of this integral is selected as "d" ranges from zero to infinity.
The time 648 at which the absolute value of C(d) exceeds a first maximum that exceed a threshold typical of artifact signals, is, except in one instance as explained below, the time that the signal first arrived. This occurs due to the following. Up until the initial receipt of the transmitted pulse, the function F(t) is made up of the rapidly oscillating signal of the main bang and the baseline (644). These signals oscillate in general at about 2 MHz. Conversely, the template signal appropriate for trabecular bone has a period of 3.3�10-6 seconds and thus has a frequency of 300 Hz. Because the main bang and baseline noise vary from positive to negative, the integral of the product of the two functions F(t) and G(t-d) will be zero at all times of rapid oscillation. It is not until the transmitted pulse has arrived (time 648) that the product of the cross correlation function, template G(t-d) and F(t), which now is comprised largely by the signal from the transmitted pulse, beings to have a non-zero value. When the received signal most closely matches the template, the product will be at a maximum. A corresponding situation pertains if the main bang, instead of having the wideband waveform of FIG. 2, comprises a plurality of separate signals.
As was mentioned above, there will be some instances where the maximum of the cross correlation function will not coincide with the arrival of the first arrived pulse. This will be in those cases where the amplitude of the first arrived pulse is of an opposite sign with respect to the template; for instance, if the template has been chosen from a positive segment of a bone signal, while the first arriving signal is negative. These cases may be easily identified by noting that the cross-correlation function will have a relatively large negative excursion before the maximum value. In this case, the arrival of the first arriving pulse is indicated at the large negative excursion. More precise measurements may be made by performing two cross correlations, one with a positive template and one with a negative template, and then choosing the appropriate record to archive based on the observed results. Or the cross correlation function may be squared, in which case the maximum of the resulting function will coincide with the arrival of the first arrived pulse. Optionally, it may be desirable to perform the matched filtering process more than once, combining the template G(t-d) with C(t) to produce C'(d).
This type of signal matching can be accomplished automatically by the data acquisition system identified above.
It should be noted that this matched filtering need not be done at the time of patient examination, and may be performed later, on stored data. After the cross-correlation has been maximized, and the elapsed time for the signal propagation has been determined, the velocity may be computed by dividing the distance between the transducers measured earlier, by the elapsed time.
Once the average velocity through the path between the transducers has been determined, it is beneficial to eliminate the effect of the passage of the ultrasound pulse through the soft tissue surrounding the bone. This is because the time for transit of the pulse from one transducer to the other includes time during which the ultrasound pulse is passing through the bone, and also time during which the ultrasound pulse is passing through soft tissue surrounding the bone. Further, the distance travelled by the ultrasound pulse includes the distance through the bone, and also the distances through the layers of soft tissue on both sides of the bone. Failure to account for this transit delay through the soft tissue reduces the accuracy of the velocity determination made by simply dividing the distance travelled by the time.
Experiments have shown that the kneecap is a very good spot on the human body to examine the condition of trabecular bone and also to test for osteoporosis. The kneecap is a part of the body substantially free of soft tissue. Further, the kneecap is largely made up of trabecular bone, the type of bone in which osteoporotic effects are felt earliest and most severely. We believe the tibial crest is also a good location on the human body at which to examine the condition of cortical bone.
Despite the advantages of measuring at the patella and tibial crest, as has been mentioned above, the presence of significant amounts of soft tissue there does influence the results to some extent. Therefore, it is beneficial to correct the measured velocity by adjusting for the patient's specific soft tissue condition. As has been mentioned above, these methods include echo techniques, skinfold tests and height and weight comparison. The velocity computed according to either method shall be referred to as the "adjusted bone velocity."
Once the adjusted bone velocity has been determined, this value may be used to evaluate the patient's skeletal condition. This may be done by comparing the adjusted bone velocity to adjusted bone velocities obtained from a large cross-section of the general population. Ideally, the general data base of adjusted bone velocities is grouped in ranges of ages and other characteristics, so that a typical velocity for a healthy person of a certain age and characteristic will be known. The data base should also include, for each age or age group, a series of velocities corresponding to a spectrum of bone density conditions, from more porous than normal to more dense than normal. By comparing the patient's adjusted bone velocity to the spectrum of adjusted velocities for their age, their relative bone condition may be determined.
