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Background Echocardiographic assessment of left ventricular assist devices (LVADs) is used as a screening tool to evaluate the integrity and mechanics of the pump and circuit. We aimed to 1) establish the normal range and upper reference limit of peak velocity of the outflow cannula for the modern era of LVADs and 2) assess the clinical performance of the currently cited and newly proposed reference limits in patients with continuous-flow LVADs as a screening tool for cannula malfunction. Methods LVAD outflow peak CW velocities were measured with the use of Doppler transthoracic echocardiography (TTE) in 57 patients with LVADs (44 with Heartmate II (HM2), 13 with Heartware (HW)). The average velocity and the upper and lower normal reference limits (defined as ±2 standard deviations from the mean) for each LVAD type was calculated. The upper reference limit was then used as a screening threshold for cannula malfunction. Results The average outflow cannula peak velocity for the normal HM2 cohort was 1.86 ± 0.44 m/s with upper and lower reference limits of 2.73 m/s and 0.98 m/s, respectively. The average outflow cannula peak velocity for the normal HW cohort was 2.36 ± 0.53 m/s with upper and lower reference limits of 3.42 m/s and 1.3 m/s, respectively, which was significantly higher than the HM2 cohort ( P = .004). Conclusions In both HM2 and HW LVADs, the average peak outflow velocity and reference limit for the normal population, as measured by Doppler TTE, was markedly higher than the currently used LVAD reference limits of 2 m/s and are significantly different between devices. Patients with peak outflow velocities above our upper reference limits should be evaluated for LVAD outflow cannula malfunction.

Purpose – The purpose of this paper is to use simulation analysis to assess farmer choice between crop insurance and supplemental revenue options as proposed during development of the Agricultural Act of 2014. Design/methodology/approach – The certainty equivalent of wealth is used to rank farm choices and assess the effects of supplemental revenue options on the crop insurance plan and coverage level chosen by the producer under a range of farm attributes. The risk-reducing effectiveness of the select programs is also examined through their impact on the farm revenue distribution. The dependence structure of yield and prices is modeled by applying copula techniques on historical data. Findings – Farm program supplemental revenue programs generally have no effect on crop insurance choices. Crop insurance supplemental revenue programs typically reduce crop insurance coverage at high coverage levels. An individual plan of crop insurance combined with a supplemental revenue insurance plan may substitute for incumbent area crop insurance plans. Originality/value – The analysis provides insights into farmers’ possible choices by focussing on alternative crops and farm attributes and extensive scenarios, using current data, crop insurance plans and programs contained in the 2014 Farm Bill and related bills. The results should be of value to policy officials and producers in regards to the design and use of risk management tools.

The purpose of this study was to investigate the differential impact of the 2 most commonly available left ventricular assist device (LVAD) types on the right ventricle (RV) and left ventricle (LV) using 3-dimensional (3D) echocardiography-based analysis of ventricular morphology.LVADs have emerged as common therapy for advanced heart failure. Recent data suggest that the heart responds differently to speed settings in the 2 main devices available (HeartMate II [HMII], St Jude Medical, Pleasanton, California, and HVAD, HeartWare International, Framingham, Massachusetts). The authors hypothesized that 3D echocardiographic assessment of LV and RV volumes and shape would help describe the differential impact of the 2 LVAD types on the heart.Simultaneous 3D echocardiography, ramp test, and right heart catheterization were performed in 31 patients with LVADs (19 with HMII and 12 with HVAD). Device speed was increased stepwise (8,000 to 12,000 for HMII and 2,300 to 3,200 revolutions per minute for HVAD). 3D echocardiographic full-volume LV and RV datasets were acquired, and endocardial surfaces were analyzed using custom software to calculate LV sphericity, conicity (perfect sphere/cone = 1) and RV septal and free-wall curvature (0 = flat; 0 = concave;0 = convex).For both devices, cardiac output increased and wedge pressure decreased with increasing speed. In HMII, LV volumes progressively decreased (meanΔ = 127 ml) as the LV became less spherical and more conical, whereas the RV volume initially remained stable, but subsequently increased at higher speeds (meanΔ = 60 ml). Findings for the HVAD were similar, but less pronounced (LV:meanΔ = 51 ml, RV:meanΔ = 22 ml), and the LV remained significantly more spherical even at high speeds. On average, in HMII patients, the RV septum became more convex (bulging into the LV) at the highest speeds whereas in HVAD patients, there was no discernable change in the RV septum.The heart responds differently to pump speed changes with the 2 types of LVAD, as reflected by the volume and shape changes of both the LV and RV. Our study suggests that adding RV assessment to the clinical echo-ramp study may better optimize LVAD speed. Further study is needed to determine whether this would have an impact on patient outcomes.

