text:
|Publication number
|Publication type
|Application number
|Publication date
|22 Oct 1996
|Filing date
|1 Jun 1994
|Priority date
|12 May 1993
|Fee status
|Publication number
|Thomas R. Porter
|Original Assignee
|The Board Of Regents Of The University Of Nebraska
|Export Citation
|BiBTeX, EndNote, RefMan
|Patent Citations (2), Referenced by (79), Classifications (7), Legal Events (4)
|External Links: USPTO, USPTO Assignment, Espacenet
This application is a continuation-in-part application of U.S. patent application Ser. No. 08/113,415, abandoned for A METHOD AND COMPOSITION FOR OPTIMIZING VIDEOINTENSITY IN ULTRASONIC IMAGING AND ECHOCARDIOGRPAHY, filed by Thomas R. Porter on Aug. 27, 1993, which is a continuation-in-part application of U.S. patent application Ser. No. 08/057,298, abandoned for A METHOD AND COMPOSITION FOR OPTIMIZING VIDEOINTENSITY IN ULTRASONIC IMAGING AND ECHOCARDIOGRAPHY, filed by Thomas R. Porter on May 14, 1993, which is a continuation-in-part application of U.S. patent application Ser. No. 08/060,751 for A METHOD AND COMPOSITION FOR OPTIMIZING LEFT VENTRICULAR VIDEOINTENSITY IN ECHOCARDIOGRAPHY, filed by Thomas R. Porter on May 12, 1993. All of said applications are commonly owned.
This invention relates to a new and improved ultrasonic contrast agent and to its manufacture and use in ultrasonic imaging and echocardiography. More particularly, the contrast agent of this invention relates to the sonicated microbubble type, but is unique in that it makes possible the non-invasive visual detection of myocardial uptake, as discussed more fully hereinafter. In addition, the contrast agent of this invention makes feasible safe and consistent, non-invasive methods for visually assessing, qualitatively or quantitatively, not only myocardial perfusion, but renal and hepatic perfusion, and for detecting severity of coronary arterial stenosis.
Ultrasonic imaging is used as a diagnostic tool to aid in therapeutic procedures. Ultrasonic energy is produced by generating and receiving sound waves with an ultrasonic scanner. Contrast agents which are echogenic are preferentially used to create ultrasonic energy in an area of interest. In ultrasound imaging, videotape images obtained following contrast injection are digitized, allowing the gray scale to be quantified from 1 to 225 gray scale units for 30 cardiac cycles. The contrast intensity is plotted on the vertical axis against time on the horizontal axis. The peak videointensity (corrected for baseline intensity) is determined as the highest point on the time intensity curve. For a discussion of contrast echographic instrumentation, see, for example, De Jong N, "Acoustic properties of ultrasound contrast agents", CIP-GEGEVENS KONINKLIJKE BIBLIOTHEEK, DEN HAAG (1993), pages 120 et seq.
Contrast echocardiography has been used to delineate intracardiac structures, assess valvular competence, and demonstrate intracardiac shunts. Myocardial contrast echocardiography (MCE) has been used to measure coronary blood flow reserve in humans. MCE has been found to be a safe and useful technique for evaluating relative changes in myocardial perfusion and delineating areas at risk.
A multiplicity of potential ultrasonic imaging agents has been reported for contrast echocardiography. It is believed that no such agent routinely attains visually discernible myocardial uptake following peripheral intravenous injection. Although there have been many reports of transpulmonary transmission of ultrasound contrast agents following intravenous injection and despite the fact that myocardial opacification on echocardiogram can be produced by left sided injection of such contrast agents, visualization of myocardial contrast has not been achieved by intravenous administration of sonicated microbubbles.
Most recently, sonicated albumin and sonicated dextrose/albumin have been shown to produce variable degrees of left ventricular chamber ultrasound contrast following intravenous injection. (See Villanueva et al. Circulation 85:1557-1564, 1992; Lin et al. Int J Card Imaging 8:53-6, 1992; Feinstein et al. J Am Coll Cardiol 16:316-224, 1990; Keller et al. Am Heart J 114:570-575, 1987; and Shapiro et al. J Am Coll Cardiol 16:1603-1607, 1990). The microbubbles of these contrast agents are small (4-6 microns) and are capable of swift transpulmonary passage. However, visually discernible myocardial uptake of such microbubbles following peripheral intravenous injection has not been possible because of the rapid diffusion of blood soluble oxygen and nitrogen inside the microbubble into the blood which consequently loses its ultrasound reflective properties (e.g., see Porter et al. J Am Soc Echocard Supplement 7:S1, May 1994, and Weyman AE: Principles and Practice of Echocardiography, Malvern, Pa.: Lea & Febiger, 1994; pp.302-26.)
An important objective of this invention is to provide a contrast agent and methods for its production and use wherein microbubble survival and subsequent myocardial ultrasound contrast is improved sufficiently to make possible visually discernible myocardial uptake of such microbubbles following non-invasive peripheral intravenous injection. This and other objectives of this invention will become apparent in the following discussion.
In accordance with this invention, there is provided an improved ultrasound contrast agent which relies on microbubbles for echogenicity, in which the improvement comprises enhancing the internal atmosphere of the microbubbles with an amount of perfluoropropane which is effective for visually detecting myocardial uptake upon echocardiogram following peripheral intravenous injection of said agent into a host. The perfluoropropane gas content of the microbubbles is sufficient to lower microbubble gas solubility and diffusivity in vivo in blood. Generally, the minimum amount of perfluoropropane gas in the microbubbles which is effective is that amount which results in microbubbles which pass reliably through the pulmonary circulation without collapse. This is evidenced by opacification of the myocardium of the left ventricle of the heart following intravenous injection and can be visually discerned by echocardiography, for example, in accordance with standard methods or the methods described more fully hereinafter.
Consequently, the invention also provides a method of ultrasonic imaging for use in medical procedures, comprising the steps of injecting the unique perfluoropropane-containing microbubbles of this invention into a host to thereby alter the acoustic properties of a predetermined area, and ultrasonically scanning an area including said predetermined area so as to obtain an image of said predetermined area.
Other pharmaceutically acceptable inert gases, such as sulfur hexafluoride, can be used, provided such gases have a diffusion coefficient and blood solubility lower than nitrogen or oxygen, the components of room air. Perfluoropropane (C3 F8) is especially preferred because of its demonstrated safety for intraocular injection in humans. Perfluoropropane has been used in human studies for intraocular injections to stabilize retinal detachments (Wong and Thompson, Ophthalmology 95:609-613) and is useful in treating complicated retinal detachments by providing internal tamponade of retinal breaks. Treatment with intraocular perfluoropropane is considered to be the standard of care for treatment of this disorder. However, it should be apparent to one of ordinary skill in the art that other inert gases with a similar or lower blood solubility to perfluoropropane can be used, provided that they are pharmaceutically acceptable.
Although intravenous echo contrast agents made from sonicated microbubbles are known (e.g., ALBUNEX, Molecular Biosystems, Inc.) and can be employed in this invention, it is preferred to use a sonicated aqueous solution containing a mixture of a pharmaceutically acceptable saccharide, e.g., dextrose, and a protein, e.g., albumin. Generally, sonication is performed in an air atmosphere. In an especially preferred embodiment, dextrose, which is readily available in pharmaceutically acceptable dosage forms, is the preferred saccharide and human serum albumin is the preferred protein. Exemplary of other saccharide solutions of this invention are an aqueous monosaccharide solution (e.g. having the formula C6 H6 O12, such as, the hexoses, dextrose or fructose, or mixtures thereof), aqueous disaccharide solution (e.g., having the formula C12 H22 O11, such as sucrose, lactose or maltose, or mixtures thereof), or aqueous polysaccharide solution (e.g., soluble starches having the formula (C6 H10 O5)n, wherein n is a whole integer between about 20 and about 200, such as amylose or dextran, or mixtures thereof.
In addition to myocardial imaging the contrast agents of this invention are useful for renal and hepatic imaging. Thus, another embodiment of this invention provides a method for myocardial, renal or hepatic opacification. The method preferred involves obtaining an echo contrast agent of this invention, introducing said echo contrast agent into a host by intravenous injection, and performing an echo contrast study on said host using a suitable Doppler or ultrasound echo apparatus as discussed more fully hereinafter.