Further, in conditions where an individual is either suspected of being osteoporotic, or is undergoing treatment for osteoporosis, specific measurements may be compared to previous measurements made of the same patient. These measurements are known as "serial measurements." Thereby, their progress or deterioration may be charted and treated.
It is also a feature of the method of the present invention to evaluate the patient's bone condition on the basis of the shape of the amplitude of the transmitted waveform. The shape of the waveform of the received ultrasound pulse contains valuable information regarding the density and condition of the patient's skeleton. We have observed that with healthy patients, the shape of the signal through the patella that first arrives at the receiving transducer may be roughly characterized as having a first portion of well-defined oscillations more than twice the rms baseline noise with a frequency of about 300 kHz, followed by very high amplitude, high frequency oscillations near 2.5 MHz. FIG. 7 schematically shows this type of bone signal. In FIG. 7, the signal that has passed through the healthy bone ("the healthy signal") is labeled "70". In FIG. 8, a signal that has passed through the diseased bone ("diseased signal") is labeled "80". As can be seen from this figure, the diseased signal first arrives with virtually no well-defined oscillations, beginning almost immediately with the high frequency, high amplitude oscillations.
The mechanics underlying this variation in waveform shape, and the significance of the waveform shape, are not well understood. It is believed that the well-defined low frequency oscillations evidence longitudinal, or compression waves, while the high frequency, high amplitude oscillations are transverse, or shear waves. Longitudinal waves result from oscillation of the medium in a direction parallel to the direction of propagation, while shear waves are evidence of oscillation perpendicular to the direction of propagation. Longitudinal waves generally travel faster than shear waves. However, it is believed that in osteoporotic bone, the pathways for travel of compressive ultrasonic pulses through trabecular bone portions are more restricted and also interrupted by the termination of trabecular formations and by interposed pockets of fluid. These discontinuities in the medium change the elasticity of the bone and cause the dissipation of energy embodied in the ultrasound pulse: consequently, the amplitude of the compressive ultrasound pulse is reduced in the osteoporotic patient.
Additionally, the transducers may be arranged to launch (i.e., transmit) head waves and shear waves. The speed of propagation of these waves, and the further waves they induce, provides still more information on the state and properties of the bone intermediate the transducers. A given bone may be excited in many different modes; the goal is to find and use those modes for which transmission is particularly sensitive to bone characteristics of interest (e.g., porosity, density and elasticity).
To generate these other types of waves, the launching and receiving transducers may be arranged in ways other than the arrangement of FIG. 4. Oblique or normal transducer dispositions may be desirable; for example, to generate head waves, the transducers are spaced apart on the same side of the bone, both facing the bone. Consequently, the present invention is not intended to be limited to the arrangement of FIG. 4 (i.e., parallel, spaced apart transducers, facing each other).
When a continuous-wave signal is injected instead of a pulse signal, the signal processing must be modified. Appropriate signal processing is known to those skilled in the art, as indicated, for example, in R.B. Ashman et al , "A Continuous Wave Technique for the Measurement of Elastic Properties of Cortical Bone," Journal of Biomechanics, Vol. 17, pp. 349-361 (1984), the disclosure of which is hereby incorporated by reference.
In a second embodiment of the invention, we have taken advantage of the foregoing observation that the low frequency oscillations and the high frequency oscillations arrive at different times, to devise a measurement technique which is independent of transducer separation and thus does not require measurement of that separation. As stated above, in this embodiment, digital caliper 38 may be omitted, although some mechanism should still be used for supporting and positioning the transducers and holding them steady against the patient; the same caliper can be employed for this purpose but its digital output is not needed. Otherwise, the apparatus is the same as that shown in FIG. 4. The primary difference between this and the prior embodiment thus lies not in the hardware, but, rather, in the processing of the signals arriving at receiving transducer 42.
This processing is illustrated in FIG. 9. First, a Fourier transform of the received signal is calculated (step 102) using conventional techniques. Next, two inverse transforms are made, one omitting all frequencies above 1 MHz (step 104) and one omitting all frequencies below 2 MHz (step 106). These inverse transforms yield a time-domain low frequency signal and a time-domain high frequency signal, respectively, illustrated at 112 and 114 in FIGS. 10A and 10B. (These two signals may also be referred to as a received first and second distinguishable component of the received signal.) Alternatively, the step of making the first of the two inverse transforms may be omitted.
