text:
A method is provided for measuring real time ambient pressure at a region of interest in a fluid-filled body cavity by introducing into the cavity a composition of gas-containing microbubbles having a predetermined fragility threshold correlating to the rupture response of their capsules to the ambient fluid pressure and/or applied acoustic pressure. An ultrasonic signal is applied at the region of interest at a power level sufficient to destroy the microbubble population having a fragility threshold below the applied power level. The ultrasound backscatter response is detected from the population of intact and disintegrating microbubbles remaining at the region of interest and this backscatter signal is correlated to predetermined acoustic response properties to determine the ambient pressure at the region of interest.
1. A method for measuring ambient pressure at a region of interest in a fluid-filled body cavity or vessel comprising the steps of:
(a) introducing into said cavity or vessel a composition of gas-containing microbubbles, said microbubbles having a predetermined fragility threshold, said fragility threshold correlating the disintegration response of said microbubbles to a combination of fluid and applied acoustic pressure, said acoustic pressure being applied from an ultrasonic energy producing source and said composition having predetermined acoustic response properties correlating to ambient pressure of a surrounding fluid;
(b) applying an ultrasonic signal at said region of interest within said cavity or vessel at a power level sufficient to cause acoustic pressure to disintegrate a microbubble population, said power level being above or equal to said predetermined fragility threshold;
(c) detecting the returned acoustic signals backscattered from the population of disintegrating and intact microbubbles remaining at said region of interest;
(d) correlating said returned acoustic signals to said predetermined acoustic response properties of said composition to determine said ambient pressure at said region of interest;
(e) repeating steps (a)-(b).
2. A method according to claim 1 further comprising the step of displaying said correlation on a monitor of an ultrasound scanner.
3. A method according to claim 1 wherein said microbubbles are characterized by having a shell comprising one or more layers.
4. A method according to claim 3 wherein in step (a) the predetermined fragility of each of said microbubbles is controlled by selecting the thickness of one or more layers of the shell.
5. A method according to claim 3 wherein in step (a) the predetermined fragility threshold of said microbubbles is controlled through the use of materials in the shell of differing moduli of elasticity.
6. A method according to claim 3 wherein in step (a) the predetermined fragility threshold of said microbubbles is controlled through use of materials in the shell of differing molecular weight.
7. A method according to claim 3 wherein in step (a) the predetermined fragility threshold of said microbubbles is controlled through use of materials in the shell of differing hoop strength.
8. A method according to claim 3 wherein in step (a) the disintegration response of said microbubbles approximates a step function at one or more pressure levels.
9. A method according to claim 1 wherein said gas in said microbubbles comprises physiologically acceptable gas.
10. A method according to claim 9 wherein said gas comprises nitrogen.
11. A method according to claim 9 wherein said gas comprises air.
12. A method according to claim 9 wherein said gas comprises a fluorocarbon compound.
13. A method according to claim 1 wherein said composition is introduced into said cavity as a bolus.
14. A method according to claim 1 wherein said composition is introduced to said cavity as a controlled rate infusion.
15. A method according to claim 1 wherein in step (a) the disintegration response is a linear relationship with ambient pressure in combination with constant ultrasound pressure.
16. A method according to claim 1 wherein said step of applying an ultrasonic signal and said step of detection are accomplished with an ultrasound imaging system.
17. A method according to claim 16 wherein the returned acoustic signals of said microbubbles is detected utilizing B-mode harmonic imaging methods.
18. A method according to claim 16 wherein the returned acoustic signals of said microbubbles is detected utilizing power Doppler decorrelation imaging methods.
19. A method according to claim 18 wherein the ambient fluid pressure is determined by comparing the intensity of the returned power Doppler decorrelation signal and the predetermined acoustic response properties of said microbubbles.
20. A method according to claim 19 wherein the ambient fluid pressure result is displayed in real time.
21. A method according to claim 19 wherein the ambient fluid pressure result is displayed as a greyscale map of ambient pressure within said body cavity. map of ambient pressure.
22. A method according to claim 19 wherein the ambient fluid pressure result is displayed as a color map of ambient pressure within said body cavity.
23. A method according to claim 22 wherein the colors of the color map are coded to the amplitude of the ambient pressure.
24. A method according to claim 19 wherein the results are displayed as a map of ambient pressure and correlated to a predetermined electrocardiogram of the subject to display pressure as a function of time point within the cardiac cycle.
25. A method according to claim 1 wherein said composition comprises two or more population of microbubbles of differing fragility thresholds.
26. A method according to claim 1 wherein the response of said microbubbles is detected by way of interrogation with an ultrasound signal of a first low power signal to establish a baseline and a second higher power signal to disintegrate the microbubble population whose fragility threshold is below said second power level and with a subsequent third high power signal to measure the resultant signal.
27. A method according to claim 25 wherein the ultrasound signal comprises a single pulse train wherein the two differing power levels are produced such that a first low power pulse is sent at the beginning of said pulse train and second and third high power pulses at the middle and the end of said pulse train, respectively.
28. A method according to claim 25 wherein the ultrasound signal comprises two or more pulse trains wherein the first pulse train is of low power and subsequent pulse trains are of higher power.
29. A method according to claim 25 wherein the ultrasound signal comprises three or more pulse trains wherein the first pulse train is of low power and each subsequent pulse train is of consecutively higher power than the previous pulse train.
30. A method according to claim 26 wherein the backscatter intensity from said microbubbles from the first low power signal is recorded as a baseline value.
31. A method according to claim 30 wherein the backscatter intensity from the third high power signal is subtracted from said baseline to yield a difference value.
32. A method according to claim 31 wherein the difference value is compared to experimental reference values to measure ambient fluid pressure.
33. A method according to claim 31 wherein the ambient fluid pressure measurement is repeated and results are displayed on the screen of an ultrasound scanner associated with the defined region of interest.
34. A method according to claim 26 wherein the second high power signal is at a power level above the fragility threshold of one or more populations of said composition.
35. A method of determining the fragility thresholds of a plurality of populations of microbubbles and correlating said thresholds to ambient pressures at rupture surrounding said microbubbles comprising the steps of:
a) determining the fragility slope of each said population from respective curves, said curves determined by measuring acoustic density as each of said population as it is acoustically interrogated along a channel versus distance along said channel;
b) determining fragility curves by plotting each of said fragility slopes versus mechanical index, a measure of the acoustic power used to interrogate each said population;
c) identifying the intercept of substantially linear portions of each of said fragility curves at zero fragility slope as the mechanical index at the threshold fragility for each said population;
d) correlating each of said mechanical indices at the threshold fragility to an ambient pressure from a predetermined mechanical index-to-pressure relationship.
36. The method according to claim 35 wherein said fragility slopes are determined for a plurality of populations of microbubbles having differing wall thickness.
37. The method according to claim 35 wherein said fragility slopes are determined for a plurality of populations of microbubbles having differing moduli of elasticity.
38. The method according to claim 35 wherein said fragility slopes are determined for a plurality of populations of microbubbles having materials of differing molecular weight.
39. The method according to claim 35 wherein said fragility slopes are determined for a plurality of populations of microbubbles having materials of differing hoop strength.
40. The method according to claim 35 wherein said fragility curves are determined for a plurality of populations of microbubbles having differing wall thickness.
41. The method according to claim 35 wherein said fragility curves are determined for a plurality of populations of microbubbles having differing moduli of elasticity.
42. The method according to claim 35 wherein said fragility curves are determined for a plurality of populations of microbubbles having materials of differing molecular weight.
43. The method according to claim 35 wherein said fragility curves are determined for a plurality of populations of microbubbles having materials of differing hoop strength.
The present invention relates to a method for measuring real time ambient fluid pressure within a fluid-filled body cavity using gas-filled microbubbles and ultrasonic acoustic energy.
Typically, cardiovascular pressures are measured using catheters which are introduced into the vascular systems via an artery or vein. Catheters exhibit a finite risk of both morbidity and mortality with routine usage in the clinical situation. More recently, sensor tipped guidewires to measure pressure have been developed. However, this procedure is also invasive with concomitant associations of morbidity and mortality. There are currently no adequately accurate direct, noninvasive real time clinical methods used to measure pressure in the cardiovascular system. An indirect method exists using Doppler ultrasound as suggested by Laaban, et al. (Laaban, J., Diebold, B., Zelinski, R., Lafay, M., Raffoul, H., and Rochemaure, J., Chest 96, (6): 1258-1262, 1989). With Doppler techniques, blood flow velocities are measured using ultrasonic scanners operating in the Doppler mode. By applying the Bernoulli equation and knowing the peak velocity, it is possible to calculate the pressure drop across a cardiac valve that created the flow. If one starts measurements in a vein such as the superior vena cava of known low pressure, one can calculate the pressure in the right ventricle and pulmonary artery and even make an estimate of the endiastolic left ventricular pressure with the technique. The indirect approach is filled with errors in difficult cases when good data is most needed and is used only for diagnosing the right side of the heart. Other non-invasive measurement schemes have been proposed (Blazek; Vladimir, Schmitt; Hans-J., U.S. Pat. No. 5,447,161; Aakhus, S., Soerlie, C., Faanes, A., Hauger, S. O., Bjoemstad, K., Hatle, L., and Angelsen, B. A. J., American Journal of Cardiology, 72: 260-267, 1993; Kyriakides, Z. S., Kremastinos, D. T., Rentoukas, E., Vavelidis, J., Damianou, C., and Toutouzas, P., International Journal of Cardiology, 33: 267-274, 1991; Neuman, A., Soble, J. S., Anagnos, P. C., Kagzi, M., and Parrillo, J. E., Journal of the American Society of Echocardiography, 11(2): 126-131, 1998) but show no significant advancement to the field.
In U.S. Pat. No. 3,640,271 to Horton, there is presented the concept of injecting a single bubble of known size into a patient for the purpose of measuring blood pressure. The concept was to stimulate the bubble into resonance ultrasonically and from the received backscattered signal, determine the resonant frequency of the bubble. It is further known that if both the diameter of the bubble and the resonant frequency are known, then the unknown pressure could be calculated. However, it is not known that the precision sized bubbles required for the technical approach have ever been achieved. Also, at present, it would be nearly impossible to locate bubbles within a specific organ or cavity for the very low concentration of bubbles required by the technology.
In Pat. No. 4,265,251 to Tickner, the concept of encapsulating a pressurized bubble within a fused saccharide shell is presented. The shell begins to dissolve in the circulatory system, thinning the wall. At some point in its dissolution, the shell fractures and the bubble escapes and expands. In so doing, it over-expands from its encapsulated diameter which sets it to free-ringing. A passive external transducer detects the free ringing signals and, by applying the same equations identified by Horton, computes the pressure. A limitation to the technology for usable clinical practice is the inability to control the point of rupture and the lack of precision (Osterle S., Sahines, T., Tucker, C., Tickner, E., et al., The Western Journal of Medicine, 1985 Ott; 143: 463-468.
In U.S. Pat. No. 5,749,364 to Sliwa, the concept for mapping cardiac pressures is presented by injecting a population of non-precision microspheres into the blood pool. Theory indicates that the resonant frequency peak of an encapsulated bubble is mathematically related to the ambient pressure. By examining the backscattered signal of the microspheres and from the change in their frequency spectrum, a map of the pressure in at least two dimensions is derived. One claimed method for doing this is to inject two microsphere population types, which exhibit different backscatter characteristics, and then use these different characteristics to deduce ambient pressures. Other work in using frequency shift has been explored. However, no clinical applications are known to have been developed (Ishihara, K., Kitabatake, A., Tanouchi, J., Fujii, K., Uematsu, M., Yoshida, Y., Kamada, T., Tamura, T., Chihara, K., and Shirae, K., Jpn. J. Appl. Phys., 27(Suppl 27-1): 125-127, 1988) possibly due to the difficulties in measuring in-vivo frequency shifts. Furthermore, commercial ultrasound scanners have relatively narrow frequency bandwidths, which would not allow for the frequency range scan needed to detect changes in resonant frequency, especially in a formulation with multiple microsphere populations with attendant multiple resonance peaks.