The method of ultrasonic imaging in which microbubbles formed by sonicating an aqueous protein solution are injected into a mammal to alter the acoustic properties of a predetermined area which is then ultrasonically scanned to obtain an image of the area for use in medical procedures is well known (e.g., see U.S. Pat. No. 4,572,203, U.S. Pat. No. 4,718,433 and U.S. Pat. No. 4,774,958, the contents of each of which are incorporated herein by reference). It is the use of the unique, stabilized perfluoropropane-containing microbubbles of this invention which constitutes a novel improvement. Thus, in accordance with another embodiment of this invention, there is provided a method of ultrasonic imaging for use in medical procedures comprising the steps of forming an aqueous protein solution (e.g., aqueous dextrose albumin), subjecting said solution to high frequency sonication while exposed to perfluoropropane gas, said sonication forming stabilized microbubbles of relatively uniform size, containing said perfluropropane, and capable of transpulmonary passage, and using the stabilized microbubbles as an injectable contrast agent for said ultrasonic imaging.
Sonicated albumin has been used to study coronary flow reserve and immediate post-angioplasty anterograde blood flow reserve in humans. In humans without significant coronary artery disease, left main coronary artery injections of sonicated albumin before and after intracoronary papaverine result in time intensity curves which can be utilized to determine coronary flow reserve. It has been demonstrated that the washout of ultrasound contrast from the human myocardium in this setting correlates with coronary flow reserve measured by more invasive techniques.
Secondly, intracoronary sonicated albumin injections in humans with coronary artery disease, before and after angioplasty, has been done. The functional reserve of the myocardium supplied by the vessel undergoing angioplasty is immediately improved following angioplasty. The degree of improvement depends not on how visually successful the angioplasty was, but on how quantitatively successful the improvement in stenosis area was after angioplasty. Sonicated albumin does not reliably cross the pulmonary circulation into the left ventricular chamber following an intravenous injection, and thus at present cannot be used to non-invasively detect myocardial blood flow.
It has been observed that a microbubble radius decreases as a function of time in a still liquid due to a diffusion gradient present between the internal and external gases of the microbubble. An increase in microbubble size has a significant effect on the persistence of a microbubble within blood. The mean microbubble size of sonicated dextrose albumin ranges from between about 5 to about 6 microns. Since this size is ideal for transpulmonary passage, the major reason for the significant loss in left ventricular and myocardial videointensity produced following intravenous injection is due to the significant diffusion of gases within the microbubble following intravenous injection during transit to the left ventricular cavity. Sonicated dextrose albumin enhanced with an inert gas such as perfluoropropane, having a lower blood solubility than air, produces a significantly higher left ventricular and myocardial videointensity than sonicated albumin alone.
Because of high surface tension, the concentration of nitrogen and oxygen gas within the microbubble is much higher than that in blood, and thus there is a rapid diffusion of this gas into the blood stream following intravenous injection. Wible et al. (Circulation, 88:I-401, 1993) have demonstrated that this diffusion process can be accelerated if one decreased the partial pressure of nitrogen within the blood stream by decreasing the inhaled fraction of nitrogen. This lower external concentration of nitrogen results in loss of the left ventricular videointensity produced by the same intravenous injection of sonicated albumin while inhaling room air. It has also been observed that oxygen rapidly diffuses out of gas bubbles into human blood (See Yang et al., J Biomech 3:275, 1971).
Both nitrogen and oxygen diffuse rapidly across these concentration gradients, but nitrogen appears to dissolve more slowly than oxygen into blood. Since nitrogen is the major component of air, decreasing the concentration gradient for nitrogen across the microbubble improves left ventricular and myocardial videointensity following intravenous injection. Exposing the microbubbles to a non-toxic gas having a lower blood solubility and/or microbubble diffusivity than that of nitrogen and having a gas density of greater than about 0.300 lb/ft3 during sonication increases the size and stability of the microbubbles in sonicated dextrose albumin, while lowering the solubility and diffusivity of the microbubbles in blood.
The contrast agent of this invention, a perfluoropropane-enhanced sonicated dextrose albumin solution is comprised of a sonicated three-fold dilution of 5% human serum albumin with 5% dextrose. During sonication, said solution is perfused with perfluoropropane for about 80 seconds, which lowers the solubility and diffusivity of the microbubble gas. The resulting microbubbles are concentrated at room temperature for at least about 120�5 minutes, wherein the excess solution settles in the sonicating syringe. The excess solution is expelled and the concentrated microbubbles are transferred to a sterile syringe and injected intravenously into a mammal.
Using perfluoropropane to enhance the sonicated contrast agent of this invention will result in a higher degree of myocardial opacification, endocardial border delineation, and enhanced detection of left-sided ultrasound Doppler signals, upon peripheral venous administration. Additionally, using perfluoropropane during sonication creates a more stable microbubble concentration, which subsequently enables ultrasonic visualization of the liver and kidneys following an intravenous injection.
The following examples demonstrate the effect of inert gases on microbubble stability and diffusibility, and the effect of perfluoropropane-enhanced sonicated dextrose albumin on myocardial uptake and videointensity as well as on ultrasonic determination of renal perfusion. In all the following examples all parts and percentages are by weight, unless stated otherwise. All dilutions are by volume.
Albumin (human) USP, 5% solution (hereinafter referred to as "albumin") and dextrose USP, 5% solution (hereinafter referred to as "dextrose") are obtained from a commercial source. The sonicating system used for sonication is a Heat Systems Ultrasonic Processor Model XL2020 (Heat Systems Inc., Farmingdale, N.Y.). The 1/2 inch horn transducer is a resonating piezoelectric device. The 1/2 inch sonicating horn tip is sterilized prior to each sonication.
Sixteen milliliter aliquots of albumin diluted 1:3 with dextrose are drawn up into a 35 cc "Monoject" syringe (Becton Dickinson and Company, Rutherford, N.J.) and sonicated for 80�1 seconds. The "Leur-Lok" of the 35 milliliter syringe is then attached to a stopcock. After mixing the dextrose albumin solution by hand for about 7 to about 10 seconds, the plunger is removed from the top of the syringe. The sterile sonicating horn is then lowered into the open end of the syringe until at the surface of the albumin-dextrose solution. The solution is placed at the horn tip and manually held at this position while continuously sonicating at a frequency of 20,000 Hz and a power output of 210 W for 80�1 seconds to form a stable microbubble solution.
During sonication, the dextrose albumin mixture is exposed to perfluoropropane gas (Commercial Grade, 99.9% by weight). The gas is drawn up into a sterile syringe through a 0.22 μM filter (Micron Separations Inc., Westborough, Mass.) to prevent contamination. During sonication, 5 milliliters of perfluoropropane gas is manually injected into the solution, over the 80 second time interval, through the stopcock so that the microbubbles produced contain this less soluble gas. The total volume of perfluoropropane-enhanced sonicated dextrose albumin produced with this formulation is 25�2 milliliters. These samples are then used for intravenous injection.
Microbubble size and purity is determined using hemocytometry. Microscopic inspection of the microbubbles is performed to determine if any coalescent microbubbles are present in the solution. Microbubble concentration is determined using a Coulter Counter. The contrast agent is rejected for use if any of the following conditions are present: the mean microbubble size is 4.0 to 6.0 microns; coalesced microbubbles or strands are detected by light microscopy; or the mean microbubble concentration is <0.8�109 or >1.5�109 microbubble/milliliter. The sample is also rejected if the number of microbubbles greater than 10 microns in the sample is greater than 4%.
All samples are stored in 35 milliliter syringes until time of injection. All solutions are given within 36 hours of production. All samples are prepared in a laminar flow hood.