In band-limiting the Fourier-transform to generate the inverse transforms, square windows have been employed, due to the limitations of the signal processing equipment. Better results might be obtained, of course, with a Hamming window or a Blackman window, in order to reduce artifacts introduced into the inverse transforms by the windowing (i.e., band-limiting) process.
Due to the separation between the frequencies of the time-domain high frequency signal and the time-domain low frequency signal, it is apparent that equivalent results can be obtained by exciting the bone with not just one broadband pulse, but rather, with two or more band-limited pulses emitted either simultaneously or in succession. That is, the low frequency response and the high frequency response can be measured at different times or at the same time. Filtering (analog or digital) may be used to separate the received signals into their "tissue" and "bone" components. This can simplify the signal processing, as the transform approach can be avoided while obtaining substantially equivalent results; a variety of spectral estimation techniques may be employed as alternatives to such exemplary processing.
The relationship between selected characteristics of the time-domain high frequency signal and the time-domain low frequency signal is evaluated (step 108) to provide an indicator of bone condition. This evaluation can involve various measurements. For example, taking the ratio of the first arrival times of the low frequency pulse component 112 and the high frequency pulse component 114 is believed to yield a good diagnostic predictor of osteoporosis. FIG. 11 shows in tabular form the average of this ratio and the standard deviation of the distribution for a sampling of 47 women who had been previously classified in three categories: osteoporotic, normal and athletic (i.e., runners). Application of the well-known "t-distribution" formula to this data indicates that the foregoing ratio distinguishes an osteoporotic patient group from a "normal" patient group to a 98% level of confidence. Thus, the calculated ratio can be compared with one or more predetermined threshold values to place the test results for the patient into a category associated with a corresponding probability that the patient has an abnormal bone condition. The various threshold values (i.e., conditional probability level ranges) need not be the same for all patients. Different threshold values may be used for patients of different age, sex or race, or possessing other characteristics. Similarly, different levels of confidence or conditional probability may be established for the rate of change of the predictor for measurements taken on the patients over a period of time. Thus, a patient whose predictor changes monotonically at a rate of x% per year may be said to have a y% chance of being or becoming osteoporotic. The establishment of appropriate confidence level groupings and threshold values therefor is a straightforward exercise simply requiring testing of a large number of patients and conventional statistical analysis of the results.
As an alternative to use of the ratio of first arrival times, we have also found on a small sampling that good results are obtained by using as an evaluator of bone condition the frequency-dependent gain function of the power spectrum of the received signal divided by the power spectrum of the excitation. However, since there may be zeroes in the denominator, it is advisable, instead of performing a simple division, to instead generate a function, using existing methods, which approximates the deconvolution of the low-frequency component by the high-frequency component while compensating for noise and for such zeroes. Such a function might be obtained, for example, by Weiner filtering. Or the gain function may be limited to the low-frequency portion of each (e.g., that part below 1 MHz). Both the area under these gain functions and their peak values appear to be useful indicators of bone condition.
Taking further advantage of the fact that the low-frequency components and high-frequency components of the acoustic signal arrive at different times, it is also possible to generate those high-frequency and low-frequency components separately, such as by launching a succession of pulses, some with lower frequency components and others with higher-frequency components. With this possibility in mind, the singular "pulse" as used above should be understood to include the possibility of at least one pulse of lower frequency content and at least one pulse of higher frequency content.
The foregoing description of the method should be taken as illustrative and not limiting. The kneecap has been identified as the preferred testing site on the human body for the evaluation of trabecular bone and diagnosis or monitoring of osteoporosis. The tibia provides useful results in examining compact bone Tibial results with respect to observing osteoporosis are limited to some extent, because the tibia is largely made up of cortical bone, rather than trabecular bone. Therefore, the effects of osteoporosis are not felt as early in the tibia as in trabecular bones, such as the kneecap and the spinal cord. Further, although the method has been described in connection with diagnosing osteoporosis, it may also be used to diagnose other bone conditions. For example, it may be used to diagnose periodontal bone loss which contributes to periodontal disease, and to assess the healing of fractures.
The invention is also applicable to evaluation of animal bone conditions, but the frequency spectrum of the applied acoustic excitation may have to be varied to adjust to the animal. It may also be desirable to modify the frequency spectrum when evaluating conditions other than osteoporosis. Various other alterations, modifications and improvements will thus be obvious and will occur to those skilled in the art. Moreover, the invention may be useful also for invasive testing of bones. For this purpose, transducer-tipped needles may be placed in direct contact with a bone to be studied. When this is done, of course, there is no need to make adjustments for soft tissue.