We theoretically examine a farmer's optimal use of area and individual crop insurance when area and individual losses are positively but imperfectly correlated. If premium rates for both plans are actuarially fair,the farmer will demand full individual insurance and no area insurance. If area insurance is free and individual insurance is offered at an actuarially fair rate, area insurance replaces a portion of individual insurance demand. If individual insurance is offered as a wrap around the area plan at an actuarially fair rate and area insurance is free, the farmer will demand excess individual insurance and some area insurance. Copyright 2012, Oxford University Press.

Objectives This study tested whether combined invasive hemodynamic and echocardiographic ramp tests can help optimize patient management. Background Guidelines for optimizing speed and medications in continuous flow ventricular assist device (cfLVAD) patients are mainly based on expert opinion. Methods Thirty-five cfLVAD patients (21 HeartMate II [Thoratec, Pleasanton, California] and 14 HVAD [HeartWare International, Framingham, Massachusetts]) underwent ramp tests with right heart catheterization (including central venous pressure [CVP], pulmonary artery pressure, pulmonary capillary wedge pressure [PCWP], and blood pressure) and echocardiography. Data were recorded at up to 9 speed settings. Speed changes were in steps of 400 revolutions per minute (RPM) for HeartMate II (8,000 to 12,000 RPM) and 100 RPM for HVAD (2,300 to 3,200 RPM) patients. Results Only 42.9% of patients had normal CVPs and PCWPs at their original RPM settings. Going from lowest to highest speeds, cardiac output improved by 0.16 ± 0.19 l/min/step (total change 1.28 ± 1.41 l/min) and PCWP decreased by 1.23 ± 0.85 mm Hg/step (total change 9.9 ± 6.5 mm Hg). CVP and systolic blood pressure did not change significantly with RPM. RPM were adjusted based on test results to achieve CVPs and PCWPs as close to normal limits as possible, which was feasible in 56% of patients. For the remainder, results indicated which type of medical management should be pursued. Conclusions Use of combined hemodynamic and echocardiographic ramp tests in patients provides objective means of optimizing RPM, and has the potential to guide medical management. It remains to be tested whether this strategy has a beneficial impact on quality of life or clinical outcomes.

ObjectivesWe tested the feasibility of real-time three-dimensional echocardiographic (RT3DE) perfusion imaging and developed and validated an algorithm for volumetric analysis of myocardial contrast inflow. The study included three protocols wherein perfusion was measured: 1) in an ex-vivo model of controlled global coronary flow, 2) in an in-vivo model during regional perfusion variations, and 3) in humans during pharmacologically induced hyperemia.BackgroundThe RT3DE technology offers an opportunity for myocardial perfusion imaging without multi-slice reconstruction and repeated contrast maneuvers.MethodsElectrocardiographically triggered harmonic RT3DE datasets were acquired (Philips 7500) while infusion of Definity was initiated and reached a steady state. Protocol 1 was performed in nine isolated rabbit hearts and included three coronary flow levels. In protocol 2, changes in regional perfusion caused by partial left anterior descending artery occlusion were measured in five pigs. In protocol 3, adenosine-induced changes in perfusion were measured in eight normal volunteers. Myocardial video-intensity (MVI) was measured over time in three-dimensional (3D) slices to calculate peak contrast inflow rate (PCIR). In pigs, PCIR was measured on a regional basis and validated against microspheres.ResultsThe RT3DE imaging allowed selection of slices for perfusion analysis in rabbit hearts, pigs, and humans. Administration of contrast resulted in clearly visible and quantifiable changes in MVI. In rabbits, The PCIR progressively decreased with coronary flow (p < 0.0001). In pigs, coronary occlusion caused a 59 ± 26% decrease in PCIR exclusively in the left anterior descending artery territory (p < 0.05) in agreement with microspheres. In humans, adenosine increased PCIR to 198 ± 57% of baseline (p < 0.05).ConclusionsContrast-enhanced RT3DE imaging provides the basis for volumetric imaging and quantification of myocardial perfusion.