Mongrel dogs of either sex (15-30 kilograms) are anesthetized with sodium pentobarbital (30 milligram per kilogram intravenously), intubated, and ventilated initially with room air using a positive pressure respirator. A left thoracotomy is performed under sterile conditions and the pericardium incised. In addition to a 19 gauge peripheral intravenous line, eight French catheters are placed in the femoral artery and vein for intravenous administration of ultrasound contrast agents and pressure monitoring. Through one femoral venous sheath, a 7F balloon-tipped thermodilution catheter is placed in the pulmonary artery using fluoroscopy for determination of pulmonary artery pressure and cardiac output. A 7F pigtail catheter is introduced into the left ventricle for pressure measurements (left ventricular systolic and end-diastolic pressure) following injection of each ultrasound contrast agent.
Following adequate surgical exposure, a 3.5 Megahertz ultrasound transducer connected to a commercially available ultrasound scanner (Hewlett Packard Company; Andover, Mass.) is placed in a warm water bath. The bath overlays the anterior epicardial surface. The transducer is mounted on a clamp and lowered into the bath. It is adjusted until an optimal stable short axis view of the left and right ventricle has been obtained at the ventricular mid-papillary muscle level. These images are then be used to assess left ventricular cavity and myocardial uptake of contrast following intravenous injection.
Five open chest dogs were given incremental intravenous injections of perfluoropropane enhanced sonicated dextrose albumin (PESDA), produced as hereinbefore described, in doses of 0.02, 0.04, 0.06, 0.08 milliliter per kilogram (ml/kg). During intravenous injection, pulmonary artery pressure, left ventricular end-diastolic pressure, systolic pressure and cardiac output were monitored. Myocardial peak videointensity was measured using a 3.5 Megahertz epicardial transducer. Mean transit time of the contrast agent and half-time of contrast washout were also measured. Table 1 demonstrates that myocardial peak videointensity increased linearly with increasing dose of intravenous PESDA (r=0.65, p<0.0001).
TABLE 1______________________________________Doseml/kg PAP LVSP CO MPVI______________________________________0.02 21.3 � 3.8 105 � 11.3 2.4 � 0.5 7.6 � 6.80.04 23.3 � 4.6 103.5 � 9.5 3.1 � 0.9 17.9 � 9.80.06 24.1 � 4.0 102.7 � 8.5 3.0 � 0.9 22.2 � 10.90.08 28.0 � 3.5 102.2 � 8.7 2.9 � 0.8 25.5 � 10.7______________________________________ PAP = pulmonary artery pressure; LVSP = left ventricular systolic pressure; CO = cardiac output; MPVI = myocardial peak videointensity;
Visible myocardial opacification was seen in 100% of the 0.04-0.08 ml.kg intravenous injections. Table 1 demonstrates that low doses of PESDA produce consistent, visual myocardial opacification following intravenous injection; the degree of myocardial opacification is linearly related to the dosage; and, PESDA causes minimal hemodynamic changes and has physiologic washout times. PESDA is, therefore, a novel contrast agent which can non-invasively detect myocardial perfusion.
Six open chest dogs were given 0.06 milliliter per kilogram (ml/kg) intravenous injections of perfluoropropane-enhanced sonicated dextrose albumin (PESDA), prepared as hereinbefore described. A total of 45 intravenous injections of PESDA were given in the eight dogs. Myocardial peak videointensity was measured and quantified using a 3.5 Megahertz epicardial transducer connected to a commercially available ultrasound scanner (Hewlett Packard Company, Andover, Mass.). Coronary blood flow was measured using a Transonic Doppler Flow Probe placed around the proximal left anterior descending artery. Cardiac output was measured using thermodilution. Table 2 demonstrates that there is a significant correlation between myocardial peak videointensity and coronary blood flow.
TABLE 2______________________________________ # con- secutive Average Average IV injec- Average CBF CODog # Dose tion MPVI (cc) (L)______________________________________1 0.06 3 13 17 1.9 ml/kg2 0.06 2 41 40 4.0 ml/kg3 0.06 2 34 28 2.9 ml/kg4 0.06 2 14 21 2.3 ml/kg5 0.06 2 29 21 3.1 ml/kg6 0.06 2 16 17 3.0 ml/kg______________________________________ IV = intravenous; MPVI = myocardial peak videointensity; CBF = coronary blood flow; CO = cardiac output
Visually evident myocardial opacification was seen with PESDA following all intravenous injections. Multiple linear regression analysis demonstrated that MPVI correlated closest with coronary blood flow and not cardiac output. The myocardial PVI produced by intravenous injections of PESDA correlates with coronary blood flow over a wide range of flows and pathophysiologic events. This new ultrasound contrast agent, therefore, may be utilized to non-invasively quantify coronary blood flow in a wide variety of coronary diseases.
Five dogs were given 0.06 milliliter per kilogram (ml/kg) intravenous injections of perfluoropropane-enhanced sonicated dextrose albumin (PESDA), produced as hereinbefore described. A total of 26 intravenous injections were given. Renal imaging and qualitative contrast enhancement were performed during the intravenous injections using an external 4.5 Megahertz linear array transducer connected to a commercially available ultrasound scanner (Hewlett Packard Company, Andover, Mass.). Renal artery blood flow was monitored using a Transonic Doppler probe around the renal artery. Ultrasound enhancement was qualitatively graded as "0"=no enhancement, "1+"=mild, "2+"=marked enhancement. Renal artery stenosis was induced at certain periods to decrease renal artery blood flow to less than 10% of baseline in order to determine a correlation between contrast and renal artery blood flow.
TABLE 3______________________________________ Average IV Average PRCV inject. Average RABF following QualitativeDog # dose PRCV (ml) RAS enhancement______________________________________1 0.06 n/a n/a n/a 2+ ml/kg2 0.06 15 n/a n/a 2+ ml/kg3 0.06 16 53 n/a 2+ ml/kg4 0.06 28 117 9 2+ ml/kg5 0.06 24 121 11 2+ ml/kg______________________________________ IV = intravenous; PRCV = peak renal cortex videointensity; RABF = renal artery blood flow; RAS = renal artery stenosis; n/a = not available.
Following all 26 intravenous injections of PESDA, there was a 2+ contrast ultrasound enhancement of the renal cortex. The results in Table 3 demonstrate that renal artery and cortical blood flow abnormalities can be detected using intravenous PESDA. These results also demonstrate that PESDA can be utilized to non-invasively detect renal artery stenosis or other causes of abnormal renal perfusion.
Six open-chest dogs were given 0.06 milliliter per kilogram (ml/kg) intravenous injections of perfluoropropane-enhanced sonicated dextrose albumin, produced as hereinbefore described. Injections were given at baseline, within fifteen (15) minutes of ligation of the proximal left anterior descending artery (LAD), and after the LAD blood flow was restored. Ischemia was attained by ligating the LAD with silk or umbilical suture. The artery was clamped for a variable time interval and then released. The duration of ischemia was 10 minutes to 160 minutes. LAD blood flow was continuously monitored with a Transonic Doppler flow cuff. Myocardial peak videointensity (MPVI) was determined following each intravenous PESDA injection. Table 4 demonstrates that quantitatively evident contrast was seen in the anterior myocardium at baseline.
TABLE 4______________________________________ MPVI at MPVI at MPVI atDog # Baseline Ligation Reperfusion______________________________________1 18 1.7 332 16 2.0 363 14 1.0 404 40 1.0 625 14 3.7 406 29 3.0 45______________________________________ MPVI = myocardial peak videointensity
Table 4 demonstrates that intravenous PESDA can identify acutely ischemic and reperfused myocardium non-invasively. This new agent significantly improves the ability to rapidly identify whether coronary patency has been achieved following mechanical or pharmacologic revascularization.
Six dogs were each given two equivalent quantities of two different samples of 0.08 milliliter per kilogram (ml/kg) intravenous injections of PESDA. One sample (PESDA-AM) was mixed with 2 milligrams (mg) of Aminophylline (AM) prior to sonication and another was sonicated without AM (PESDA). Myocardial peak videointensity was measured from the anterior myocardium using a 3.5 Megahertz epicardial transducer. Cardiac output was measured following each intravenous injection using thermodilution technique. Mean pulmonary and left ventricular systolic artery pressures were monitored during intravenous injection and coronary flow was measured using a Transonic Doppler flow cuff around the left anterior descending artery. Table 5 demonstrates the ability of this subtherapeutic dose of Aminophylline to enhance the contrast effects of PESDA.
TABLE 5______________________________________ CO LAD CF LVS MPA MPVI______________________________________PESDA 3.2 � 0.8 33 � 13 103 � 11 24 � 5 21 �alone (L/min) ml (mm Hg) (mm Hg) 12PESDA - 3.5 � 1.0 34 � 18 104 � 11 24 � 5 30 �AM (L/min) ml (mm Hg) (mm Hg) 12*______________________________________ *p<0.0001(paired t test) CO = cardiac output; LAD CF = left anterior descending artery; LVS = left ventricular systolic pressure; MPA mean pulmonary artery pressure; MPVI myocardial peak videointensity; L/min. = liters per minute; mm Hg = millimeters of mercury; ml = milliliter.