In PCT No. 98/32378 (De Jong, N., Frinking, P., PCT No. WO 98/32378, Jul. 30, 1998; Bouakaz, A., Frinking, P., De Jong, N., Non-Invasive Pressure Measurement in a Fluid Filled Cavity, Abstract: The Fourth Heart Centre Symposium on Ultrasound Contrast Imaging, Jan. 21-22, 1999) there is disclosed the use of the decay of free gas bubbles to measure ambient pressure or temperature. The decay time of the gas bubble is dependent on the gas type, the liquid characteristics, the solubility of the gas within the liquid, the excitation frequency and the ambient temperature and pressure. However, in their scheme the microsphere is used only as a transport mechanism which releases the free bubble upon insonation and the properties of the free bubble are utilized for pressure measurement. They propose using a series of intermittent high power pulses to break the capsule of the microsphere, releasing the gas bubble and then using a series of intermittent low power pulses to determine the decay time of the bubble and therefore calculate pressure or temperature. Although the mechanism described uses a power level to rupture the capsule that is above a threshold, the fragility or release mechanism of the microsphere capsule itself is not controlled. Furthermore, if the microsphere has a very weak capsule, breakage of the capsule can occur at very low ultrasound powers. This leads to a response which is not controlled relative to imaging depth and applied power.
The present invention is directed to a method for measuring real time pressure in a region of interest in a fluid-filled body cavity. A composition of gas-containing microbubbles is introduced into the cavity, the microbubbles having a predetermined fragility threshold where the fragility threshold is correlated with the rupture response to fluid pressure, applied acoustic pressure, or a combination of both fluid and applied acoustic pressures. The acoustic pressure is applied from an ultrasonic energy producing source. The composition of microbubbles has predetermined acoustic response properties correlating to ambient pressure of the surrounding fluid. When the microbubbles are at the region of interest, an ultrasonic signal is applied at a power level sufficient to cause acoustic pressure sufficient to destroy or disrupt the membrane of the encapsulated microbubble population having a fragility threshold below the applied power level. Then, the ultrasound backscatter response is detected from the population of intact and failing microbubbles remaining at the region of interest and the backscatter signals are correlated to the predetermined acoustic response properties of the microbubble composition to determine the ambient pressure at the region of interest.
FIG. 1 is a plot of average acoustic density versus ambient fluid pressure of microbubbles tested in Example 1;
FIG. 2 is a plot of power Doppler plume length versus ambient fluid pressure of the test on microbubbles tested in Example 2;
FIG. 3 is a plot of mean acoustic density versus distance, defining the fragility slope of the microbubbles tested in Example 4;
FIG. 4 is a plot of the fragility slopes of three microbubble compositions versus mechanical index as described in Example 4 to define the fragility curve;
FIG. 5 is a graph showing the fragility thresholds of three different microbubble compositions having three different wall thickness;
FIG. 6 is a plot of the backscatter signal versus mechanical index at three different pressures of a microbubble composition having 110 nm wall thickness;
FIG. 7 is a plot of fragility slopes versus mechanical index of a microbubble composition having 110 nm wall thickness at three different pressures;
FIG. 8 is a plot of the fragility slope intercept versus pressure from the data shown in FIG. 7.
As used herein the term microbubbles is intended to include microspheres, microcapsules and microparticles which are hollow and enclosing a core which may be filled with a gas. This may be a matrix material. It is not necessary for the microbubbles to be precisely spherical although they generally will be spherical and described as having average diameters. If the microbubbles are not spherical, then the diameters are referred to or linked to the diameter of a corresponding spherical microparticle having the same mass and enclosing approximately the same volume of interior space as a non-spherical microbubble. Microbubbles may be comprised of surface tension stabilized gas bubbles, surfactant stabilized gas bubbles, lipids and lipisomes, synthetic polymers and biopolymers; and may further comprise one or more layers of suitable material.
Ultrasonic backscatter of gas filled microbubbles and bubble resonance are well known in the ultrasound contrast field. It is known from the bubble resonance equations that resonant frequency and pressure are mathematically related. Theory indicates that an encapsulated gas bubble under insonation has a spectral envelope with a pronounced peak value at microbubble resonance and this aspect leads to the prior art methods of using resonant frequency shifts to determine pressure. However, in simulations with commercially available microbubble contrast agents, a nearly flat frequency response has been measured and reported by Boualaz, et al., (Bouakaz, A., DeJong, N., Cachard, C., and Jouini, K., Ultrasonics 36: 703-708, 1998). Thus, using frequency shift, it may be difficult to estimate in-vivo pressure.
To overcome the microbubble resonance detection problem, this invention focuses on the encapsulated bubble property of capsule fragility. The capsule of a microbubble can structurally fail from both static and dynamic pressure or combinations of the two. The ultrasonic waves can then disrupt or disintegrate the freed/escaping gas bubbles sufficiently to decrease their backscattering cross-section.
The intensity of backscattered signals depends upon the number of bubbles present in the sample volume and the size of the bubbles. If the size of the microbubble population is constant, then if capsules are broken for any reason and the encapsulated gas within dissolves or disintegrates into smaller bubbles, there is a concomitant decrease in backscattered signal intensity.
In the case of a gas filled microbubble used in the method of the present invention, the materials of the capsule wall, and the properties of those materials are selected and prepared to allow for the rupture of the capsule at critical or threshold pressures or within defined pressure limits. The microbubbles prepared in this manner are referred to herein as having engineered fragility. By fabricating a microbubble agent with a specifically designed fragility response and by controlling the applied ultrasound power, one can selectively rupture a gas containing microbubble, releasing the gas bubble, which then dissolves or breaks up under insonation in the ambient fluid. Since backscatter depends upon the presence of gas bubbles or gas containing microbubbles and their ability to re-radiate incident signals, backscatter signal intensity is decreased when the population of microbubbles or free bubbles decreases or the diameter of the bubbles decreases. However, in order to alter the backscatter on a clinically useable timescale, it becomes necessary to both structurally fail the capsule wall and have the released gas bubble dissolve or disintegrate quickly in the blood stream. The method herein disclosed takes advantage of this process by using the decrease in signal intensity and/or amplitude as a means of identifying the unknown pressure, instead of the shift in resonant frequency or decay time of a free gas bubble. Since microbubbles can be seen within cardiac chambers and even destroyed by ultrasonic imaging scanners, the present invention provides a viable way for measuring pressure in real time provided that the microbubbles are designed and fabricated to meet certain specifications. These specifications concern the relationship between static and dynamic stresses within the membrane or capsule shell that when exceeded cause structural failure. The released free gas bubble should quickly dissolve or disintegrate into much smaller bubbles so as not to continue to backscatter incident signals.
Accordingly, having prepared microbubble compositions with engineered fragility, such compositions are used to measure the real time ambient fluid pressure at a region of interest in a fluid-filled cavity, such as the heart. Typically the microbubble composition will be introduced into the blood system and the location of the composition within the body can be monitored by conventional ultrasound scanning. At the region of interest, acoustic pressure can be applied by a focused ultrasound source to rupture the capsules of the microbubbles which have a fragility threshold below the power level of the applied acoustic pressure. Then the ultrasound backscatter response from the remaining population of intact microbubbles or disintegrating gas bubbles at the region of interest is made and correlated to predetermined acoustic response properties of the microbubble composition to determine the ambient pressure at the region of interest. The results may be displayed as a qualitative or quantitative pressure map using greyscale or color overlays of the base image.
In general, the ambient pressure at a region of interest can be determined by correlating pressure to the acoustic energy required to rupture the capsule of the microbubbles. First, a predetermined correlation of acoustic energy, typically given as a mechanical index, to pressure is made. This may be experimentally determined by measuring the microbubble response under pressure at an acoustically targeted site. Fragility slopes of various populations may then be experimentally determined from the results of acoustic density vs. distance along a channel containing an acoustically interrogated population of flowing microbubbles. The fragility slopes are then plotted to derive fragility curves of fragility slope vs. mechanical index. There are substantially linear portions of each fragility curve which, when extended to the intercept at the zero fragility slope value, determine the mechanical index at the threshold fragility. This mechanical index correlates to the threshold fragility when the microbubbles rupture, and is dependent upon the ambient fluid pressure.
This can be accomplished by several methods. Since the microbubble formulations can be made with uniform properties, a fragility versus pressure characteristic of the composition may be predetermined by in vitro experiments to develop a response curve. In one such method when the composition is injected into the bloodstream, a focused ultrasound scanner is applied at a low power sound pulse or pulse train to establish a baseline. Then a second pulse or pulse train is applied at a higher power which is selected to destroy the segment of the microbubble population whose fragility threshold is below the power level of the second pulse. A third pulse or pulse train also at high power is then used to measure the post destruction backscatter response. The difference of the backscatter signal from the third pulse versus the baseline is a measure of the pressure in the ambient fluid and can be determined by reference to the response curve. The results may be displayed on the monitor of the ultrasound scanner as a real time overlay, either in greyscale or color.
Another method of utilizing the microbubbles to measure ambient pressure is to combine a microbubble composition fabricated from two or more populations of gas-filled microbubbles where each population comprises differing fragility thresholds. The fragility versus pressure characteristics of each population as well as the combined population are predetermined by in vitro experiments and the response curve is developed. After administering the formulation into the bloodstream by bolus injection or infusion, an ultrasound scanner is focused on the region of interest to apply successively increasing power pulses or pulse trains. At each power setting, that population of microbubbles whose fragility threshold is below the power level of the pulse will be destroyed. The decay in the intensity of the backscatter signal from each successive pulse is a measure of the pressure in the ambient fluid. The pressure measurement is calculated from this decay, referenced to the known response curve, and is displayed on the monitor.
Yet another method is to inject a single population of microbubbles having a population with a fragility threshold that is linearly decreasing with increasing ambient pressure and under constant applied ultrasound pressure. The fragility curve is determined by empirical analysis. An ultrasound scan of the cardiac chambers, for example, may be performed under a power Doppler mode at a constant power level so that the quantity of microbubble destruction within the chambers will be dependent upon the ambient pressure. Each destruction event of a microbubble will result in a decorrelation signal being detected and displayed by the ultrasound scanner. The intensity of the Power Doppler ultrasound display will be directly proportional to the ambient fluid pressure, by way of the predetermined response.
By yet another method, the pressure in the chamber of the heart or across a heart valve may be measured. The acoustic density value of a series of adjacent regions of interest are measured along a scanline axis of the ultrasound transducer a rapid sequence. The slope of a plot of the acoustical density versus distance along the scanline axis is determined and compared to predetermined values of the acoustical density versus pressure. The data can then be displayed as a pressure value along the scanline. By repeating the determination as subsequent scanlines, the pressure value for a region within the chamber can be determined and displayed.
An alternate method to measure pressure is as follows. A region of interest containing microbubbles of engineered fragility is interrogated with a series of ultrasound pulses in rapid succession of steadily increasing power values: P1, P2, . . . Pn, and respective acoustic density or backscatter signal levels are determined: B1, B2, . . . Bn. A fragility curve, as shown in Example 4 below, made by plotting the slope (taken from the results of acoustical density versus distance) versus mechanical index, is computed to determine the pressure from either the slope of the fragility curve which occurs in a nearly linear high power region or from a computed zero slope intercept as shown in Example 4 below. Comparing the data to a predetermined table of correlation to pressure will show pressure at the point of measurement. Real time display of the pressure can then be accomplished by the ultrasound scanner.
The microbubbles according to the present invention may be a surface tension or surfactant stabilized gas bubble or have a mono-layer shell but preferably have at least a bi-layered shell. The outer layer of the shell will be a biologically compatible material or biomaterial since it defines the surface which will be exposed to the blood and tissues within the body. The inner layer of the shell will be a biodegradable polymer, which may be a synthetic polymer, which may be tailored to provide the desired mechanical and acoustic properties to the shell. The cores of the microbubbles contain gas, typically air, nitrogen or a fluorocarbon gas. To make the microbubbles rupturable by ultrasound energy, they must contain a gas to allow acoustic coupling and particle oscillation. Microbubbles are constructed such that the majority of those prepared in a composition will have diameters within the range of about one to ten microns in order to pass through the capillary system of the body.