The invention is therefore intended to be limited only by the following claims and equivalents thereto, and not by the foregoing examples
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|Methods, systems, and computer program products for acoustic radiation force impulse (ARFI) imaging of ablated tissue
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|Method and apparatus for scanning confocal acoustic diagnostic for bone quality
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|Ultrasound device and method of use
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|Method and apparatus for determining the depth of a gingival pocket
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|Abnormality detection in medical images
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|Ultrasonic bone assessment apparatus and method
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|27 Jun 2005
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|Analyzing Body Tissue
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|The Research Foundation Of State University Of New York
|Phased Apply Ultrasound With Electronically Controlled Focal Point For Assessing Bone Quality Via Acoustic Topology And Wave Transmit Functions
|3 Sep 2008
|4 Mar 2010
|Biomet Manufacturing Corp.
|Revision patella prosthesis
|13 Nov 2007
|11 Mar 2010
|Kagoshima University
|Osteoporosis progress stage measuring device and osteoporosis progress stage measuring method
|1 Feb 2010
|27 May 2010
|Biomet Manufacturing Corp.
|Porous Titanium Modular Revision Patella System
|19 Nov 2009
|3 Jun 2010
|Neeraj Agrawal
|X-Ray Apparatus for Bone Density Assessment and Monitoring
|24 Nov 2009
|19 Aug 2010
|New Jersey Institute Of Technology
|System and method for ultrasound analysis of biological structures
|18 Feb 2010
|19 Aug 2010
|West Virginia University Research Corporation
|Systems and Methods for Echoperiodontal Imaging
|20 Mar 2009
|23 Sep 2010
|Palmeri Mark L
|Ultrasound Methods, Systems and Computer Program Products for Imaging Fluids
|8 May 2009
|11 Nov 2010
|Neeraj Agrawal
|Apparatus for Bone Density Assessment and Monitoring
|27 Jan 2011
|26 May 2011
|Cyberlogic, Inc.
|Ultrasonic bone assessment apparatus and method
|8 Nov 2013
|5 Jun 2014
|Samsung Electronics Co., Ltd.
|Method and apparatus for processing signal
|30 Aug 2001
|3 Apr 2003
|Advanced Acoustix Gmbh
|Determination of the distance to a soft sound object, whereby measurements are made at two or more different frequencies so that a material dependent phase correction can be made
|14 Dec 1995
|11 Dec 1996
|Sekisui Kagaku Kogyo Kabushiki Kaisha
|Osteoporosis diagnosing apparatus and method
|14 Dec 1995
|14 Jul 1999
|Seikisui Chemical Co Ltd
|Osteoporosis diagnosing apparatus and method
|3 Sep 2008
|31 Mar 2010
|Esaote S.p.A.
|Method and device for determining local characteristics of an object, particularly with ultrasounds
|2 Dec 2008
|25 Aug 2010
|Jukka Jurvelin
|Method for measuring of thicknesses of materials using an ultrasound technique
|2 Dec 2008
|22 Aug 2012
|Method for measuring of thicknesses of materials using an ultrasound technique
|17 Mar 2010
|21 Sep 2011
|Esaote S.p.A.
|Method and device for determining the structural organization of an object with ultrasounds
|25 Jan 1996
|1 Aug 1996
|Stuessi Edgar
|Process and device for determining the propagation properties of mechanical waves in a spatial structure
|4 Sep 1997
|12 Mar 1998
|Orthologic Corporation
|Ultrasonic bone assessment method and apparatus
|28 Feb 2002
|19 Sep 2002
|Research Foundation Of State University Of New York
|Method and apparatus for scanning confocal acoustic diagnostic for bone quality
|18 Apr 2002
|31 Oct 2002
|Imadent Ltd.
|Method and apparatus for non-invasive ultrasonic imaging of hard tissue
|18 Apr 2002
|8 May 2003
|Imadent Ltd
|Method and apparatus for non-invasive ultrasonic imaging of hard tissue
|27 Jun 2005
|5 Jan 2006
|Tissuomics Limited
|Analysing body tissue
|1 Oct 2007
|26 Jun 2008
|Odetect As
|Ultrasound measurement techniques for bone analysis
|2 Dec 2008
|11 Jun 2009
|Jukka Jurvelin
|Method for measuring of thicknesses of materials using an ultrasound technique
|16 Mar 2011
|22 Sep 2011
|Esaote S.P.A.