A 0.04-0.08 milliliter/kilogram injection of the sonicated dextrose albumin produced as described in Example 7, is given intravenously over 3-5 seconds followed by a 10 milliliter normal saline flush. (The dose range is patient-specific: large patients may require slightly higher doses to produce equivalent left ventricular contrast effects). All patients receive a 0.04 ml/kg dose as the initial injection. If this fails to produce myocardial opacification, a 0.08 ml/kg dose is then given. The dose which produces myocardial opacification and improved detection of abnormal wall motion and left ventricular ejection fraction is used to determine myocardial blood flow by contrast echocardiography performed using the standard technique described in Weyman, Arthur E., "Principles and Practice of Echocardiography", Lea & Febiger, Malvern, Pa. (1994, 2d Edition) and using the commercially available Hewlett Packard Sonos 1500 Phased Array Imaging System (Hewlett Packard, Andover, Mass.). Throughout the echocardiographic procedure, the patient's heart rate, blood pressure and oxygen saturation are monitored and recorded. The peak videointensity (corrected for baseline intensity) in the left ventricular cavity and myocardium for each injection is obtained.
For most ultrasound imaging, the contrast agent of this invention is formulated in a pharmaceutically effective dosage form for peripheral intravenous administration to the host to be imaged. Generally, such host is a human subject, although other mammalian hosts, such as canine or equine, can be imaged equally effectively. For preparation of the dosage forms of the contrast agents of this invention, generally, a sonicated mixture of commercially available albumin (human), USP, solution (generally supplied as 5% or a 25%, by weight, sterile aqueous solutions), and commercially available dextrose, USP, for intravenous administration are employed. This mixture is sonicated under ambient conditions, i.e., room air, temperature and pressure, and is perfused with perfluoropropane or other commercially available inert gas (99.9% by weight) during sonication.
Generally, USP dextrose is commercially available as 5% up to 70%, by weight, aqueous solutions; 5% dextrose, injection, USP being preferred. Upon peripheral venous administration of the contrast agent of this invention to a subject to determine myocardial blood flow and peak myocardial videointensity by echocardiography, optimization of myocardial uptake and left ventricular videointensity is attained.
The contrast agents of this invention can be produced by first preparing a solution of human serum albumin diluted with a dextrose solution. Thereafter, small and persistent echogenic contrast agent microbubbles are produced by sonicating the solution in room air with exposure to perfluoropropane during sonication. These bubbles appear to be the source of the echo contrast effect. Thus, the method employed for producing these bubbles must be capable of producing bubbles of sufficiently small size to pass through the microvasculature, yet large enough to permit effective echocardiographic visualization of the left ventricular myocardium and ultrasonic visualization of the liver and kidneys. Sonication by ultrasonic energy causes cavitation within the dextrose-albumin solution at sites of particulate matter or gas in the fluid. These cavitation sites eventually resonate and produce small microbubbles (about 4 to about 7 microns in size) which are non-collapsing and stable.
It has been demonstrated that a microbubble concentration of greater than 4�108 /ml and microbubble size range of 5-6 microns are preferred for obtaining optimum left ventricular videointensity. However, the contrast agents of this invention, using a mixture containing suitable quantities of albumin and dextrose sonicated in the presence of perfluorpropane in accordance with the methods of this invention, produce the critical microbubble concentrations and enhanced myocardial uptake, which can be correlated with myocardial blood flow. Such concentrations are believed to be unique and critical to obtaining the equally unique echocardiographic properties demonstrated hereinafter. In general, and as discussed more fully hereinafter, sonication conditions which produce concentrations of greater than about 4�108 /ml of between about 5 and about 6 micron microbubbles are preferred.
During sonication, the solution is perfused with perfluoropropane, which has a lower gas diffusion coefficient and blood solubility than oxygen and nitrogen, to modify the internal gas composition of the microbubble. Perfusing the contrast agent with the gases of this invention during sonication, to produce more stable microbubbles, results in a significantly improved transpulmonary passage, myocardial uptake and left ventricular chamber uptake, when compared with a similar sample of sonicated albumin alone. This has three very important clinical implications. First, by improving myocardial and left ventricular uptake compared to sonicated albumin alone, the perfluoropropane-enhanced dextrose/albumin combination improves myocardial opacity and makes possible not only the qualitative echocardiographic detection of myocardial uptake and perfusion after an intravenous injection, but also enable echocardiographic quantification of myocardial perfusion. Such quantification is comparable to state of the art nuclear imaging, but without the need for radiation. Secondly, formulation with dextrose permits administration of the mixture by a non-invasive intravenous pathway. Thirdly, the use of dextrose solutions to dilute scarce and expensive human serum albumin, reduces contrast agent cost.
In one embodiment of this invention, a contrast agent is provided, consisting essentially of a sonicated mixture of about a two-fold to about a five-fold dilution of sterile human serum albumin, preferably a commercially available 5% by weight aqueous solution, with about 5% by weight aqueous dextrose, said contrast agent being in a pharmaceutically effective dosage form for intravenous injection.
In a preferred embodiment of this invention a multifold dilution of aqueous albumin with between about 5% and about 50% by weight of aqueous dextrose solution is employed. Excellent results have been achieved when the contrast agent is sonicated (in accordance with the procedures hereinafter described) for at least about 80 seconds and concomitantly exposed to perfluoropropane for at least about 5 seconds during sonication.
In another embodiment, the microbubbles of this invention are produced by sonication under conditions which optimize myocardial uptake and videointensity. In a preferred embodiment, the microbubbles are exposed to gaseous conditions which improve microbubble stability, decrease microbubble gas solubility and diffusibility in blood, and subsequently increase myocardial uptake. Consequently, highly preferred is an echocardiographic contrast agent comprising a sonicated mixture of between about a two-fold and about a five-fold dilution of human serum albumin with aqueous dextrose, exposed during sonication to a pharmaceutically acceptable gas of this invention.
In yet another embodiment, the sonicated microbubble solution is concentrated to enhance transpulmonary passage and myocardial uptake of the contrast agent. Consequently, highly preferred is an echocardiographic contrast agent in a pharmaceutically effective dosage form, enhanced with a pharmaceutically acceptable inert gas which lowers microbubble gas solubility and diffusivity in blood, and having a microbubble concentration of greater than about 5�108 /ml, capable of producing a peak myocardial videointensity which correlates quantitatively with coronary and myocardial blood flow.
Another embodiment of this invention relates to an improved method and composition for determining hepatic and renal perfusion using the ultrasound contrast agent of this invention.
As will be discussed hereinafter, in accordance with this invention, it has been found that an approximately two-fold to five-fold dilution of albumin with dextrose, sonicated under a room air atmosphere and perfused with a pharmaceutically acceptable inert gas, such as perfluoropropane, and administered intravenously, results in the best myocardial uptake and videointensity of any of the contrast agents investigated to date.
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|Roy Harris
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|5 Jan 2004
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|Tom Francke
|Examination method and apparatus
|25 Feb 2005
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|Thrombolytic agents and methods of treatment for thrombosis
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|Targeted site specific drug delivery compositions and method of use
|U.S. Classification
|424/9.52, 600/458
|International Classification
|Cooperative Classification
|European Classification
|2 Sep 1994
Owner name: BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA, NE
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:PORTER, THOMAS R.;REEL/FRAME:007118/0303
Effective date: 19940824
|21 Apr 2000
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text: Hi Sorry as this may be a simple question but im hoping for a little bit of assistance if anyone can help. Ive noticed that any text created in adobe illustrator no matter what format it is saved in seems to never look 100% crisp. Im creating a logo which is just based on pure text in different fonts. Within illustrator as an ai file or when saved as a tiff or jpeg the colour and outline to the text never looks 100% sharp. Any help will be appreciated. Thanks