Since the microbubbles preferably have an outer and inner layer, the layers can be tailored to serve different functions. The outer shell which is exposed to the blood and tissues serves as the biological interface between the microbubbles and the body. Thus it will be made of a biocompatible material which is typically amphiphilic, that is, has both hydrophobic and hydrophilic characteristics. Blood compatible materials are particularly preferred. Such preferred materials are biological materials including proteins such as collagen, gelatin or serum albumins or globulins, either derived from humans or having a structure similar to the human protein, glycosoaminoglycans such as hyaluronic acid, heparin and chondroitin sulphate and combinations or derivatives thereof. Synthetic biodegradable polymers, such as polyethylene glycol, polyethylene oxide, polypropylene glycol and combinations or derivatives may also be used. The outer layer typically has a chemistry which allows charge and chemical modification. The versatility of the surface allows for such modifications as altering the charge of the outer shell, such as by selecting a type A gelatin having an isoelectric point above physiological pH, or by using a type B gelatin having an isoelectric point below physiological pH. The outer surfaces may also be chemically modified to enhance biocompatibility, such as by PEGylation, succinylation or amidation, as well chemically binding to the surface a targeting moiety for binding to selected tissues. The targeting moieties may be antibodies, cell receptors, lectins, selecting, integrins or chemical structures or analogues of the receptor targets of such materials. The mechanical properties of the outer layer may also be modified, such as by cross linking, to make the microbubbles suitable for passage to the left ventricle.
The inner shell will be a biodegradable polymer, which may be a synthetic polymer. An advantage of the inner shell is that it provides additional mechanical properties to the microbubble which are not provided or insufficiently provided by the outer layer or, enhances mechanical properties not sufficiently provided by the outer layer, without being constrained by surface property requirements. For example, a biocompatible outer layer of a cross-linked proteinaceous hydrogel can be physically supported using a high moduli synthetic polymer as the inner layer. The polymer may be selected for its modulus of elasticity and elongation, which define the desired mechanical properties. Typical biodegradable polymers include polycaprolactone, polylactic acid, polylactic-polyglycolic acid co-polymers, co-polymers of lactides and lactones, such as epsilon-caprolactone, delta-valerolactone, polyalkylcyanoacrylates, polyamides, polyhydroxybutryrates, polydioxanones, poly-beta-aminoketones, polyanhydrides, poly-(ortho)esters, polyamino acids, such as polyglutamic and polyaspartic acids or esters of polyglutamic and polyaspartic acids. References on many biodegradable polymers are cited in Langer, et. al. (1983) Macromol.Chem.Phys.C23, 61-125.
The inner layer permits the modification of the mechanical properties of the shell of the microbubble which are not provided by the outer layer alone. For use as an ultrasonic contrast agent, the inner layer will typically have thickness which is no larger than is necessary to meet the minimum mechanical requirements, in order to maximize the interior gas volume of the microbubble. The greater the gas volume within the microbubble the better the echogenic properties.
The combined thickness of the outer and inner layers of the microbubble shell will depend in part on the mechanical properties required of the microbubble, but typically the total shell thickness will be in the range of 25 to 750 nm.
The microbubbles may be prepared by an emulsification process to control the sequential interfacial deposition of shell materials. Due to the amphiphilicity of the material forming the outer layer, stable oil/water emulsions may be prepared having an inner phase to outer phase ratio approaching 3:1, without phase inversion, which can be dispersable in water to form stable organic phase droplets without the need for surfactants, viscosity enhancers or high shear rates.
Two solutions are prepared, the first being an aqueous solution of the outer biomaterial. The second is a solution of the polymer which is used to form the inner layer, in a relatively volatile water-immiscible liquid which is a solvent for the polymer, and a relatively non-volatile water-immiscible liquid which is a non-solvent for the polymer. The relatively volatile water-immiscible solvent is typically a C5-C7 ester, such as isopropyl acetate. The relatively non-volatile water-immiscible non-solvent is typically a C6-C20 hydrocarbon such as decane, undecane, cyclohexane, cyclooctane and the like. In the second solution containing the polymer for the inner layer, the polymer in water-immiscible solvents are combined so that the polymer fully dissolves and the two solvents are miscible with agitation. The polymer solution (organic phase) is slowly added to the biomaterial solution (aqueous phase) to form a liquid foam. Typically about three parts of the organic polymer solution having a concentration of about 0.5 to 10 percent of the polymer is added to one part of the aqueous biomaterial solution having a concentration of about 1 to 20 percent of the biomaterial. The relative concentrations of the solutions and the ratio of organic phase to aqueous phase utilized in this step essentially determine the size of the final microbubble and wall thickness. After thorough mixing of the liquid foam, it is dispersed into water and typically warmed to about 30-35° C. with mild agitation. While not intending to be bound by a particular theory, it is believed that the biomaterial in the foam disperses into the warm water to stabilize an emulsion of the polymer in the organic phase encapsulated within a biomaterial envelope. To render the biomaterial envelope water insoluble, a cross linking agent, such as glutaraldehyde, is added to the mixture to react with the biomaterial envelope and render it water insoluble, stabilizing the outer shell. Other cross-linking agents may be used, including the use of carbodiimide cross-linkers.
Since at this point the inner core contains a solution of a polymer, a solvent and a non-solvent with different volatilities, as the more volatile solvent evaporates, or is diluted, the polymer precipitates in the presence of the less volatile non-solvent. This process forms a film of precipitate at the interface with the inner surface of the biomaterial shell, thus forming the inner shell of the microbubble after the more volatile solvent has been reduced in concentration either by dilution, evaporation or the like. The core of the microbubble then contains predominately the organic non-solvent. The microbubbles may then be isolated by centrifugation, washed, formulated in a buffer system, if desired, and dried. Typically, drying by lyophilization removes not only the non-solvent liquid core but also the residual water to yield gas-filled hollow microbubbles.
It may be desirable to further modify the surface of the microbubble, for example, in order to passivate surfaces against macrophages or the reticuloendothelial system (RES) in the liver. This may be accomplished, for example by chemically modifying the surface of the microbubble to be negatively charged since negatively charged particles appear to better evade recognition by macrophages and the RES than positively charged particles. Also, the hydrophilicity of the surface may be changed by attaching hydrophilic conjugates, such as polyethylene glycol (PEGylation) or succinic acid (succinylation) to the surface, either alone or in conjunction with the charge modification.
The biomaterial surface may also be modified to provide targeting characteristics for the microbubble. The surface may be tagged by known methods with antibodies or biological receptors.
The microbubbles may also be sized or processed after manufacture. This is an advantage over lipid-like microbubbles which may not be subjected to mechanical processing after they are formed due to their fragility.
The final formulation of the microbubbles after preparation, but prior to use, is in the form of a lyophilized cake. The later reconstitution of the microbubbles may be facilitated by lyophilization with bulking agents which provide a cake having a high porosity and surface area. The bulking agents may also increase the drying rate during lyophilization by providing channels for the water and solvent vapor to be removed. This also provides a higher surface area which would assist in the later reconstitution. Typical bulking agents are sugars such as dextrose, mannitol, sorbitol and sucrose, and polymers such as PEG's and PVP's.
It is undesirable for the microbubbles to aggregate, either during formulation or during later reconstitution of the lyophilized material. Aggregation may be minimized by maintaining a pH of at least one to two pH units above or below the isoelectric point(Pi) of the biomaterial forming the outer surface. The charge on the surface is determined by the pH of the formulation medium. Thus, for example, if the surface of the biomaterial has a Pi of 7 and the pH of the formulation medium is below 7, the microbubble will possess a net positive surface charge. Alternatively, if the pH of the formulation medium is greater than 7, the microbubble would possess a negative charge. The maximum potential for aggregation exist when the pH of the formulation medium approaches the Pi of the biomaterial used in the outer shell. Therefore by maintaining a pH of the formulation medium at least one to two units above or below the Pi of the surface, microbubble aggregation will be minimized. As an alternative, the microbubbles may be formulated at or near the Pi with the use of surfactants to stabilize against aggregation. In any event, buffer systems of the final formulation to be injected into the subject should be physiologically compatible.
The bulking agents utilized during lyophilization of the microbubbles may also be used to control the osmolality of the final formulation for injection. An osmolality other than physiological osmolality may be desirable during the lyophilization to minimize aggregation. However, when formulating the microbubbles for use, the volume of liquid used to reconstitute the microbubbles must take this into account.
Other additives may be included in order to prevent aggregation or to facilitate dispersion of the microbubbles upon formulation. Surfactants may be used in the formulation such as poloxomers (polyethylene glycol-polypropylene glycol-polyethylene glycol block co-polymers). Water soluble polymers also may assist in the dispersion of the microbubbles, such as medium molecular weight polyethyleneglycols and low to medium molecular weight polyvinylpyrolidones.
It will be realized that various modifications of the above-described processes may be provided without departing from the spirit and scope of the invention. For example, the wall thickness of both the outer and inner layers may be adjusted by varying the concentration of the components in the microbubble-forming solutions. The mechanical properties of the microbubbles may be controlled, not only by the total wall thickness and thicknesses of the respective layers, but also by selection of materials used in each of the layers by their modules of elasticity and elongation, molecular-weight, hoop strength, and degree of cross-linking of the layers. Hoop strength being defined as a mechanical property of a sphere based on the resistance of a section on the sphere to radial force. Mechanical properties of the layers may also be modified with plasticizers or other additives. Adjustment of the strength of the shell may be modified, for example, by the internal pressure within the microbubbles. Precise acoustical characteristics of the microbubble may be achieved by control of the shell mechanical properties, thickness, as well as size distribution. The microbubbles may be ruptured by ultrasonic energy to release gases trapped within the capsule into the blood stream. In particular, by appropriately adjusting the mechanical properties, the particles may be made to remain stable to threshold diagnostic imaging power, while being rupturable by an increase in power and/or by being exposed to its resonant frequency. The resonant frequency may be made to be within the range of transmitted frequencies of diagnostic body imaging systems or may be a harmonic or subharmonic of such frequencies. During the formulation process the microbubbles may be prepared to contain various gases, including blood soluble or blood insoluble gases.
The preferred embodiment is a bi-layered microbubble with a biopolymer outer shell and a synthetic polymer inner layer.
Typical diagnostic or therapeutic targets for microbubbles of the invention are the heart, liver, kidney, vascular system and tumors.
The following examples are provided by way of illustration, and are not intended to limit the invention in any way.
A Hewlett Packard SONOS 2500 ultrasonic scanner was used. This scanner has the capability of measuring the acoustic density (AD)as a function of time within a region of interest (ROI) displayed on the video monitor. The scanner was set in the 2D harmonic mode with send frequency of 1.8 MHZ and receive frequency of 3.6 MHZ. A test cell was constructed comprising a 3.8 mm diameter cellulose tubing (the imaging tube)running through a plastic beaker approximately 3 cm below the top. Degassed water was used to fill the beaker. A flow system was connected to the imaging tube consisting of a mixing reservoir with microsphere contrast agent suspended in it, a peristaltic pump and a pressure transducer with digital readout. A backpressure valve was placed on the drain end of the tube to be able vary the system pressure. The transducer focus was set on the center of the imaging tube and the ROI placed within the image of the tubing lumen. The scanner was set in the AD mode and the AD readings were recorded by the scanner. The system was run with zero back pressure to establish a baseline and then the discharge flow valve was closed to achieve a desired pressure and the procedure repeated. Pressures were increased to roughly 200 mm Hg and then decreased during the study.
Several different gas containing microbubble agents were employed and all yield a linear relationship as exemplified in FIG. 1. Also, several different power values (mechanical index or "MI")were utilized. In all cases, a linear decrease of AD was observed as a function of pressure for a fixed MI, thus demonstrating selective fragility.