We recently developed a new approach for contrast echocardiographic quantification of myocardial perfusion, based on brief interruptions of contrast infusion, which was designed to overcome the limitations of existing techniques. In this study, our technique was initially validated in a series of animal experiments designed to detect regional perfusion variations in vivo. Subsequently, clinical feasibility of perfusion measurements was tested.Regional perfusion was measured transthoracically in 6 anesthetized pigs during baseline, partial left anterior descending coronary artery occlusion, and reperfusion, and validated with fluorescent microspheres. Adenosine-induced changes in perfusion were measured in 8 healthy volunteers. In both protocols, imaging was optimized during contrast infusion (Definity). Infusion was interrupted to allow contrast clearance and images were acquired during subsequent contrast inflow. Myocardial videointensity was measured over time and peak contrast inflow rate was calculated.In pigs, partial coronary occlusion resulted in a 47 +/- 23% decrease in peak contrast inflow rate in the left anterior descending coronary artery perfusion territory (P.05), which was reversed during reperfusion, without concomitant decrease in other perfusion territories. These changes were in agreement with microspheres. In human beings, adenosine increased peak contrast inflow rate to 278 +/- 123% of baseline (P.05).The interruption of contrast infusion technique is a sensitive tool for accurate quantification of myocardial perfusion, which may constitute an alternative to currently used techniques.

Echocardiographic quantification of myocardial perfusion is based on analysis of contrast replenishment after destructive high-energy ultrasound impulses (flash-echo). This technique is limited by nonuniform microbubble destruction and the dependency on exponential fitting of a small number of noisy time points. We hypothesized that brief interruptions of contrast infusion (ICI) would result in uniform contrast clearance followed by slow replenishment and, thus, would allow analysis from multiple data points without exponential fitting.Electrocardiographic-triggered images were acquired in 14 isolated rabbit hearts (Langendorff) at 3 levels of coronary flow (baseline, 50%, and 15%) during contrast infusion (Definity) with flash-echo and with a 20-second infusion interruption. Myocardial videointensity was measured over time from flash-echo sequences, from which characteristic constant beta was calculated using an exponential fit. Peak contrast inflow rate was calculated from ICI data using analysis of local time derivatives. Computer simulations were used to investigate the effects of noise on the accuracy of peak contrast inflow rate and beta calculations.ICI resulted in uniform contrast clearance and baseline replenishment times of 15 to 25 cardiac cycles. Calculated peak contrast inflow rate followed the changes in coronary flow in all hearts at both levels of reduced flow (P.05) and had a low intermeasurement variability of 7 +/- 6%. With flash-echo, contrast clearance was less uniform and baseline replenishment times were only 4 to 6 cardiac cycles. beta Decreased significantly only at 15% flow, and had intermeasurement variability of 42 +/- 33%. Computer simulations showed that measurement errors in both perfusion indices increased with noise, but beta had larger errors at higher rates of contrast inflow.ICI provides the basis for accurate and reproducible quantification of myocardial perfusion using fast and robust numeric analysis, and may constitute an alternative to the currently used techniques.