subset: commoncrawl


text:
Donald Trump tweets a motive for 'voter fraud' claim
This morning, President Donald Trump finally offered a motive for his insistence, contrary to all evidence, that he lost the popular vote in November because of massive voter fraud:
I will be asking for a major investigation into VOTER FRAUD, including those registered to vote in two states, those who are illegal and….
— Donald J. Trump (@realDonaldTrump) January 25, 2017
even, those registered to vote who are dead (and many for a long time). Depending on results, we will strengthen up voting procedures!
— Donald J. Trump (@realDonaldTrump) January 25, 2017
"We will strengthen up voting procedures!" being the key phrase.
Alternative facts are popping up all over the place. A purported Trump administration wish list of infrastructure projects that included the Savannah port's expansion project is fake, according to Politico.
McClatchy reported Tuesday afternoon that the document amounted to a dream list of 50 projects, totaling at least $137 billion, that would be prioritized should Congress approve funding for a $1 trillion infrastructure package on which Trump campaigned.
Included on the initial list was the $706 million project to deepen the Savannah port from 42 to 47 feet. Georgia is seeking $440 million from the feds over several years to help foot the bill.
But Politico Pro on Tuesday evening quoted a former member of the Trump administration's landing team at the Department of Transportation, who questioned the list's authenticity.
Some of the 50 projects included were not seeking federal funding. At least one project, the Gateway Program to overhaul rail traffic around New York City, did not have an accurate cost estimate listed.
The White House later confirmed to your Insiders that the document did not come from them.
The Marietta Daily Journal reports that an aide to U.S. Sen. Johnny Isakson sat down with representatives of 70 protesters who crowded his local office on Tuesday.
A 25-year-old Atlanta author penned a $50 book riddled with inaccuracies about President Donald Trump that was pulled from the National Museum of American History's gift shop after The Washington Post revealed a raft of problems with the text.
It was written by Brandon Christopher Hall, who told the Post he wasn't surprised it landed a place in the Smithsonian Institution's gift shop on inauguration weekend to appeal to the Republican's supporters.
His book said Trump "took the fall for what should have been the fault of Hillary Clinton" when addressing the current president's challenges to Barack Obama's citizenship. The book denied the Russians had any role in hacking the Democratic National Committee's computers. And it said Clinton won the popular vote by 200,000 ballots — not the nearly 3 million edge she had.
Our assessment following Tom Price's second Senate confirmation hearing? Certainly choppy waters for the Roswell GOP congressman, but he's seemingly well on his way to being confirmed.
His support among Republican senators appeared to hold following a tense and testy hearing before the Senate Finance Committee, which is what truly matters at this point. Read our summary here.
If you haven't had the chance to see this Netherland response to President Donald Trump's inauguration, now's your chance:
View Comments 1
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my Aunty Mackenzie just got a new black Infiniti G Convertible IPL only from parttime off a
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Well at least it has taken our minds off his golden showers
Baron dekalb-
Dole received 46% of the white vote. Clinton- 44%. Nice try. This was the highest since Jimmy Carter who won 48% of the white vote in '76.
I never said I had proof and I doubt I will ever obtain proof considering i am a normal citizen. Go back and read my post. For a party who has not won the white vote (majority) in many years it seems oddly convenient that Clinton won the popular vote out of a state with 6 million illegals and no voter id laws. If you think your own parties politicians are not just as crooked and corrupt as the other party you are sorely mistaken.
What Kellyanne Conway meant by "alternative facts" was that she disputed the alleged facts being asserted by the interviewer. Trump was accused of a "provable falsehood" about a topic (the size of the inauguration crowd) which is not rigorously tabulated. The news media simply showed a photograph selected from an angle that made the crowd look small. Trump (with his usual hyperbole) was saying that from his angle on the podium, the crowd looked much bigger.
There is no way of knowing how many non-citizens voted, because courts have overturned every attempt to verify the citizenship of voters. But there is a videotape of President Obama urging non-citizens to vote, assuring them that no one is going to check. With 20 million illegal immigrants in this country, and with Democrats up to and including President Obama urging them to vote, 3 to 4 million illegal votes is probably a low estimate.
@duke14 Sorry, but ignorance (feigned or otherwise) is NOT the new normal in this country.
The news media showed an aerial photograph taken at the same angle and at the same time of day at both inaugurations. It was Trump that attempted to refute by showing a photograph taken at a much lower angle. You, just like Kellyanne Conway, are attempting to circulate lies (alternative facts).
DemoCRAPS always find ways to cheat in every election. DemoCRAP nominee killary was SUCH A BAD CANDIDATE THAT EVEN THEIR CHEATING (in the primaries they cheated Bernie Sanders) COULD NOT GET KILLARY ELECTED !!!!
Good. The voter rolls need some serious review and overhaul, especially in states that both offer drivers licenses to illegals and perform "motor voter" registrations. This is a loophole big enough to drive a truck through. We also need to scrub convicted felons from the voter lists.
Only LAW-ABIDING CITIZENS should be voting...period.
@Don't Tread You're basically asking us to take your word for it that this is a legitimate problem, which is not enough. Come back when you have some proof, otherwise stop throwing this red herring around as if it's something real. "Voter fraud" has been investigated and found to be a negligible influence on election results. You are trying to discredit the process as a distraction from and denial of Trump's failure to win any kind of a "mandate" from the voters this past November.
@Don't Tread felons who have done their time should be allowed to vote. sorry.
Dems haven't won the white vote in 50 years. The Dems lost millions of Obama voters that switched to Trump. The state that housed these 3.7 million votes is a state that has no voter id laws and is known to house around 6 million illegal immigrants.
Trump wants to put jobs back in Americans' hands, make our country more secure, pledging to give the power back to the people, ask people to work instead of standing around having kids out of wedlock with their hands out whining about how life isn't fair, what a terrible person.
@dawgfacedboy too funny . . . what happened 50 years ago?
@dawgfacedboy More whites voted for Bill Clinton in 1996 than for Dole. That wasn't 50 years ago. And if you have some proof of voter fraud in California or elsewhere, please, by all means, provide it... so far you and your unethical president are all talk, no facts...
@Baron_DeKalb @dawgfacedboy I think you mean all LIES, no facts...
Dole received 46% of the white vote. Clinton- 44%. Nice try. Which was the highest since Jimmy Carter who won 48% of the white vote in '76.
I never said I had proof and I doubt I will ever obtain proof. Go back and read my post. For a party who has not won the white vote (majority) in many years it seems oddly convenient that Clinton won the popular vote out of a state with 6 million illegals and no voter id laws. If you think your own parties politicians are not just as crooked and corrupt as the other party you are sorely mistaken.
Please help, when was the last time democrats won anything of significance?..........8 ,9 15 years ago?
hmmmm, that's still less time that it's been since the GOP actually governed. Get on it. That, or continue to let O'Reilly give Donald his marching orders from the teevee.
@TrueFan1 Well there was WWII and the Great Depression... when Trump starts WWIII and bankrupts the country you'll probably want us to pull your chestnuts out of the fire again.
@TrueFan1 Oh yeah, I almost forgot that we also won the popular vote by 3 million votes in this last election... now remind me, how many confirmed cases of voter fraud did you say that y'all were able to track down?Steve Bannon Is Registered to Vote in Two States (Update: So Is Tiffany Trump) http://nymag.com/daily/intelligencer/2017/01/steve-bannon-is-registered-to-vote-in-two-states.html?mid=facebook_nymag
President Trump will not pander to minorities who think they are entitled....John Lewis (the racist) raping his constituents of money by scare tactics.....Trump is president......got to love it
@Tealiban_Party @TrueFan1 ok,,,,minorities would like to hear you.....maybe in" your world" trump is not president.....and about john lewis......well, he is not running my district........thank god......lets pray
@TrueFan1 More #AlternativeFacts brought to you by the Drumpf brownshirt
@TrueFan1 @Tealiban_Party Trump may be President, but he is certainly not presidential nor a leader.
Sounds like Donald is advocating getting rid of the Electoral College. If everyone 18 and older had a SINGLE vote, tied to your social security number and status, then we wouldn't have to worry about people registering in multiple states. Let the states worry about registration and locations for congressional district purposes.
@Tealiban_Party get your hearing checked
Lmao, voter fraud. What a joke
Says the liberal loon
You don't know me lol
Like Bannon. He got busted.
There is no voter fraud according to the democrats but the Russians put lies in Hillary's mouth, a server in her bathroom, then erase her emails.
@DS GASP!!!!! A leftist newspaper says "there is nothing to see here"?!?!?!?!?!?!? Jokes that Republicans are full of crap?!?!?!?!?! Well I didn't see that one coming!!!!!
Press: The Russians hacked the election. The election was a fraud. (even though the DNC doesn't actually run the election.)
Trump: There was a lot of voter fraud.
Press: Voter fraud (feigned indignation)? We demand proof.
Trump: I'll start an investigation.
Press: That's not the proof we demand.
Donald states that he knows there was fraud . . . but his peeps claim they need to investigate to find out for certain.
Donald lies. He doesn't know squat. He thinks, but he thinks this only because he LOST the popular vote and that makes him . . . well, Sad.
This ain't going to go well for the Demonrats. Already 3 millions illegal votes have been discovered for Hillary. And that was without a serious investigation. Curbing voter fraud will cut the Demonrats off at the knees. Now the Demonrats will resort to their favorite techniques, whining and lying.
Trump himself represents a much greater threat to our country's integrity than non-existent "Democrat voter fraud"
U.S. downgraded to flawed democracy for the first time
i'm thinking the investigation is more about the failures of conservatives to engage in fraud. he did lose the popular vote you know. his people were slacking.
I like that Trump is pissing everyone off.......He keep throwing these tidbits out there so you all can whine and moan while real stuff is getting accomplished.......Nice to see a President with a real backbone back in office. Obama was making the jellyfish look bad
@TrueFan1 so you like the alpha male bluster. good for you. got any idea of what they're doing besides trying to bully and belittle their 'enemies', i.e. fellow Americans? yeah, didn't think so.
@TrueFan1 if by pissing people off, you mean wasting tax money on frivolous investigations.....then ok, i'm pissed, but laughing.
@consumedconsumer @TrueFan1 nope , just trying to piss you off....got to like it
@TrueFan1 Are tidbits the new "Alternative Facts" i.e. LIES?
@Can'o'corn @TrueFan1 yep , keep laughing, it's your tax dollars he is spending......
@Tealiban_Party @TrueFan1 yep, ( I could be giving you a tidbit)
@TrueFan1 @Tealiban_Party Sorry I don't swing that way.
@Tealiban_Party @TrueFan1 don't tell your other liberal friends that
@Can'o'corn @TrueFan1 Yep, "the real stuff is getting accomplished"--"The Democracy Index has downgraded the U.S. from a full democracy to a flawed one, marking the first time the nation has fallen into the lower ranking. Other flawed democracies include Botswana, India, Japan and Ghana, while much of Western Europe stayed in the full democracy category."
@TrueFan1 And how many MILITARY DEFERMENTS did your "macho man" of a president take in order to get out of going to actually fight (not just bluster and tweet)? Two? Three? Four? NO, it was FIVE.
"Backbone"? Please! The man is a petulant child.
@TrueFan1 and yours...but at least i know i didn't vote for this.
and doesn't like to pay those who do do an honest day's work for him . . .
@TruthReallyHurts @TrueFan1 Never done an honest day's work in his life
@consumedconsumer @TrueFan1 So you liked Obama who championed illegal immigrants, non vetted refugees and radical Islam ...All while styling his mommy jeans.
[…] visit main article […]