Hewlett Packard SONOS 5500 ultrasound scanner was used in conjunction with a an ATS Laboratories, Model 524 Doppler Flow Phantom. The setup was essentially the same as Example 1. However, the scanner was set up in the Angio (Power Doppler or Doppler decorrelation) mode. In this mode, decorrelation events as determined by Doppler signal processing above a preset threshold are displayed on the monitor of the ultrasound scanner. The flow phantom consists of a housing filled with an elastomer which is designed to mimic the attenuation of living tissue and has four flow channels of 2, 4, 6, & 8 mm diameter respectively running through it. The 6 mm diameter channel of the flow phantom was chosen. The sector scan transducer was oriented along the centerline of the flow tube. When operated in the Angio mode and when microbubbles are present in the flow tube of the phantom, a colored plume derived from the decorrelation events is displayed on the monitor. The plume corresponds to the disruption or disintegration of microbubbles within the scanned ultrasound field. All tests were performed with a pulse repetition frequency of 1.2 kHz, an triggering interval of 2000 ms, 8 pulse Doppler packet and various values of TIS (Thermal Index, Soft tissue: a measure of output power) and various formulations microbubbles having an outer layer of albumin and an inner layer of d, 1 lactide. Using the caliper function of the system, one can measure the distance from the first point of insonation to the end of the plume on the centerline of the channel. Very fragile microbubbles fail instantly as they enter the sound field and the plume is very short, typically only a few millimeters, whereas more durable microbubbles produce a plume which can extend across the image. Since the plume changes with number of decorrelation events, a measure of, agent fragility is accomplished and one can then examine the results under varying ambient pressures. By adjusting the discharge (backpressure) valve, one can take measurements of the plume length with varying pressure. If the microbubbles exhibit engineered fragility properties, the plume length should change under differing pressure conditions which are dependent upon the properties of the microbubbles. Indeed this is the case as exemplified in the FIG. 2.
As can be seen in FIG. 2, there is a linear decrease in plume length with pressure with a correlation coefficient of 0.98. This particular test did not require high power levels. The tests were performed under various power conditions ranging from a TIS value of 0.2 to 1.0 and in all cases tested there was a linear relationship between plume length and pressure.
The set-up as presented in Example 2 above was used with the exception that the flow phantom was exchanged for a 6.5 cm diameter by 7.6 cm high acrylic cylindrical phantom chamber with a sealed top and bottom. A magnetic stirring bar was placed in the chamber and the chamber filled completely with de-gassed water. Two ports with luer lock syringe fittings are present to allow connection to the chamber. One port is connected to the pressure transducer, and the other port connected through a 3-way valve to a pressurizing syringe and a sample injection syringe. The S4 transducer of the HP 5500 scanner was placed in a water-filled well on the top of the chamber, imaging directly downward through a thin acrylic cover. The HP SONOS 5500 was run in Angio mode and in B-mode Harmonic. The transducer focus was set at 4 cm in depth, near the mid chamber position. A diluted sample of gas filled, dual walled microbubbles (described in Example 8) was injected into the chamber with the pressure transducer port open to relieve the pressure build-up from sample introduction. The pressure transducer port was closed and the 3-way valve switched to the pressurizing syringe, which is filled with water. The chamber is placed on a magnetic stirrer set to slow speed.
The ultrasound scanner was turned on and the Power Doppler image displayed is of a somewhat spherical region of signals from Doppler decorrelation events within the central region of the phantom. The pressurizing syringe is then engaged to bring the pressure up to approximately 150 to 200 mm Hg and back to ambient at approximately 30 cycles per minute. The display shows the region of decorrelation signals diminishing in size significantly with the increase in pressure and returning to baseline as the pressure returns to ambient. The image changes indicate the correspondence of the Doppler decorrelation signals to the ambient pressure. The results were recorded to videotape.
Using the set-up with the HP SONOS 5500 and Doppler Flow Phantom as detailed in Example 2 above, a test was performed to determine the variations in fragility thresholds and their relationship to ambient pressure of microbubbles fabricated with differing wall thickness. Three samples of microbubbles (described in Example 8) were fabricated with polylactide inner walls of thickness approximately 28, 55 and 110 nm respectively. The samples were interrogated using B-mode Harmonic imaging at 1.8 MHz send and 3.6 MHz receive frequencies. Using the AD function, an ROI was placed at the input end of the image of the flow channel and densitometry readings taken at each increment. The ROI was moved laterally, in increments along the flow direction and readings taken. The resultant graph, FIG. 3, shows the exemplary results for one sample (55 nm thickness) as a function of mean AD value versus distance in centimeters along the flow channel. The slope of this line is called the Fragility Slope (FS). The results from all samples indicate a linear decrease in backscattered signal with distance from the source, and exposure to the ultrasound field.
The test is repeated at MI values from 0.0 to 1.6, in increments of 0.1 MI. The slopes of the resultant measurements are then plotted versus the power or MI value, as shown in FIG. 4. This curve is termed the Fragility Curve (FC). All three samples show a region at low power levels where the slopes are essentially zero, then a power level where the decrease in signal from the destruction of microcapsules begins. Determining the curve intercepts with the zero slope value as shown in FIG. 5, yields fragility threshold values for the various samples.
Values of AD vs Distance (FIG. 3) were determined at ambient and at approximately 100 and 200 mm Hg respectively. The y-intercept of FIG. 3 was taken as an indication of peak backscatter signal. The peak AD backscatter signal was then plotted versus MI at the three test pressures in FIG. 6. The curves are roughly equal indicating that the agent is stable under the test pressures examined and exhibits the same acoustic behavior at each pressure, and furthermore that agent concentrations in each test were comparable.
Fragility Slopes and resultant Fragility Curves for the 110 nm wall thickness sample where generated at different pressures as above. Taking the data in the high MI region, from 1.0 to 1.6, wherein the behavior of the Fragility Curve is nearly linear, three distinct linear results are seen as in FIG. 7. The intercept of these lines with the zero slope value is shown in FIG. 8. These curves may be used to compute the ambient pressure of the fluid.
A solution of 1.0 gms gelatin (275 bl, isoelectric point of 4.89) dissolved in 20 ml deionized water was prepared at approximately 60 C. Native pH of the solution was 5.07. Separately, 1.0 gms polycaprolactone (M.W. 50,000) and 6.75 ml cyclooctane was dissolved in 42 ml isopropyl acetate with stirring at approximately 70 C. After cooling to 37 C., the organic mixture was then slowly incorporated into the gelatin solution maintained at 30 C. and under moderate shear mixing using a rotary mixer. Once the organic phase was fully incorporated, the mixing rate was increased to 2,500 rpm for 5 minutes and then stirred at low shear for an additional 5 minutes. The resulting o-w emulsion was then added with stirring to 350 ml deionized water maintained at 30 C. and containing 1.2 ml 25% gluteraldehyde. Immediately after the addition of the emulsion, the bath pH was adjusted to 4.7. After 30 minutes, the pH was adjusted to 8.3. Low shear mixing was continued for approximately 2˝ hours until the isopropyl acetate had completely volatilized. Polyoxamer 188 in the amount of 0.75 gm was then dissolved into the bath. The resulting microbubbles were retrieved by centrifugation and washed 2 times in an aqueous solution of 0.25% polyoxamer 188.
Microscopic inspection of the microbubbles revealed spherical capsules having a thin-walled polymer shell encapsulating a liquid organic core. Staining the slide preparation with coomassie blue G indicated the presence of an outer protein layer uniformly surrounding the polymer shell.
The particle size spectrum was determined using a Malvern Micro. Median diameter was 4.78 microns with a spectrum span of 0.94.
A quantity of microbubbles prepared in a manner similar to example 5 were suspended into an aqueous solution of 25 mM glycine, 0.5% pluronic f-127, 1.0% sucrose, 3.0% mannitol, and 5.0% PEG-3400. The suspension was then lyophilized. The resulting dry powder was reconstituted in deionized water and examined under the microscope to reveal that the microbubbles now contained a gaseous core. Staining the preparation with commassie blue G confirmed that the outer protein layer surrounding the capsules was intact and had survived the lyophilization process.
Echogenicity was confirmed by insonating at both 2˝ and 5 MHZ a quantity of lyophilized microbubbles dispersed in 120 ml deionized water. Measurement was taken at least 15 minutes after dispersion of the microbubbles to insure that the back scattered signal was due solely from the gas contained within the microbubbles. The B mode display showed a high contrast indicating that the microbubbles were gas filled.
A 6% aqueous solution was prepared from a 25% solution of USP grade human serum albumin (Alpha Therapeutic Corp) by dilution with deionized water. The solution was adjusted to a pH of 3.49 using 1 N HCl. Separately, 8 parts by weight polycaprolactone (M.W. 50,000) and 45 parts cyclooctane were dissolved in 300 parts isopropyl acetate at approximately 70° C. Once dissolution was complete, the organic solution was allowed to cool to 37° C. With mild stirring, 42.5 gm of the prepared organic solution was slowly incorporated into 25.0 gm of the albumin solution while the mixture was maintained at 30° C. The resulting coarse o-w emulsion was then circulated through a stainless steel sintered metal filter element having a nominal pore size of 7 microns. Recirculation of the emulsion was continued for 8 minutes. The emulsion was then added with stirring to 350 ml deionized water maintained at 30° C. and containing 1.0 ml of 25% gluteraldehyde. During the addition, the pH of the bath was monitored to insure that it remained between 7 and 8. Final pH was 7.1. Low shear mixing was continued for approximately 2˝ hours until the isopropyl acetate had completely volatilized. Poloxamer 188 in the amount of 0.75 gm was then dissolved into the bath. The resulting microbubbles were retrieved by centrifugation and washed 2 times in an aqueous solution of 0.25% poloxamer.
Microscopic inspection of the suspension revealed spherical particles having a thin-walled polymer shell with an outer protein layer and an organic liquid core. The peak diameter as, determined by the Malvern Micro particle size analyzer, was 4.12 microns.
The suspension was then lyophilized in a manner similar to that described in Example 6. The resulting dry cake was reconstituted with deionized water and examined under the microscope to reveal that the microbubbles were spherical, discrete, and contained a gaseous core.
A 6% aqueous solution was prepared from a 25% solution of USP grade human albumin by dilution with deionized water. Ion exchange resin ( AG 501-X8, BioRad Laboratories) was then added to the solution at a ratio of 1.5 gm resin to 1.0 gm dry weight of albumin. After 3 hours the resin was removed by filtration and the pH of the solution was adjusted from 4.65 to 5.5. Separately, 0.41 gm d-1 lactide (0.69 dL/gm in CHCl3: at 30° C.) and 5.63 gm cyclooctane were dissolved in 37.5 gm isopropyl acetate. The organic solution was then slowly incorporated into 25.0 gm of the prepared albumin solution with mild stirring while the mixture was maintained at 30° C. The resulting coarse o-w emulsion was then circulated through a stainless steel sintered metal filter element having a nominal pore size of 7 microns. Recirculation of the emulsion was continued for 8 minutes. The emulsion was then added with stirring to 350 ml deionized water maintained at 30 C. and containing 1.0 ml of 25% gluteraldehyde. During the addition, the pH of the bath was monitored to insure that it remained between 7 and 8. Final pH was 7.0. Low shear mixing was continued for approximately 2˝ hours until the isopropyl acetate had completely volatilized. Polyoxamer 188 in the amount of 0.75 gm was then dissolved into the bath. The resulting microbubbles were retrieved by centrifugation and washed 2 times in an aqueous solution of 0.25% polyoxamer.
Microscopic inspection revealed hollow spherical polymer microbubbles having an outer protein layer and an inner organic liquid core. The suspension was formulated with a glycine/PEG 3350 excipient solution, then lyophilized. The resulting dry cake was reconstituted with deionized water and examined under the microscope to reveal that the microbubbles were spherical, discrete, and contained a gaseous core.
Microbubbles were prepared in a manner similar to Example 7. After centrifugation, 4 ml of the microbubbles containing cream (approximately 11 ml total yield) was resuspended in 31 ml deionized water. To this was added a 10 ml solution containing 0.3 gm methoxy-peg-NCO 5000 and the pH was adjusted to 8.7. The mixture was allowed to react at room temperature with mild agitation for 4˝ hours. At the end of this period the pH was measured to be 7.9. The microbubbles were retrieved by centrifugation and washed 2 times in a 0.25% solution of polyoxamer 188. The suspension was formulated with a glycine/PEG 3350 excipient solution, then lyophilized. The resulting dry cake was reconstituted with deionized water and examined under the microscope to reveal that the microbubbles were spherical, discrete, and contained a gaseous core.
Albumin coated microbubbles were prepared in a manner similar to Example 7 with the exception that 0.20 gm paraffin was also dissolved into the organic solution along with the polycaprolactone and the cyclooctane.
Microscopic inspection of the finished microbubble suspension revealed spherical particles having a morphology and appearance virtually identical to those prepared without the addition of paraffin.
During a patient examination, the physician injects a bolus of microbubble pressure agent intravenously. Using the ultrasound scanner, the physician images the chambers of the heart, primarily the left ventricle. With the scanner focused within the left ventricle and electrocardiogram (ECG) leads attached to the patient, the physician sets the scanner in Power Doppler (Doppler Decorrelation) mode. The ultrasound scanner is set-up to trigger based on ECG input, with the trigger point near to or at the end of diastolic cycle. The intensity of the image is correlation to the ambient pressure by way of a predetermined response of the microbubble agent. The resultant image intensity, when compared to the predetermined response, yields the end diastolic left ventricular pressure. This information is especially useful in determine cardiac ejection fraction which is a measure of the output of the heart.
Patent Citations
Non-Patent Citations
Referenced by
Legal Events
Original Image