|Method and device for determining the structural organization of an object, particularly with ultrasounds
|26 Feb 2014
|4 Sep 2014
|Rivanna Medical, LLC
|Systems and methods for ultrasound imaging
|U.S. Classification
|600/449, 73/597
|International Classification
|Cooperative Classification
|European Classification
|3 Jun 1986
Owner name: MASSACHUSETTS INSTITUTE OF TECHNOLOGY, 77 MASSACHU
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST.;ASSIGNOR:DUCHNOWSKI, PAUL;REEL/FRAME:004565/0117
Effective date: 19860530
Owner name: MASSACHUSETTS INSTITUTE OF TECHNOLOGY, 77 MASSACHU
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST.;ASSIGNOR:PRATT, GEORGE W. JR.;REEL/FRAME:004567/0278
Effective date: 19860529
|3 Sep 1991
|Certificate of correction
|30 Sep 1993
|Fee payment
Year of fee payment: 4
|15 Sep 1997
|Fee payment
Year of fee payment: 8
|15 May 2001
|Fee payment
Year of fee payment: 12


text:
Neikirk, Dean P. and Rutledge, David B. (1984) Air-bridge microbolometer for far-infrared detection. Applied Physics Letters, 44 (2). pp. 153-155. ISSN 0003-6951. http://resolver.caltech.edu/CaltechAUTHORS:NEIapl84
See Usage Policy.
Use this Persistent URL to link to this item: http://resolver.caltech.edu/CaltechAUTHORS:NEIapl84
A new microbolometer for far-infrared detection has been fabricated that allows an increase in sensitivity of a factor of 4 over the best previously reported bolometer. By suspending the detector in the air above its substrate a reduction in the thermal conductance out of the device by a factor of 5 has been achieved. At a modulation frequency of 100 kHz this microbolometer has an electrical noise equivalent power of 2.8×10^−11 W(Hz)^−1/2. A thermal model is also presented that accurately fits the response of the detector.
|Item Type:
|Additional Information:
|© 1984 American Institute of Physics. Received 22 August 1983; accepted 24 October 1983. We would like to acknowledge the support of the Jet Propulsion Laboratory through Dr. M. Litvak, and the Department of Energy under contract DEAM03-765F-00010 Task 11A.
|Record Number:
|Persistent URL:
|Alternative URL:
|Usage Policy:
|No commercial reproduction, distribution, display or performance rights in this work are provided.
|ID Code:
|Deposited By:
|Tony Diaz
|Deposited On:
|21 May 2008
|Last Modified:
|26 Dec 2012 10:02
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subset: commoncrawl


text:
|2013-09-16, 11:11
|Link #8046
Old Wine
Join Date: Jul 2013
Location: In my Body
Honestly, considering Taketsuki's track record, I'm not expecting anything big really. In fact, I'm expecting about at least two chapters worth of fillers/SoL/harem antics in them. And maybe another [Ram] too.
Though there is an off-chance that it will be a Dark Hour like what happened with High School DxD when Ise 'died'. Which I support. The story needs to get more serious soon.
One problem I have with the story though, is that they just keep on adding the cast instead of flashing more of the previously shown characters. I want to see more of Voban, Alec, Luo Hao, JPS. They all have interesting stories and possibly backstory (Alec excluded). Honestly, they even seems more interesting than Godou, but that's just me.
|2013-09-17, 08:40
|Link #8050
Senior Member
Join Date: Nov 2009
Location: Poland
Age: 31
Unless it's going to be revealed that there is something more sinister behind the system / reason why the King of the End was forced to kill all the Campione's that are active in the era, when the King of the End awakens from his slumber.
|2013-09-17, 09:03
|Link #8051
Master of Coin
Join Date: Mar 2008
|2013-09-17, 09:10
|Link #8053
Senior Member
Join Date: Apr 2013
Well, I always hope the final battle will become something like a Revelation to the public about Magic so the series will have more political shitstorm and governments's conspiracies. Oh, and more battles of Campiones and Gods at a scale they need to redraw the world's map.