text:
A BRAVE acid attack victim has revealed the twisted low-life who scarred her permanently has pulled out of their meeting.
Adele Bellis 24, from Suffolk, had her ear burnt off two years ago by coward Jason Harrison, 29, who was paid to carry out the depraved assault by her controlling ex-boyfriend.
Speaking with the Sunday Mirror, the former beautician said that the sick convict sent her a letter last year demanding a meeting to apologise.
However, Adele says that the thug has now refused to meet her and will be released from prison early next year.
She said: "I thought his letter was genuine. Now I can't help thinking it was all lies. He only wrote the letter so the judge would give him a shorter sentence.
related stories
PARENTS PLEAMum of missing schoolboy 'desperate' for his return after learning he chatted to stranger night before vanishing
HUNT FOR LADFears grow for missing Manchester schoolboy, 11, who vanished on the way to class early this morning
"He'll be out in March, free to move on with life, while I've been left with no ear and half a head of hair. It's really upsetting."
Last month, Adele returned to the place where the acid was thrown on her, leaving her without an ear and scarring to her face, neck and hand.
She went back to the bus stop where she was attacked using sulphuric acid, to put up a giant poster for her new book.
The book, titled Brave, tells her story in a bid to help other women recognise the signs of domestic abuse and seek help.
Her ex-boyfriend, Anthony Riley, 26, had abused her in the six months leading up to the attack at the bus stop near her home in Suffolk.
He was jailed for life after he paid accomplice Harrison to throw acid on her in August 2014.
One year on from the attack she told The Sun on Sunday: "He wanted my face and he didn't get that, I still have it and I'm still here.
"He couldn't beat me then and I won't let him beat me now."
We pay for your stories! Do you have a story for The Sun Online news team? Email us at email@example.com or call 0207 782 4368


text:
Equipments And Tools Used For Proposed Copper Mining In Tanzania
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text:
Investment Habits Of Filipinos
I have observed hundreds of emails, ads and even faxes explaining the virtues of penny stocks. The incredibly lowest priced stocks are known as penny stocks." These providers may well have little or no earnings. Do your own analysis and due diligence, never ever letting one particular persuade you to get a stock simply due to the fact they claim they did their research and all you have to do is to get what they you say (or whatever their software tells you). If you are young and saving for a extended-term purpose such as retirement, you may possibly want to hold additional stocks than bonds.
So you invest in penny stocks and take advantage of a potentially profitable opportunity to study much more about the market. With the rush of oil value the last handful of years, numerous investors are searching to oil penny stocks also identified as oil tiny cap stocks, nano stocks, or micro stocks. But stock costs move down as well as up. There's no assure that the business whose stock you hold will develop and do properly, so you can lose income you invest in stocks. For making a relative get from these stocks, you should think dealing with a handful of of the higher performing stocks.


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Pfc.Raheen Tyson Heighter
- Date of passing: Jul 24, 2003
|Let the memory of Pfc.Raheen be with us forever
22, Bay Shore, N.Y.; assigned to the 2/320th Field Artillery, Fort Campbell, Ky.; killed when his convoy came under enemy fire north of Hawd, Iraq, on July 24. Pfc. Raheen Tyson Heighter recently wrote to his mother from Iraq, saying he was fine and urging his family not to worry. "Time goes by like a continuous Groundhog Day over here," he wrote in a letter dated June 20. "In the beginning, there was a lot of bloodshed, but now it's all over. The good news is I will be coming home in September — October at the latest." Heighter was one of three soldiers killed July 24 when their convoy was ambushed. He was stationed at Fort Campbell, Ky. "He was a good boy and a phenomenal talent," his uncle Ron Adams said. "He would display his work at arts festivals. No matter what he was doing, he aspired to be be
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Vulcan Bomber: Return to the Skies Trailer (2007)
"Return to the Skies" 15 June 2007 Factual, War 45 mins
During the Falklands War, a team of Vulcan Bombers staged the longest bombing raid ever attempted. We tell the amazing story of the machines that undertook the near impossible mission of bombing Port Stanley. The programme features archive footage spanning the Vulcan's entire dramatic history, including newsreels, amateur video and film shot by the pilots themselves. We also make use of an enormous array of archival sources, including the plane's original design specification, and orders for construction from the War Office.
Watch the official Vulcan Bomber: Return to the Skies 2007 trailer in HD below or find more Vulcan Bomber: Return to the Skies videos on Vidimovie.


text: Question: Craig- Recetly bought a cabin in the woods. Previous owner had a wood stove in the basement but took it with them. The wall behind where the stove was located is natural stone and after they took the stove out apparently- water came down the chimney and has badly stained the stone. We have tried many different remidies with no good results. It looks awful and sure would like to get it off. Help!! Answer: Can be tough - but try:Mr. Muscle Oven Cleaner or Speedy White (available at many Hearth and fireplace stores)...some people say theyÕve had good luck with baking soda and water paste.


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Wenger Sea Force Mens Dive Watch - Black Dial - Bracelet - 200m - Date
Durable and dependable. The Sea Force is equipped with a 200 meter water resistance, perfect for recreational diving or those who spend a lot of time in the water. Its classicdesign take it from the water to the office any time.
- Stainless steel case and bracelet
- Swiss RONDA 515 Quartz Movement
- Date display
- Sapphire coated crystal
- Unidirectional rotating bezel
- Screw down crown
- Water resistant to 200 meters (660 feet)
- 43mm case width (approximately 1 3/4 inches)
Princeton Watches is an Authorized Wenger watch retailer, your watch will include an original 3 Year Manufacturer Warranty from Wenger.
In stock items ordered by 4pm Eastern time ship the same day.
All orders $50.00 or more qualify for FREE UPS Ground delivery. Watch orders $149.00 or more qualify for FREE UPS 2nd Day Air delivery. Please note that FREE 2nd Day Air Delivery does not apply to clocks.


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Georgie Boy Could Return Next Month
Georgie Boy, a three-time graded stakes winner and Kentucky Derby Presented by Yum! Brands (gr. I) contender before suffering an injury in late March, has resumed training and is being pointed towards a return to the racetrack in October, his owner-breeder George Schwary said Sept. 19.


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WS-Comp Internet service Internetwerbung is an advertising agency of Frankfurt, Germany dedicated to the positioning of sites through SEO and SEM strategies with extensive experience in optimizing sites and search engine positioning. \n
Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.
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Morrison set to leave Robins
Highly-rated Swindon defender Sean Morrison is set to leave the County Ground, says boss Danny Wilson.
Last Updated: 15/01/11 11:09pm
Highly-rated Swindon Town defender Sean Morrison is set to leave the County Ground.
Robins boss Danny Wilson has confirmed the news, with Skysports.com having revealed earlier this week that Reading were lining up a move for the 20-year-old.
Wilson also confirmed the club have received one firm bid for striker Charlie Austin and he hopes to bolster his squad with new recruits during the window.
The Swindon boss told the club's official website: "We can't look back and cry over spilt milk (concerning Morrison).
"We managed to keep Sean at the club for another twelve months and the chairman did a great deal at that time.
"However once the vultures started to circle there wasn't a lot more we could do to keep him here."
Regarding potential new recruits, he said: "We will look after the weekend and see what is available.
"It is obvious that we need to strengthen the side and whilst we don't have money to throw around, there is a chance that we could pay a fee for one or two.
"We have seen what's happened here over previous years. After all the good work that has gone on we certainly won't be 'going for broke' and leave the club in jeopardy.
He added: "Progress has been made here and whilst we are very frustrated with the way things have gone of late, we have to stick together and move forward as a group and not individuals."