text:
Nike Kids Power Tank Top (Little Kids/Big Kids)SKU: #8066932
Black/Black/Black/Matte SilverFusion Red/Fusion Red/White/Atomic PinkGeranium/Geranium/Matte SilverUrban Lilac/Urban Lilac/Matte SilverWhite/White/White/Matte Silver
Product Information
- Nike Kids Girls' Size Chart
- Hit the court with strength and style thanks to the tennis-ready Nike® Kids Power Tank Top!
- Dri-FIT™ high-performance polyester fabric wicks perspiration away from your body and towards the surface where it can evaporate.
- Scoop neck.
- Sleeveless.
- Strategically placed mesh back panel helps to quickly vent excess heat.
- Flat-seam construction reduce chafing and increase comfort.
- Straight hem.
- 92% polyester, 8% spandex.
Mesh: 86% polyester, 14% spandex.
- Machine wash cold, tumble dry low.
- Imported.
- Measurements:
- Length: 22 in
- Product measurements were taken using size LG (14-16 Big Kids). Please note that measurements may vary by size.

subset: commoncrawl


text:
People tend to check in during these times:
Add hours
Only ok when drunk.
Get the $4 deal. Two slices any topping, large drink, and your choice of two breadsticks or a pepperoni roll.
Get the large pizza..and get the $3 take out deal..it's a great deal and it's a great pizza!
If you're looking to watch (or participate in) some drunken antics while enjoying pizza, then look no further: you've found the social epicenter of a weekend night in State College.
Gotta be super drunk... Get the ranch. You'll need it
Tell the counter girls they are gorgeous and then tip them $2. But whatever you do, don't ask for their number, many have tried and failed...
Never eat during the day or sober.
Always good to cure your pizza cravings. Pizza is ALWAYS better during the off hours, not when the line is out the door late nights on the weekend!
Stick with the classic. You can't beat a $1 slice of cheese pizza. Not only is the pizza good, but can more than likely reconnect with some friends there as it is a hotspot on the weekends!
Cinnamon stix are awesome after a full chelsea pizza... I'm gonna destroy a bathroom in the morning.
This pizza sux donkey dick tonight! You guys have been around for ever, come prepared with more than just cold cheese pizza you bitches!!!
Order General Tso's Chicken Pizza. Another delicious treat!
Try the BBQ and Buffalo Chicken pies. Best in the house!
Order the taco pizza. It is delicious.
Great pizza after a long night at the bars!
Can't complain too much. $4.00=2 slices, breadsticks & a soda. However, I threw away half of each slice. It wasn't very good. Probably great when you're drunk.
Nothing can go wrong with a $1 cheese slice.
This place is known for only being good while drunk...so I mean take that as you will
Great bread sticks. Cheap as hell too. Get one for 50¢ or like twelve for $3.50. The ranch is great, but stay away from it when Canyon is full of drunk college kids. I've seen them spit in it.
Awesome pizza. The only place for pizza !!!@@!
It's hard to live across the street from a place like this and not cave into my late-night cravings!
Ask to speak to the grand master pizza chef whose father was killed by ninjas. If you are privileged to his graces, bow before him and scream, "I'm not worthy!" This chef's name is Alex.