|2013-09-17, 12:42
|Link #8057
Old Wine
Join Date: Jul 2013
Location: In my Body
|2013-09-17, 12:50
|Link #8058
Senior Member
Join Date: May 2007
and we know from alec exemple it's possible to gain autority from fallen angel.
whatever god manage to kill lucifer would become quite the god of steel.
|2013-09-17, 14:23
|Link #8059
Old Wine
Join Date: Jul 2013
Location: In my Body
^ Course he is, he's the freaking Michael, aka, the one "who is like God," and the leader of God's force in the war in heaven where he defeated Satan in a literature where all the other Gods are demons and Lucifer is their leader, not to mention having the attributes of "Archangel; Treading on a dragon; carrying a banner, scales, and sword," and depicted many times trumping the dragon.
Interestingly, the archangels are hailed as "the first deed of knighthood and chivalrous prowess that was ever achieved," and that during the "Time of the End" when there will be "distress such as has not happened from the beginning of nations" and that "At that time Michael, the great prince who protects your people, will arise." If one were to look at Artus as actually being a hero...
|2013-09-17, 15:49
|Link #8060
Senior Member
Join Date: May 2012
may the last boss , the one after the king of the end, Zeus?? We have arleady seen a lot of greek gods , it would not strange to see the boss as an enemy especially considering this "
|action, campione, ecchi, godslayer, harem, light novel, myth, romance, sd bunko, shounen, supernatural, time travel, true harem
|Thread Tools


text:
Hills Prescription Diet L/D feline Hepatic Health is used in the management of liver disease, hepatic encephalopathy and heptatic lipidos. To be initiated by a veterinary surgeon.
Please note that all food items will be sent separately from other goods ordered.
Hills Feline L-D is a veterinary diet formulated for the management of cats with liver disease which has resulted in reduced liver function.Hills L-D is made with highly digestible proteins, carbohydrates and fats which helps to limit the production of toxins so reducing the workload of the liver.Hills Feline L-D is a prescription diet and should be used under the guidance of your veterinary surgeon.
Pork liver, maize gluten meal, rice, flour, pasta, vegetable oil ,soybean meal, animal fat, dried whole egg, soy fibre digest, fish oil, dicalcium phosphate, cellulose, potassium chloride, L-lysine hydrochloride, calcium sulphate, L-arginine, taurine, iodised salt, calcium carbonate, DL-methionine, L-carnitine supplement, vitamins and trace elements.
* We don't sell food to non-UK addresses
** Includes N.Ireland, Scottish Highlands, UK Offshore Islands, Isle of Man, Scilly Isles
UK, Channel Islands, N Ireland, Highlands and Islands - Standard delivery arrives 2-3 days after dispatch or for heavy parcels Courier next day after dispatch Mon-Thu.
Europe - Royal Mail International Services or Courier arrives 7-10 days after dispatch.
Express delivery arrives 1-2 days after dispatch or for heavy parcels Courier 1-2 days after dispatch Mon-Thu. Saturday delivery is not available.
24hr MON-FRI DELIVERY:
Non-Food - Light parcels, delivered Tue-Fri, signature required or for heavy parcels Courier next day Mon-Thu delivery after dispatch^.
Food Mainland UK - If ordered before 12pm, next day courier delivery.
Food Other UK - Two day courier delivery service.
^ Please note - Items usually dispatched within 24 - 72 hours. This is to factor in weekends or stock needing to be ordered in the next day, this time is in addition to the courier service you select at checkout.


text:
First of all, thank you so much for pointing out where Viva had disappeared to. I was really distracted and when I turned around and noticed she was gone my brain immediately short-circuited and went to the following headline: GAY MORMON MARRIED MAN WHO RECENTLY CAME OUT LOSES DAUGHTER AT MALL BECAUSE HE'S TOTALLY IRRESPONSIBLE AND SHOULDN'T BE A PARENT. OBVIOUSLY HE SHOULD HAVE PARTNERED WITH A MAN. AND THEN CHOSEN NOT TO ADOPT.