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4605 Brunswick Street, Bakersfield CA, 93307 (Residential)
Sold Price:
3 beds , 2 Full baths
1,510 sqft
Status: Sold
Last Updated: 11/22/2017 4:23 PM
Description for 4605 Brunswick Street Bakersfield, CA 93307
Charming 3 bedroom 2 bath Single Family home is 1,510sqft. on a 7,405sqft. Lot. 2 car garage built in 1969. Perfect for first time home buyer or investment property.
Sold Price:
Sold Date:07/29/2015
2 Full
1,510 (approx)
Charming 3 bedroom 2 bath Single Family home is 1,510sqft. on a 7,405sqft. Lot. 2 car garage built in 1969. Perfect for first time home buyer or investment property.
Listing Information
Public Water Service
Sewer at Street
Room Information
Living Room
Interior Features
Central Air
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2 Garage Spaces, 2 Parking Spaces, Garage
Curbs Walk
Financial Considerations
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Bakersfield Real Estate
Bakersfield is located in California. Bakersfield, California 93307 has a population of 373,640.
The median household income in Bakersfield, California 93307 is $56,842. The median household income for the surrounding county is $48,574 compared to the national median of $53,482. The median age of people living in Bakersfield 93307 is 30.2 years.
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I was born in St Andrews Hospital, Billericay in 1954.
Trevor Savage
First of all we lived at Maplemead, at the Bottom of Bell Hill on the Southend Road. My earliest memories are in the back garden and playing toy cars with Peter Pinsion on the front step. After my sister Hazel arrived, we moved to Kennel Lane with a Large Garden and views over the fields with horses and a stream looking towards the Essex Union Hunt foxhound kennels. Tales can be told of playing in the stream on the footpaths across the field. In the middle of the field called Buckinghams field off Kennel lane, on the opposite side of the road to the kennels, there was a small anonymous brick building consisting of a tall brick enclosure topped with barbed wire. For several years during our youth we tried find out what this building was used for and to gain access we eventually found a way of climbing the wall. However it remains a mystery what this small partially roofed brick enclosure was for. The most peculiar part was that in the centre of the open yard was a thing similar to a wooden bird table.
My first school was Billericay Infants in Laindon Road, now The Fold Arts Centre. My first teacher was Mrs Arthy with a yellow reading book "Here we go" and spelling word cards. Our first class room was in what is now the pottery room and we then moved up to Mrs E Williams in the room that is The Fold's performance space. I can remember that our class as late as 1959 used slate and chalk to work out sums, do words and of course pictures. We then moved to Mrs R Williams class and I recall she was always angry. We had horrible school dinners in the prefabricated dinner hall and for some reason there always was the radio playing the latest tunes like "Charlie Brown" by The Coasters. We climbed on the climbing frame in the summer and also a sports day. If I was in luck and dad was not at work I got a lift on his cross bar home instead of the long walk. Thankfully the new South Green School at the end of our road eventually opened under the headship of Mrs Scot Farthing and I switched schools and was in Mrs Pennels Class. Progressing as each year came along through Mrs Phelps (nee Miss Clowes), Mr Ryan, Mr McGuinley & finally Mr Ryan. My mum tells me that Mr Ryan said to her, on parents evening for 2nd year juniors, that if she could read my writing and tell him what I had written he would give me a mark for it but my writing was impossible. The school had annual Eisteddfod which was instigated by Mrs Scott Farthing, as both she and Mr Ryan were Welsh. This festival included poetry speaking and story composition, arts and crafts of all sorts and various types singing, music and cookery. One year I was first for singing and second for baking a victoria sponge jam sandwich; Mrs Scott farthing said I was the "singing chef" and I won a prize. We played shinty on the Playground as there was no playing field and we went swimming via contract coach at the baths at Hutton Poplars near Brentwood. Each year, as well as regular lectures by our local policemen, the school was visited by the Essex Police road safety bus, a very old double decker which had a cinema upstairs. We used to lark about when it came because if you touched the body work of the bus you got a mild electric shock; the bus had a mains supply plugged into the school for the cinema projector to work etc. and there must have been some sort of earthing problem
At South Green school I first met the girl who still is my wife.
After I was eleven I went to Billericay Secondary School.
I have written about my time with 4th Billericay scouts on another page, A Scouting Career. After Scouts I joined 2393 Billericay Squadron Air Training Corp; Squadron Leader Ferris was in Charge with Flying Officer Hiscox and Warrant Officer Dave Burley. Apart from flying and training in Gliders and Chipmunk aircraft at Cambridge and rifle shooting at Rainham Marshes annual camps were organised. I remember camps at RAF Ouston near Newcastle upon Tyne and RAF St Mawgan near Newquay in Cornwall, there is a Squadron photograph taken at the St Mawgan camp in the book of the Billericay School History.
The trip to St Mawgan
I moved away from Billericay down to Basildon in 1975.
I thoroughly enjoyed these recollections, particularly linked to 2393 ATC - my husband knew all characters mentioned. This group of young men (and now ladies) are still going and thriving - superb organisation for young people.
Just read recollections. Glad to hear you enjoyed 2393 sqn, I joined in 1980. Great time, and went on to join the RAF. I grew up on Scrub Rise off Laindon Road. Thanks 4 memories.
Hi Trevor, I was in 2393 with FLT Ferris et al and in fact was at St. Mawgan with you. I'm the 3rd from the left front row. After a leaving school spent a bit of time in RAF but didn't like it much! After many adventures am now a Boeing 737 captain at Stansted. Still visit family in Billericay. Great days.
I went to South Green School then onto Billericay School. I lived in Grange Road, South Green - best years of my life. Now living in Pitsea for my sins. lol
Can anyone settle an argument. What year did south green primary school open?
I believe South Green primary school was built in 1963. I lived at no.12 Hickstars Lane and the school in that road was being built just as we moved out in 1963. Before that it was a corn field.
Pat Ebdon, I remember you well, I was then Teresa Evans.
I have just found this link to a photo of the police road safety bus I mention in my article:- http://www.sct61.org.uk/mf94
Billericay History > http://www.billericayhistory.org.uk/


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OpenFOAM(intro/advanced) & Paraview training course 2012
In collaboration with the
Centre for Scientific Computing (Technical University Braunschweig),
move is announcing OpenFOAM and Paraview training courses
in Berlin and Braunschweig (english and german language):
German language courses:
08.-09.10.2012: Introductory OpenFOAM course in Braunschweig
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English language courses:
03.-04.12.2012: Introductory OpenFOAM course in Berlin
05.12.2012: Paraview training in Berlin
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Benefit from early booking discounts!
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For further information or customized courses
visit our web page or contact us directly.
|All times are GMT -4. The time now is 00:26.


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This press release came in from the Lou Correa for Congress campaign. Santa Ana, CA– Bao Nguyen is not a true progressive. He has made a career out of promising one thing to voters, but then immediately abandoning his principles the moment it becomes personally or politically expedient to do so. That's why it is not…
Tag Archive for Progressive Values
Voices From Street Corners: 2012 Quite a Year Already
by Mike Pouraryan •
Thinking about the state of leadership in the country right now I recalled this thought from Sergio Marchionne, CEO of Fiat and the Chrysler Group: "…. Leadership is not a quantitative thing…people either smell it in you or they don't…People need to trust you that you're going to pull them out and they will follow you when you pull them out. If they don't get that comfort, they're going to drop you.
Voices From Street Corners (Vol 22): What a Summer….
by Mike Pouraryan •
It has been an absolutely tumultuous and exciting summer, to say the least. As kids go back to school, I reflected upon the Summer as I had the good fortune to hang out with my Son throughout the Summer. For me, the climax of the Summer was when I escorted my Son to the "Rule The Pool"…
Voices From Street Corners (Vol.13)
by Mike Pouraryan •
Throughout the past few weeks, I have been "on the road" and looking to check on the voices I have had the pleasure and good fortune to meet. Surprisingly enough, I had not seen them for the longest time. As I thought about them, I hope they were able to get themselves squared away and…
California needs a majority vote budget – and you can help
by Editorial Staff •
From the California Democratic Party's web site at http://www.cadem.org Teachers, firefighters and nurses have launched a petition drive to put a majority vote budget on the ballot in November. Their measure changes the vote requirement to pass a budget from two-thirds to a simple majority and penalizes legislators for failing to do their most important…
Time to run for OC Central Committee seats
by Chris Prevatt •
The California Democratic Party is governed by ordinary citizens who are, for the most part, elected members of Democratic Central Committees from their various counties. Candidates for County Central Committee appear on the June primary ballot, and six members are elected from each Assembly District. The responsibility of Central Committee members is attend a monthly…
Controller John Chiang to Come to OC This Thursday!
by Andrew Davey •
If you can make it to OCYD this Thursday, please do. They'll have a very special guest who knows a thing or two about the state's current fiscal crisis. But don't worry, there'll be lighter moments, too. 😉 Dear Andrew, Young Democrats Meeting With Controller John Chiang We invite you to attend our next Orange…