text:
Soundtrack Artists Lyrics
Overview / Lyrics (see all) / Photos / Videos / News
Going Nowhere Lyrics
(No other information is available for this lyric - would you like to add something today?)
show more
Edit | show less
What chart rank did the song debut? What is the song about? Has it won any awards?, etc.Cancel Submit
Thank You
Your introduction will appear once it has been deemed awesome by our team of wizards.
Featured Video
What's That Line? Misheard Lyrics From Some of Music's Biggest Artists
What's That Line? Misheard Lyrics From Some of Music's Biggest Artists
Latest News
Artist Gallery
Hot Songs
- Top Lyrics
- Featured Lyrics
- Latest Lyrics
- All Falls Down Lyrics by Kanye West
- Escape Route Lyrics by Paramore
- Roman Holiday Lyrics by Nicki Minaj
- What's My Name Lyrics by Rihanna
- In Your Eyes Lyrics by Inna
- I'll Be There Lyrics by Tiffany Evans
- Gorgeous Lyrics by Kanye West
- Fly Lyrics by Nicki Minaj
- Your Love's A Drug Lyrics by Leighton Meester
- Dead Flowers Lyrics by Miranda Lambert
- What About Us Lyrics by Saturdays
- To Love Somebody Lyrics by Michael Buble
- Beauty And A Beat Lyrics by Justin Bieber
- I Need A Doctor Lyrics by Eminem


text:
StartUpHire is the place to find Director, Marketing - Society6 jobs. Review the list of Director, Marketing - Society6 career opportunities to the left. These Director, Marketing - Society6 jobs represent some of the most rewarding careers available.
You can refine your job search for Director, Marketing - Society6 career opportunities by adding a job title, company name, or keyword to the search box above … or click the "Advanced Search" link for more options.
Don't see the employment opportunity you're looking for? Check back soon for more Director, Marketing - Society6 jobs, or sign up for an email alert (link below) to receive periodic updates on new Director, Marketing - Society6 jobs.
Perfect opportunity for brand builders and product marketers with an entrepreneurial mindset who are excited about Consumer Products and getting in at the stealth stage of a venture-backed startup.2/20/2015 New York, NY Save This Job
The Director, Marketing Automation will play an influential role within AppNexusâ growing Marketing team. In this role, you will partner with the senior management team to provide both strategic leadership of direct marketing initiatives and hands-on execution of marketing3/15/2015 New York, NY Save This Job
Marketing Sunnyvale, CA Azul Systems is an innovative software provider serving global enterprises with Java runtime products. Azul?s marketing team is responsible for designing, developing, implementing and managing a wide array of programs ranging from Sales enablement and2/18/2015 Mountain View, CA Save This Job
Marketing San Francisco, United States You're the voice to our customers and products Director Marketing Operations DocuSign is the Electronic Transaction & Signature Management leader and global standard for signing anything, anytime, anywhere, on any device. We have3/23/2015 San Francisco, CA Save This Job
Company Overview Relypsa, Inc. is a late clinical-stage pharmaceutical company leading the discovery and development of novel non-absorbed polymeric drugs for important applications in cardiovascular and renal diseases. Relypsa's lead product candidate is patiromer, a3/16/2015 Redwood City, CA Save This Job
Aternity is seeking a well-rounded, hands-on marketing professional to develop, implement, and manage critical lead generation campaigns designed to reach Global 2000 companies for both North America and EMEA, while also being responsible for running and resourcing partner3/10/2015 Westborough, MA Save This Job
Who We Are Aras is a fast growing, rapidly expanding global company that provides advanced Product Lifecycle Management (PLM) software solutions to business customers worldwide including Motorola, XEROX, Honda, GE, Kawasaki and more. Learn more at www.aras.com & apply online3/16/2015 Andover, MA Save This Job
Location: Menlo Park, CAType: Full TimeMin. Experience: Manager/Supervisor The (Sr) Director of Marcom & PR will report to the Vice President of Marketing, and will be responsible for the corporate brand, corporate positioning and messaging, PR and analyst relations, and social1/24/2015 Menlo Park, CA Save This Job
Location Corporate - Richardson, TX 75080 US (Primary) Job Type Full Time Job Description The Director of Marketing is responsible for managing both the people and projects of HRsmart?s worldwide marketing efforts. This includes web site design and presentation, branding efforts,2/14/2015 Richardson, TX Save This Job
The Boston city marketing manager is a key team member who will join a driven and excited team of a quickly expanding, awesome startup!3/12/2015 Boston, MA Save This Job
The Downtown Alliance seeks an ambitious and driven sales professional to serve as the Membership and Sales Director for LMHQ (Lower Manhattan HQ). LMHQ will be a cutting edge, 12,500sq ft. space for collaboration, events and networking.3/3/2015 New York, NY Save This Job
The Director of Product Marketing will be instrumental in driving the company's global go-to-market planning and execution for this rapidly growing segment that is projected to eclipse 3 billion in the next four years. The ideal candidate will have3/19/2015 Santa Clara, CA Save This Job
Marketing Operations Specialist Job Description: The Marketing Operations Specialist is a key position responsible for optimizing our data, systems, Salesforce.com information and processes; supporting demand generation efforts; providing2/26/2015 Waltham, MA Save This Job
We are looking for a leader and visionary to lead the growth of the company. The Sr. Director of User Acquisition will be responsible for orchestrating global marketing strategies across the portfolio. This person will play an essential role in the succesSan Francisco, CA Save This Job
The CRM Database Marketing Manager will be responsible for developing integrated marketing campaigns and lifecycle marketing strategies to increase member lifetime value among buyers.3/11/2015 Brooklyn, NY Save This Job
The Integrated Marketing Specialist will help coordinate and develop creative brand campaigns that bring Etsy to life, generate brand awareness, build loyalty, and attract buyers and sellers.3/21/2015 Brooklyn, NY Save This Job
TrackMaven, the competitive intelligence platform for digital marketers, is hiring an SDR Director in our Washington, DC office.1/25/2015 Washington, DC Save This Job
The Impact You'll Have at RPAs a Regional Sales Director at Return Path you're tasked with leading a team of Regional Sales Executives to meet large revenue goals for a specific region in North America. A great candidate has managed3/23/2015 New York, NY Save This Job
As a key member of the North American Market Strategy team, you will be responsible for pipeline fulfillment and effective collaboration with our marketing, research, and field sales teams.2/21/2015 Austin, TX Save This Job
TrackMaven, the competitive intelligence platform for digital marketers, is growing incredibly fast and seeking to hire our first full-time recruiting professional, a Director of Talent Acquisition.1/25/2015 Washington, DC Save This Job


text:
Big Apple buzzmaker Zak Downtown has come together with The DJBooth to bring fans his latest street release, mini-mixtape Always Down Vol. 1.
The project features four reader-approved records originally released as part of the underground emcee's Always Down August digital series: "Catch Me," "Yellow Diamonds," "Girl Like You" and "Do It Forever."
Booth fave Donnis makes the sole guest appearance on Always Down Vol. 1, which features production by Baauer, DJ Fresh Direct, Yellow Claw and Yung Felix .
Written by richard on Aug 29, 2012
Submit your Rating
Related Songs & Features
First DJ Booth Appearance:
"Rock The Show" (2011)
Total DJ Booth Features:
12 Songs
Commentsblog comments powered by Disqus
DJBooth TV
Discover the best new songs, videos, and albums added to the Booth.


text: POPSUGAR Celebrity POPSUGAR Celebrity Robert Pattinson by Celebrity 6/22/09 0 Shares Like us on Facebook Previous Photo 1 of 33 View on One Page ADVERTISEMENT ( more slides) Next Share This Link Copy 1 Robert Pattinson Previous Photo 1 of 33 View on One Page ADVERTISEMENT ( more slides) Next Get the scoop with our daily newsletter Enjoy the latest news on the celebs you love. Movies Young Hollywood A Listers TV Sign up with 5 years I LOVE HIM. CUTE. I LOVE HIS SUNGLASSES bugsbrat 5 years been watching some of his interviews on youtube and he really is a genuine, sweet kind of guy. i hope he stays that way! 5 years He's so adorable. Cuddly, non threatening but also very very sexy . lovexpeacexhope 5 years Awwwwwwwwwwwwwww sweet lovexpeacexhope 5 years Awwwwwwwwwwwwwww sweet Debie 5 years I love smily Rob :) Debie 5 years I love smily Rob :) Link Love Ryan Phillippe talks about his youthful appearance — Us Weekly Paula Patton on "becoming an adult" after split from Robin Thicke — ET Hilary Duff shares what she got for her 12th tattoo — Gossip Girl This PLL star understands your Tinder struggles — HuffPost Celebrity Christina Aguilera's fiancé is reportedly angry at this Jonas brother — OK! This famous pop star was missing from Jay Z's Tidal launch — Lainey Gossip Russell Crowe reveals Michael Jackson used to prank call him — BuzzFeed Scott Eastwood has landed a new movie role — People Have these celebrities lost touch with reality? — Cracked Latest Celebrity