But anyway, while I have you here, I wanted to
First off, when I got angry with the old man who was setting up for a photo-shoot by the carousel, I need you to understand that it was the second time he had gotten mad at Tessa for crossing an invisible barrier he created directly on the path to the carousel. Here's a diagram:
I needed him to know that if he wants to do a photo shoot in a mall, that's totally fine. But if he wants to do a photo shoot in a mall where no children cross an invisible line into the "off limits" section, setting up said shoot directly in front of the carousel is a very, very bad idea. I don't know if he's met a child before, but the formula goes something like this: child sees carousel, child experiences adrenaline rush leading to near-cardiac-arrest, child runs full throttle towards the carousel in a direct line without consideration of invisible barriers or one pink "caution" sign arbitrarily placed upon said invisible barrier. Yelling at my child for doing this is pointless. A one-year old will not learn how to not have this response to a carousel. The same rule applies but is not limited to: Chuck E. Cheese, toy stores, Grandpas, large stuffed animals, any Disney character anywhere, and busily trafficked roads. This is part of growing up as a human.
Second, when you saw me scratching my nose, I was really just scratching my nose. I didn't mean to have to flick. Accidents happen.
Third, I washed my hands.
(Fourth, no I didn't.)
Fifth, doesn't everybody let their children crawl along the railing of a flight of stairs in the mall, even where the drop-off would probably break a bone? No? Okay, well, now we know! I think we've all learned an important lesson today! How very valuable! *The NBC "The more you know" logo chimes in the background*
Sixth, when you saw me actually lose my child, a few factors were in place that
Anyway, you can see why when you approached me after pointing out Viva had disappeared into an automated photo booth, I probably seemed a little sheepish. But I wanted you to know that I really appreciated you saving Viva's life, and that I actually really enjoyed that you came up and talked to me, and also thanks a lot for reading my blog.
Yours affectionately,
The Weed


text:
Jan. 6, 2014
Source: Feedstuffs news release
The Tennessee Farmers Cooperative of Rockford, Tenn., has been named the 2013 Feed Mill of the Year. The annual award recognizes overall excellence in feed manufacturing operations and is sponsored by the American Feed Industry Association and "Feedstuffs."
TFC's feed mill is third-party certified in hazard analysis and critical control points (HACCP) as well as AFIA's Safe Feed/Safe Food (SF/SF) Certification Program. TFC employs 38 people who help to manufacture 120,000 tons of feed annually--65 percent in bulk production and 35 percent in bagged feed. The feed is supplied to stores and dealers throughout Tennessee and bordering states. The company was established in 1945 and currently has 57 member co-ops.
"The workers never knew they were in a competition," said Mark Rule, TFC plant manager. "It was just business as usual, but they were very thrilled to learn they were named Feed Mill of the Year."
Rule said TFC operates on four basic fundamentals: use all your resources; develop a team philosophy; hold everyone to a professional conduct; and, most importantly, have an open line of communication.
The Feed Mill of the Year Award runner-up is the Hubbard Feeds facility in Rapid City, S.D.
The facility has 16 team members, including 10 production assistants, and is managed by Thad Olsen. It produces 40,000 tons of feed annually, 74 percent of which is delivered to customers and 26 percent is bagged.
Olsen said the recognition is a "great honor."
"It was an honor originally just to be in the top three," Olsen stated. "It is a great morale booster for the guys, and it will help them strive to work harder for next year."
To ensure food and feed safety, Hubbard Feeds is HACCP and SF/SF certified, ISO 9001 and U.S. Food and Drug Administration registered, and has established a comprehensive written biosecurity program. The facility also offers an employee-run safety committee designed to train workers in safety techniques for both on and off the job.
"The winner and runner-up of the Feed Mill of the Year Award were two of the many qualified applicants that were considered this year," said Keith Epperson, AFIA vice president of manufacturing and training. "Our judges evaluated submissions on increased safety, quality, regulatory compliance, operating efficiencies and overall industry awareness of food safety among other things, and Tennessee Farmers Cooperative (Rockford) and Hubbard Feeds (Rapid City) proved they produce safe, consistent and quality products."
"Please join us in offering them a round of applause for their continuous hard work," added Epperson.
Selection of the top plant starts with an online application process and concludes with personal visits to the top sites by an inspection team from AFIA and "Feedstuffs." Final selection is based on a combined scoring of the application and personal visit.
Additional details on the 2013 Feed Mill of the Year and the runner-up are available in the Dec. 30, issue of "Feedstuffs." Visit www.feedstuffs.com [1] to learn more. Photos are available upon request to email@example.com.
The 2014 Feed Mill of the Year program will be open for applications in the spring.


text:
UC San Diego has revised a guaranteed admission program for transfer students who complete at least 60 semester units at a local community college and meet other criteria.