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You know those ultra fluffy and delicious swiss rolls from Asian bakeries? How good are they! I love the simplicity of it, it's essentially 2 components but they do it so well. I have to say besides the usual flavours like coffee, chocolate, matcha, and even taro, one of my favourite flavours is pork floss, where you have a plain sponge with shallots, and it's filled with a sweet mayonnaise and pork floss (that's sweet, salty, and meaty all at the same time). The best thing is how versatile they are. Once you have a master swiss roll cake recipe, you can make any flavour combination imaginable.
Which is why I've been trying to replicate these swiss rolls at home. For a long time, I've always used a recipe that's quite similar to how you would make a chiffon cake – combine the dry and liquid ingredients, then fold in stiff meringue mixture. The cake itself is fine, it's fluffy like a chiffon, but I've always had to pre-roll the cake while it's still hot so that it doesn't crack later. However, I find that a huge disadvantage of pre-rolling is you end up with a sponge that is slightly deflated, and not as fluffy.
Then, on my hunt for baking books while I was in Taiwan early last year, I came across a book by Takako Inata on swiss rolls.
The swiss rolls in this book looked ridiculously perfect, but it was in Chinese and I unfortunately can't read Chinese. I bought it regardless hoping to have it translated. About a year and a half went by and the book sat on the shelf untouched, until a few weeks ago I finally got one recipe translated.
I was HUGELY sceptical of this recipe, because it calls for a stiff meringue to be made, then yolks whisked into it. This was completely foreign to me, as I thought whisking fat into a meringue was a big no no. The other somewhat different component to this recipe is the addition of thickened cream that had been heated – again, not something I had seen before, but I guess not that different to adding your typical diary ingredients like milk, just with more fat.
Despite my reservations, what I ended up with was an incredibly soft and flexible cake, that was so easy to roll when cold. No pre-rolling when hot, and no cracks when rolled cold!
I really love the flavours in this cake, and without sounding too up myself, I do think this is better than the swiss rolls in the Asian bakeries. Big call I know! But I just love the coffee and chocolate together, and the salted caramel oozing out, and the mascarpone!
I added the meringue purely for decoration really. I don't think it adds anything extra to the cake, just extra sweetness. I think the cake is perfect eaten by itself, and oh by the way, it's better the next day, because the flavours are intensified.
So here's the recipe for what I think is the perfect swiss roll and I hope that it comes out perfect for you too!
p.s. don't be stingy with the salted caramel.
Makes 2 swiss rolls.
Salted Caramel
225g caster sugar
100g unsalted butter, cut into cubes, at room temperature
150ml thickened cream, gently heated so it is warm
2 teaspoons sea salt
Chocolate Sheet Cake
50g plain flour
20g corn flour
20g dutch processed cocoa powder
6 egg whites (room temperature, approx. 180g)
140g caster sugar
6 egg yolks (room temperature, approx. 90g)
60g thickened cream (heated in the microwave so it is warm)
1 teaspoon vanilla extract
Coffee Syrup
2 teaspoons instant coffee
2 teaspoons hot water
2 tablespoons coffee liquor (Tia Maria or Kahlua)
Coffee Mascarpone Cream
125g mascarpone cheese
200ml thickened cream
1 tablespoon caster sugar
1 teaspoon instant coffee
1 teaspoon vanilla extract
Honeycomb (optional)
180g caster sugar
60g glucose syrup
30ml water
7g bicarbonate of soda
Swiss meringue (optional)
3 egg whites (approx. 90g)
135g caster sugar
- Make the salted caramel. In a heavy based saucepan, heat the sugar over medium heat. Swirl the sugar around the pan occasionally to get the sugar melting evenly. As the sugar starts to brown on the edges of the pan, use a spoon or spatula to gently stir the sugar around so the edges don't get burnt. If you get any small hard lumps of sugar, you can turn down the heat slightly, keep stirring and just let it melt. When the caramel reaches a dark amber colour, add the butter, and whisk until incorporated. Pour in the cream, and whisk until smooth. Take the pan off the heat and stir in the salt. Pour into a heatproof bowl or container and leave to cool.
- Make the chocolate sheet cake. Preheat the oven to 160°C (fan forced). Grease and line 2 baking trays with baking paper (I used 22cmx32cm swiss roll pans). Sift the plain flour and corn flour together six times. Then sift the cocoa powder into the flour, and mix until dry ingredients are combined. Place the egg whites in a clean and dry stand mixer bowl, and whisk on high speed until frothy. With the mixer still on, gradually add the sugar. Continue mixing until stiff peaks. With the mixer still on, add the egg yolks, one at a time and mix until well incorporated (not long, about 30 seconds after the last yolk has been added). Fold in sifted dry ingredients using a spatula, followed by the heated cream, and vanilla extract. Divide mixture between trays and level with an offset spatula. Bake in preheated oven for 10-12 minutes. It's really important that you don't over bake the cake, as it will become dry, and more likely to crack when rolled. The cake is ready when it springs back lightly when touched. Once baked, take the trays out of the oven, lift the cakes out of their trays (with the baking paper still attached) and leave on cooling racks. Once the cakes have cooled slightly, cover the top with another piece of baking paper, then cover with cling wrap (you're trying to keep the cake moist as it cools).
- Make the coffee syrup. Dissolve the instant coffee in the hot water. Once cooled, stir in the liquor.
- Make the coffee mascarpone cream. Combined thickened cream with sugar, instant coffee, and vanilla, and whip until stiff peaks. Fold in mascarpone cheese. You want the final mixture to be stiff, and thick enough to spread easily on the cake. If it's too soft, simply whip until the mixture thickens further.
- To assemble. Remove the cling wrap and baking paper from the sheet cake. The cakes should be skin side facing up (the same as when you removed it from the oven). Using another piece of large baking paper, flip the sheet cake on to the new piece of baking paper so that the skin side is now facing down. Peel the original baking paper off the cake, then flip the cake back onto another piece of baking paper so that it is skin side facing up again.
- You will be rolling the cake from the shorter sides. Using a serrated knife, trim the edge of one of the shorter sides of the cake diagonally, so that this side is slanted (like a trapezoid instead of a rectangle).
- Brush the cake with half of the coffee syrup, then drizzle salted caramel over the cake. Be generous and make sure the entire cake is covered. Spread the mascarpone cream over the cake.
- Gently roll the cake, starting with the trimmed edge. Using your fingers to tuck the end in as you roll the cake, away from you. Wrap the roll in cling wrap and keep in the fridge. Repeat with the other sheet cake. When ready to eat or decorate, cut off the ends of the swiss roll.
- Decorate as desired.
- To make the honeycomb (if desired). Line a baking tray with baking paper. Place the sugar, glucose syrup and water in a large heavy based saucepan and cook over high heat until the mixture reaches a caramel colour. Add the bicarbonate of soda and whisk quickly (it will bubble and expand in volume). Pour into the prepared tray and leave to cool. Once cool, break into pieces and store in an airtight container.
- To make the swiss meringue (if desired). Place the egg whites and sugar in a very clean and dry stand mixer bowl. Place the bowl over a saucepan of simmering water, and while whisking, heat until hot to the touch (about 75°C). Remove from the heat and whisk on high until stiff and mixture has cooled to room temperature. It must be used immediately.
Keep the cake refrigerated and it's best served cold (nobody wants to eat warm mascarpone cream!).
The cake is best eaten the next day, to allow the flavours to intensify.
When cutting the cake, use a very sharp knife and wipe the knife between cuts.


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PANDORA Rose™ have finally landed here at Williams and Griffin and we are showcasing the new collection in-store now.
Join us to see this beautiful new collection.
PANDORA Rose™ luminous beauty is expressed in pink. A unique blend of metals have combined to create the feminine, warm look to create blush-hued jewellery.
PANDORA Rose is a delicately hand-finished, the new collection fuses together a unique blend of metals to create a beautiful rose colour.
These stunning new arrivals are guaranteed to bring elegance and warmth to every outfit. Wear together or alongside your Silver Pandora pieces to create a new style for summer.
Discover the luxurious warmth of the Pandora Rose Collection, created from Pandora's own unique blend of metals and plated in blushing pink 14ct rose gold. Delicate florals and vintage glamour create an unforgettable collection which will illuminate every


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Wild parties, late nights, and lots of sex, drugs, and alcohol. Many assume these are the things that define an American teenager's first year after high school. But the reality is really quite different. As Tim Clydesdale reports in The First Year Out, teenagers generally manage the increased responsibilities of everyday life immediately after graduation effectively. But, like many good things, this comes at a cost.
Tracking the daily lives of fifty young people making the transition to life after high school, Clydesdale reveals how teens settle into manageable patterns of substance use and sexual activity; how they meet the requirements of postsecondary education; and how they cope with new financial expectations. Most of them, we learn, handle the changes well because they make a priority of everyday life. But Clydesdale finds that teens also stow away their identities—religious, racial, political, or otherwise—during this period in exchange for acceptance into mainstream culture. This results in the absence of a long-range purpose for their lives and imposes limits on their desire to understand national politics and global issues, sometimes even affecting the ability to reconstruct their lives when tragedies occur.
The First Year Out is an invaluable resource for anyone caught up in the storm and stress of working with these young adults.
"This is an excellent book, with scholarship and writing of the kind that more sociologists ought to be producing. It is exceptional in its longitudinal and qualitative focus on this life-course transition, its fascinating big-picture story, its consistent and understandable plot-line, and its counter-intuitive overturning of big cultural stereotypes about life after high school. Clydesdale's observations about stability and managing daily life tasks are fascinating, and provide important contributions to our substantive understanding of this important piece of social life."--Christian Smith, author of Soul Searching: The Religious and Spiritual Lives of American Teenagers
Christian Smith