text:
(Editor's Note: Now that farmers' market season is back, we're going to revisit some past Market & Garden radio shows that highlight produce at it's peak.)
[HOST INTRO] Asparagus is at it's peak right now at area farmers' markets. But asparagus season is short. So, in this week's Market & Garden Report, Guy Hand finds out how to make the most of this quintessential, spring vegetable.
Listen Now to the Audio Version of This Story:
Or Download this Episode to Your Computer, iPhone, etc.
(Sounds of market) (Hand) Asparagus is actually an immature fern, a delicacy even the Greeks and Romans loved. And nothing shouts spring louder than fresh asparagus. So I've stopped by the Capital City Public Market to soak up some asparagus wisdom from Jerry Stelling. He runs AC&D Farms in New Plymouth and has asparagus plants that are 20 years old. He knows how to pick great asparagus.
(Stelling) First off you want to make sure that it's not too pliable, but you can kind of bend it a little bit and tell that it's not dried out and that there's actually some firmness and some crispness to it.
(Hand) Stelling gives a spear a little flex test. It bends, but just a bit. Next he looks at the base.
(Stelling)You want to make sure you're not buying three or four inches of white down at the bottom end that's real fibrous and real woody. You wanna have 5, 6, 7 inches of good spear.
(Hand) But don't snap the bottom off before you cook it. That's a wasteful wive's tale. Just cut the white part off. The rest should be tender. Next Stelling checks the top.
(Stelling) If the top looks a little bit mushy, you can maybe give it a little touch and tell that it has already starting to break down. To get to that point, it's either had to be exposed to heat for a while or it's been harvested for probably a week and a half at that point.
(Hand) Let's talk a little bit about the size of the spears. I know that some people really like small spears, some people like large spears.
(Stelling) Well, we eat all of it. Some people prefer larger stuff for grilling for obvious reasons, it's a little bit easier to handle and the smaller spears, some people like them 'cause they steam up really quick.
(Hand) I used to think fat spears were older and therefore tougher, but that's not true. Thick asparagus can be just as young and tender as thin, though you may want to take a vegetable peeler to the bottom part of a thick spear, where the skin can get a little fibrous. But how does Jerry Stelling's family cook asparagus?
(Stelling) We like to put a little bit of butter in a pan and some asparagus on top there, fry it around until it's warmed up and crack some eggs over it. (Hand) That sounds pretty good. (Stelling) Yea, it is. We really enjoy that. Another way, you can steam it . . .
(Hand) There are tons of way's to fix asparagus: grilled, sauteed, even pureed into pesto for pasta sauce. That's really good. But you've only got a few weeks of the fresh, local stuff to work with. That's why I've posted a bunch of recipes at Northwest Food News dot com.
(Hand) For Edible Idaho's Market & Garden Report and Boise State Radio, I'm Guy Hand.
Here are links to recipes and stories on asparagus:
- Asparagus is a Rite of Spring/L.A. Times
- Asparagus-and-Camembert Sandwiches/The Oregonian
- How to Can Pickled Asparagus/Year of Plenty
- Asparagus Pesto/N.Y. Times
And here's Guy's Asparagus and Tuna Pesto recipe (it's great)
- 1 5 -1/2 oz. can good quality tuna in olive oil
- 1/2 cup walnuts or pine nuts (reserving a little for topping)
- 1/2 lemon and grated zest of whole lemon (reserving a little for topping)
- Dash Worcestershire sauce
- Dash soy sauce (optional, but I like it)
- Fistful of tarragon, basil or dill
- Olive oil to taste
- One bunch asparagus
- Blanch trimmed asparagus in salted water until just tender.
- Chop asparagus in half inch sections, reserving heads for topping.
- Put the tuna with its oil, nuts (reserving a few for topping), lemon zest, juice from 1/2 lemon, Worcestershire, soy, tarragon, basil or dill and asparagus (minus reserved heads) in food processor and chop coarsely.
- Add olive oil to taste and to bring mixture to a saucy consistency.
- Adjust seasonings, adding salt and pepper to taste.
- Cook pasta of your choice
- Toss with sauce.
- Top with reserved asparagus heads, pine or walnut pieces and a little grated lemon zest. Drizzle extra lemon juice on top and sprinkle on some good, course salt.
Guy Hand is a writer, public radio producer and photographer specializing in food and agriculture.


text:
Negative Hiv Test Result
Here's a taste of what TheBody.com has to offer on this topic:
Ask the Experts
Can herbs cause a false negative hiv test result?...If you are taking herbs, and then get tested for hiv, is it possible for the herbs to cause a false negative hiv test result?
Response from Bruce Dezube, M.D.
Harvard Medical SchoolNot to my knowledge. Read more »
PCP Diagnosis Despite Negative HIV Test ResultMy boyfriend tested negative for HIV five weeks ago. Last week while away onbusiness he suddenly... Read more »
Will HINI Vaccination casued my HIV test result to be fault negative?Hi Dr Bob,I just read yr Forum regrading to guy who has a HINI vaccination and suspected the result... Read more »
Negative HIV Antibody Test Results Among People Treated During Acute/Early Infection...It is a scenario that keeps the worried well worried: the possibility of a false negative HIV antibody test. Since HIV screening began, it has been acknowledged that false negative results do occur with ELISA assays, Read more »
HIV Results by Phone: Can We Predict Who Will Test HIV-Negative?... To study a requirement that all patients return to the health care setting to learn their HIV test results, the researchers described the number of HIV cases detected at Sydney Sexual Health Center among persons who disclosed no known Read more »
Factors Associated With HIV Testing Among HIV-Positive and HIV-Negative High-Risk Adolescents: The REACH Study...the only factor associated with a greater number of tests, indicating that the appearance of symptoms triggered the need for HIV tests. Yet, because the majority of HIV-positive participants in this study were asymptomatic, many did not pursue... Read more »
California: HIV Tests Negative for Porn Actors Who Performed With "Patient Zero"...first-generation and second-generation exposures there are "due to confidentiality," he said. Hirsh said he will wait for final test results from one of the first-generation performers before Vivid starts filming again. "We are just being... Read more »
Connect With Others
neg. test=hiv neg.?
Posted by Anonymous, 2 Replies...the most experts mean a 6-month-negative hiv-test is conclusive. but I have read some(rare) people take a longer time. you need such people? my question is: I have Read more »
conversion after 12 weeks?
Posted by Anonymous, 1 Reply...can someone go from a negative hiv test result to a positive hiv test result after 12 weeks? and if so, when would that be - 13 weeks -14 weeks - 17 weeks? or a neg is a neg Read more »
Question 4 GmanBill
Posted by Anonymous...I had unprotected sex with a man of unkown status, I am female. I had a negative HIV test result at 14 weeks. I am still very unsure and able to belive my test results because I have now found out that he was a former IV Read more »
Hiv test rules may change
Posted by Anonymous, 2 RepliesI heard that they may change testing guidlines to only include rare cases of blood transmittions. That hiv rates are very low and that thet tesing company is being sued by several people in a class action suite for false claims. Read more »
Resource Centers
Guides for People With HIV


text:
Marlboro Revision Rhinoplasty Doctors and Reviews
Marlboro Revision Rhinoplasty cost
Average cost in US: $8,775
Average cost in Marlboro: $9,025
Marlboro Revision Rhinoplasty reviews
100% of Marlboro reviewers said Revision Rhinoplasty was worth it
"Revision Rhinoplasty 20yrs in Making..."
Ok folks, here's my revision story. Let's start at the beginning….I had primary when I was 17 yrs old by some fancy schmacy surgeon in NYC. It didn't go well considering I woke up multiple times during surgery, was overdosed on meds because of repeated attempts to knock me out and then hospitalized. I was left with a thin bridge, polybeak deformity and bulbous tip. Admittedly, I... more
I was never a big fan of my nose ever since I entered high school. I finally decided to do something about it. In June of 2009 when I was 23 years old, I chose Dr. Andrew Miller to perform my Rhinoplasty. Not only am I extremely happy that I chose to do this procedure, but I'm even more happy that I chose Dr. Miller. He did a FANTASTIC job. He knew exactly what I was looking for during my... more
"Thrilled with my Revision..."
I had a Revision Rhinoplasty with Dr. Robert Glasgold on August 21st, 2013. My experience was amazing. I'm really thrilled with the results. It was more than I even expected and I love it. Going in, I wasn't pleased with the results from my first one, because the previous doctor I went to just didn't listen and do what we had agreed on. He did more than I liked. He over scooped my bridge and... more
"Revision Rhinoplasty - New Jersey"
When I was 14, I had a rhinoplasty to correct a crooked nose. The surgery instead made my nose wider than it originally was before. I was disappointed with the results. Years after surgery, I decided to get revision rhinoplasty to narrow and straighten my nose. I surfed the web to look for a doctor when I came across dr. joseph. He had great reviews so I gave him a call to schedule a... more
Featured Doctors
Revision Rhinoplasty Specialist
Eric M. Joseph, MD
5.0 out of 5 stars 302 reviews
NJ / NY Double Board Certified
Get a consultation, (973) 327-3946 www.ericmjoseph.com
Revision Rhinoplasty Expert
Oleh Slupchynskyj, MD, FACS
5.0 out of 5 stars 220 reviews
Double Board Certified Facial Surgeon
Call Dr. Slupchynskyj (646) 770-3943 www.facechange.org
New Jersey Revision Rhinoplasty Expert
Andrew Miller, MD
5.0 out of 5 stars 84 reviews
Achieve your best aesthetic outcome
Complimentary Consultation (732) 962-6874 www.associatesinplasticsurgery.com
Revision Rhinoplasty Expert
Steven J. Pearlman, MD
5.0 out of 5 stars 48 reviews
Renowned Specialist, Rhinoplasty
Get more info (646) 461-2419 www.mdface.com


text:
will throttle cleaning fix the problem?
View questions for:All Mercury
2003 Mercury Sable
Mercury Q&AAsk Your Question
2003 Mercury Sable Question: new Idle Control Valve installed. still get P1506
tomz215, 3.0L V6 DOHC, Waterbury, CT, May 16, 2013, 10:26
1 Answer
Answer #1pushrod May 16, 2013, 18:50Master
Is it idling ok?? How were codes cleared after IAC install??
Replytomz215, May 18, 2013, 11:02Rookie
disconnected the battery engine light came back on in 40 miles idle is ok..no smoke
Replypushrod, May 18, 2013, 13:38Master
Check wires/connector to IAC. Try cleaning T-body and back side of the throttle plate as well with a toothbrush and flush with clearner, clean IAC passages as well. Start engine to purge cleaner and warm up to operating temp. Disconnect battery for at least 20 min. to reset KAM. Or (keep alive memory)
Answer Ranks
This week's top 10
|1 stevieray1
|6 CharlesAutomotive
|2 pushrod
|7 Hal...
|3 globalhelper
|8 RCMotors
|4 csubak30
|9 wrayauto
|5 ziptie12
|10 raytucker


text:
Changes related to "User talk:Luw134"
From OpenWetWare
This is a list of changes made recently to pages linked from a specified page (or to members of a specified category). Pages on your watchlist are bold.< User talk:Luw134
22 March 2015
|Help:Wiki questions (diff; hist) . . (+638) . . Matthew Todd (Talk | contribs)


text:
A meal and a message
Service for homeless is 'making a difference'
Candi McKee's husband, Dwayne, preached a powerful message at their church. "Do you have the lay-down-your-life kind of love?" he asked the congregation. "Would you give your life for someone who, for instance, is homeless?"
Subscribe to the Times Record News
Ready to subscribe to the Times Record News? Choose between a Premium or Digital subscription below.
Need Help? Call us at 1-877-710-6181.
Monday-Friday: 5:30am-8pm / Saturday: 6am-1pm / Sunday: 6am-1pm