The new program is limited to local students with high GPAs and who are from low-income families. Officials hope it will result in a larger number of qualified transfer students seeking admission to the university.
To be eligible for the updated UniversityLink program, students must have a family income of $40,000 or less and a cumulative 3.5 GPA. They also must declare a major when they apply and have taken required courses in their chosen major.
Alan Houston, interim vice chancellor for student affairs, estimated that potentially 200 students may qualify and take advantage of the program. An earlier version required a 3.0 GPA and did not spell out a clear income limit, he said.
He said the program is designed to improve access for local students.
"Many of our students, our low-income students, can only attend a regional university," he said. "They can't afford to travel to Santa Barbara and attend UC Santa Barbara. Our regional community college partners are saying because of limited financial means, they can't attend any UC except UC San Diego."
Partner colleges covered by the agreement include Cuyamaca, Grossmont, Imperial Valley, MiraCosta, Palomar, San Diego City, Mesa, Miramar and Southwestern colleges.
Students enroll in UniversityLink as high school seniors who are planning to attend one of the partner community colleges or as first-year community college students. The program also is open to student veterans, active-duty military and former foster youth.
Students in the program will have access to counseling, workshops and special events.
UCSD has offered other guaranteed admission programs for transfer students in the past, but is phasing those out. Its Transfer Admission Guarantee program, or TAG, was halted in 2012, even after GPA requirements were boosted from 3.0 to 3.5, because it was attracting too many applicants from community colleges around the state, officials said.


text:
want to change careers, but don't want to spend four plus years in school preparing?
you're not alone.
according to barbara silva, a career educational specialist, many people are returning to school for certificate and associate's degree programs - programs that can generally be completed in as little as one to two years.
"some may not be academically inclined and prefer more 'hands-on' learning," silva says. "there are also those who are employed, but need at least an associate's degree to qualify for higher pay in the place where they work."
check out these speedy career options that you could prepare for in as little as one to two years.career #1 - computer support specialists
are your friends and family always asking you to help them with technical problems? a position where you're helping others solve computer issues may be ideal for you.
as a computer support specialist, you could use your skills to help people and companies with their computer systems. you might use automatic diagnostics programs to solve software problems, or teach people to use new computer hardware and software.
education options: some computer support specialist positions might require a bachelor's degree in computer science, computer engineering, or information systems. the good news, according to the u.s. department of labor, is that you can apply for some positions with a computer-related two-year associate's degree.*
do you have a good head for numbers? consider preparing to transition to a career in bookkeeping.
in this career, you might update and maintain accounting records, oversee bank deposits, or even handle payroll. you might also produce financial statements, prepare invoices, and keep track of overdue accounts.
education options: look into earning a two-year associate's degree in business or accounting. according to the u.s. department of labor, it's required for some bookkeeping positions.*
do you have a knack for research? are you a naturally curious person?
your research and investigation skills could come in handy as a paralegal, where it would be your job to investigate the facts of cases, prepare written reports for attorneys, and assist attorneys during trials.
education options: there are a couple options for aspiring paralegals, according to the u.s. department of labor. a two-year associate's degree in paralegal studies is one option. if you already have a bachelor's degree, you could earn a paralegal studies certificate in as little as a few months.*
are you motivated by a strong desire to help others? do you want to transition to a rewarding career in the medical field?
as a medical assistant, you might help with patient care by recording vital signs and performing basic lab tests. you might also play an important role in keeping your doctor's office running smoothly by scheduling appointments and handling insurance claims.
education options: according to the u.s. department of labor, formal education is usually preferred. consider earning a two-year associate's degree in medical assisting. another option is to earn a medical assisting certificate, which could take as little as one year to complete.*
want to pursue a career where you can put your detail-oriented mind to work? consider studying pharmacy technology.
as a pharmacy technician, you might process prescription requests and help licensed pharmacists prepare medications. that might include counting, weighing, and sometimes mixing medications, and - when the prescription is filled - pricing and filing the medication.
education options: according to the u.s. department of labor, employers favor applicants who have formal education, certification, or previous experience. the good news: you could prepare to transition into this career by earning a pharmacy technician diploma, a certificate, or an associate's degree.*
*all education information is from the u.s. department of labor. all time to completions are average and will vary by student, full or part-time status, schedules, school, program, and other factors.
From: education.yahoo.net