text:
FTB Advisors | Our Team | Middle Tennessee
Vice President,Senior FinancialAdvisor
615-734-6083E-mail Bryan Read Bio
Vice President,Senior FinancialAdvisor
615-790-5058E-mail PhillipRead Bio
Vice President,Financial Advisor
615-734-6080E-mail Joseph Read Bio
Vice President,Senior Planner
615-790-5287E-mail Brian Read Bio
615-790-5168E-mail Lonnie Read Bio
615-300-7436E-mail JamesRead Bio
Senior FinancialAdvisor
615-443-5942E-mail JamesRead Bio
615-896-6659E-mail CarrieRead Bio
615-452-6377E-mail ScottRead Bio
Vice President,Financial Advisor,Corporate RetirementServices
615-734-6012E-mail Ryan Read Bio
615-790-6153E-mail Kevin Read Bio
615-734-6265E-mail MattRead Bio
615-497-7062E-mail DavidRead Bio
615-734-6512E-mail ShariRead Bio
615-849-7672E-mail Leo Read Bio
Vice President,Business andEstate InsurancePlanning Agent
615-574-9222E-mail Chris Read Bio
615-734-6367E-mail RichardRead Bio
931-528-4750E-mail TodRead Bio
About FTB Advisors
One of the toughest aspects of developing a financial plan or an investment strategy is recognizing how your personal style, mindset, and life situation might affect your decisions.
© 2014 FTB Advisors, Inc.
Insurance Products, Investments & Annuities: Not A Deposit | Not Guaranteed By The Bank Or Its Affiliates | Not FDIC Insured | Not Insured By Any Federal Government Agency | May Go Down In Value
Insurance Products and Annuities: May be purchased from any agent or company, and the customer's choice will not affect current or future credit decisions.
FTB Advisors is the trade name for wealth management products and services provided by First Tennessee Bank National Association ("FTB") and its affiliates. Financial planning and trust services provided by FTB. Investment management services, investments and annuities available through FTB Advisors, Inc., member FINRA, SIPC, and a subsidiary of FTB. Arkansas License # 416584. Insurance products available through FTB Advisors Insurance Services, Inc. ("FTBIS"), a subsidiary of FTB. Arkansas License # 247414. In some states, insurance products and annuities are provided by First Horizon Insurance Services, Inc. ("FHIS"), a Tennessee corporation, and a subsidiary of FTB. The principal place of business of FHIS is 165 Madison Ave., Memphis, TN 38103. California License # OD12174. FTBIS, FTB Advisors, Inc., and FHIS may transact insurance business or offer annuities only in states where they are licensed or where they are exempted or excluded from state insurance licensing requirements. FTB Advisors does not offer tax or legal advice. You should consult your personal tax and/or legal advisor concerning your individual situation.
Banking products and services provided by FTB. Member FDIC.


text:
Winnipeg Free Press - PRINT EDITION
Playoff picture clear as mud
Vikings putting the 'wild' into wild-card battle
HOUSTON -- Minnesota Vikings coach Leslie Frazier knows all that's ahead this week, most notably a gigantic regular-season finale at Mall of America Field against the rival Packers with a playoff berth on the line.
"If you were going to write a script," Frazier said, "this is the way you'd want it to be done."
Rebuilding year? Maybe to the outside world.
But now the surging Vikings are 9-6 and in the middle of a wild-card battle royale.
One final weekend remains in the quest to gain admittance into the exclusive postseason bracket, and if the Vikings beat the Packers, they will make the postseason.
Still, in a dark and quiet interview room below Reliant Stadium, Frazier did not want to fast-forward too quickly, still too enraptured by his team's 23-6 destruction of the Texans to give too much thought to next week's win-and-advance showdown with Green Bay.
"We'll deal with that one after 24 hours of jubilation," Frazier insisted. "I don't want to think too far ahead. I want to bask in the glory of this win on the road."
Who could blame the usually tranquil coach for wanting to bounce through the roof? Throughout Sunday afternoon his hungry Vikings delivered so many energizing moments.
There was the 78-yard touchdown march on the first possession, a drive on which Christian Ponder completed all three of his passes for 62 yards, including a 3-yard score to Kyle Rudolph.
Not bad for a newly married quarterback who could have been flustered by a feisty Texans defense. Instead, Ponder (16-for-30, 174 yards, 48 rushing yards) appeared in control much of the day.
"I think not being single has been a plus for him," Frazier joked about his newly married quarterback.
More significantly, Frazier's defense locked with its most dominant effort this season. It wasn't just that the Vikings held Houston to 187 yards and six points -- 22 below its season average -- it's that they played smart, fast and ultra-physical.
There were fumbles forced by Jasper Brinkley and Harrison Smith with recoveries by A.J. Jefferson and Everson Griffen. And there was impressive discipline used to stifle Houston's running attack.
Arian Foster, the AFC's leading rusher coming into the day, managed 15 yards on 10 carries.
"There was a focus on being physical," Brinkley said. "And you have to be hungry. Everybody took the challenge. The d-line got their penetration up front and didn't get reach. And that's the way to shut that zone scheme off."
Still, arguably no play was more important than Fred Evans' third-down sack of Texans quarterback Matt Schaub with a minute left in the third quarter. Houston had driven to the Vikings 1, just missing out on a touchdown when Smith tackled Kevin Walter an instant before he could extend the ball across the goal line. With a quicker reach, Houston could have closed to within 16-13.
Instead, the Vikings dug in on three consecutive goal-to-go plays from the 1, with Evans taking advantage of Kevin Williams' inside push and knifing in to take down Schaub.
-- Minneapolis Star-Tribune
Republished from the Winnipeg Free Press print edition December 24, 2012 C1
Fact Check
Have you found an error, or know of something we've missed in one of our stories?
Please use the form below and let us know.
Having problems with the form?Contact Us Directly
More Football
You can comment on most stories on winnipegfreepress.com. You can also agree or disagree with other comments. All you need to do is be a Winnipeg Free Press print or e-edition subscriber to join the conversation and give your feedback.
You can comment on most stories on winnipegfreepress.com. You can also agree or disagree with other comments. All you need to do is be a Winnipeg Free Press print or e-edition subscriber to join the conversation and give your feedback.
Have Your Say
New to commenting? Check out our Frequently Asked Questions.
The Winnipeg Free Press does not necessarily endorse any of the views posted. By submitting your comment, you agree to our Terms and Conditions. These terms were revised effective April 16, 2010.
- Back to Top
- Return to Football
More Football
(1 of 2 articles for this year)
Let Sam's skill set be deciding factor03/24/2015 3:00 AM 0
The narrative that once told us Michael Sam was not being given a serious shot in pro football because he ...
Photo Store Gallery
Most Popular
- Willy, Blue not running same pattern
- He'd look good in Blue
- Let Sam's skill set be deciding factor
- Fiancee of ex-Patriots player Aaron Hernandez to be called to testify in murder trial Friday
- Seattle Seahawks add 3 assistant coaches to defensive staff
- Judge: Prosecutors to rest murder case against ex-New England Patriot Aaron Hernandez soon
- U of M Bison would love to play for Bombers
- Let's spice it up: NFL likely to make changes to boring extra point conversions for 2015
- Tampa Bay coach says he believes Winston has matured, his problems are behind him
- Peterson standoff: Zimmer says no trade coming, agents says runner wants to play elsewhere
- Willy, Blue not running same pattern
- He'd look good in Blue
- Let Sam's skill set be deciding factor
- Argos GM Barker, coach Milanovich and QB Ray in final year of their contracts
- Demski's blue-chip, but Blue better off drafting hog
- U of M Bison would love to play for Bombers
- Big Bryant a bit of nasty business
- Darren Sharper guilty in Arizona sex assault, pleads no contest in Los Angeles drug-rape case
- Edmonton Eskimos quarterback Pat White announces his CFL retirement
- Bombers introduce 'quiet, tough guy' Bryant
- Stadium owner to sue architect, builder over water drainage, insulation problems
- Willy, Blue not running same pattern
- Blue looking hard at Demski
- He'd look good in Blue
- Bombers introduce 'quiet, tough guy' Bryant
- Bombers sign Millington, Pierre
- Bombers add RB Bradley Randle
- Demski's blue-chip, but Blue better off drafting hog
- Big Bryant a bit of nasty business
- Two legends, one team being inducted into Manitoba Sports Hall of Fame
Ads by Google


text:
For Better or For Worse by Lynn Johnston
- June 05, 2014
- From Beginning
- Previous feature
- Next feature
- Current
Comments (27) (Please sign in to comment)
Yes, that "or so" can definitely be a problem…Big Time… ;)
She'd BETTER be back in that hour… not "or so."
Elly's mental comment tells us this is not the first time Annie has saddled her with her kids and then lied about when she was coming back, especially when she has the car and Steve is downtown (wink wink nudge nudge say no more.) Elly knows that wherever Annie is going and whatever mischief she is up to with Steve gone, it's going to take longer than an hour.
Unfortunately for Elly, Annie's kids are demon children. Fortunately for Elly she has Michael in the house and at age 9, he is just the right age to take on babysitting duties for Annie's kids.
I HATE IT WHEN PEOPLE DO THAT!! My sister always suckers me into watching her niece…I love my niece but still…she gets me every time
Connie is running out for a nooner. So it all depends on what Steve is up to.
Connie maybe running out for a nooner but it was Anne who left the two monsters
There is no reason she can't take the kids with her to get Steve. My mother never dropped us kids (there were four of us) on anyone else. The rare times we had a babysitter, it was because my parents were going out on a "date."
We, men, know what "or so" means too. It means don't expect me until you see me.
except when we were small and my mom had to work and left us with my grandparents, my parents NEVER left us with a sitter. If we couldn't go they didn't go. I also don't remember leaving my kids with a sitter, except for work, more than 3 or 4 times. We just never went out without them. Also my children don't leave their kids with a sitter very often. Maybe once a year.
yes wonder why she couldn't take the kids. an interesting "excuse." lol time away from the kids, maybe?
My stepdaughter used to leave the kids for an hour and disappear for the weekend.
???? 8^(
I've got one to top that. One of my nieces asked my sister to watch one of her children(back when she only had one) as she was going to do some shopping. FIVE YEARS later, she calls, advising that she living in Wisconsin with her boyfriend and would she 'look after' the child for a little while longer while she and the boyfriend 'get on their feet' there and, oh, by the way, she's a
grandmother, again ! ! ! ! ! !
Lynn's Notes:
When I was a teenaged baby sitter, I resented it when the parents who hired me came home late. Having had kids (and now being a grandma) I understand why parents want to stretch their freedom for as long as possible — and often forget the time.
Kids are a lot of trouble.
But, it's the only way you get grandkids!
- Load the rest of the comments (12).
You must be signed in to make a comment.