Background No technique exists for objective evaluation of left ventricular wall motion in contrast-enhanced images. We tested a new technique for quantification of regional fractional area change using contrast-enhanced power modulation imaging with color kinesis. Methods The feasibility of this technique for detecting acute ischemia was first tested in 11 pigs. Next, the accuracy for detecting resting wall-motion abnormalities was determined in 52 patients requiring contrast and compared with conventional interpretation of 2-dimensional images by inexperienced readers. Expert interpretation of 2-dimensional images served as the gold standard. Results In pigs, coronary occlusion resulted in reversible hypokinesis and reduced regional fractional area change. In patients with poor acoustic windows, this technique's accuracy for quantitative detection of resting wall-motion abnormalities was 86% compared with 81% for conventional interpretation by inexperienced readers ( P Conclusions Regional wall motion can be accurately assessed using color-encoded power modulation imaging for patients requiring contrast. This technique may prove a useful diagnostic aid to echocardiographers of varying levels of experience.

Genetic defects in the plasma membrane-associated sarcoglycan complex produce cardiomyopathy characterized by focal degeneration. The infarct-like pattern of cardiac degeneration has led to the hypothesis that coronary artery vasospasm underlies cardiomyopathy in this disorder. We evaluated the coronary vasculature of gamma-sarcoglycan mutant mice and found microvascular filling defects consistent with arterial vasospasm. However, the vascular smooth muscle sarcoglycan complex was intact in the coronary arteries of gamma-sarcoglycan hearts with perturbation of the sarcoglycan complex only within the adjacent myocytes. Thus, in this model, coronary artery vasospasm derives from a vascular smooth muscle-cell extrinsic process. To reduce this secondary vasospasm, we treated gamma-sarcoglycan-deficient mice with the calcium channel antagonist verapamil. Verapamil treatment eliminated evidence of vasospasm and ameliorated histological and functional evidence of cardiomyopathic progression. Echocardiography of verapamil-treated, gamma-sarcoglycan-null mice showed an improvement in left ventricular fractional shortening (44.3 +/- 13.3% treated versus 37.4 +/- 15.3% untreated), maximal velocity at the aortic outflow tract (114.9 +/- 27.9 cm/second versus 92.8 +/- 22.7 cm/second), and cardiac index (1.06 +/- 0.30 ml/minute/g versus 0.67 +/- 0.16 ml/minute/g, P0.05). These data indicate that secondary vasospasm contributes to the development of cardiomyopathy and is an important therapeutic target to limit cardiomyopathy progression.

Although harmonic imaging (HI) improves endocardial visualization and is necessary for myocardial perfusion imaging, it has yet to be implemented in transesophageal echocardiography. Our goal was to determine whether HI implemented in a prototype transesophageal echocardiography probe improved endocardial visualization and allowed perfusion imaging.In 23 patients, fundamental and harmonic images were obtained in the transgastric short-axis (TSAX) and midesophageal 4-chamber views, and reviewed for endocardial visualization by 3 readers blinded to imaging mode. In 14 additional patients, perfusion imaging was performed in the TSAX view during contrast infusion.HI improved overall endocardial visualization, most noticeably in the anterior and lateral segments (P.004) in the TSAX view, and in the lateral segments (P.01) in the midesophageal 4-chamber view. The salvage rate was 8.3% in the TSAX view and 12.6% in the midesophageal 4-chamber view. Myocardial perfusion was consistently confirmed in the inferior (86%), posterior (100%), and lateral (79%) segments, but rarely in the septal (21%), anteroseptal (0%), and anterior (14%) segments.Use of HI with transesophageal echocardiography improves endorcardial visualization and allows partial assessment of myocardial perfusion.

We hypothesized that color-encoded, contrast-enhanced, power modulation imaging could allow simultaneous quantification of myocardial perfusion and regional left ventricular function. We studied 12 anesthetized, closed-chest pigs at baseline, during acute ischemia, and during reperfusion, and 8 patients after acute myocardial infarction. Color kinesis was used to color encode endocardial motion during real-time contrast perfusion imaging with high-energy ultrasound pulses. Wall motion was assessed by calculating regional fractional area changes. Translation-free perfusion analysis was performed in automatically identified myocardial regions of interest. Steady-state intensity and postimpulse rate of contrast replenishment were calculated. In all animals, ischemia caused reversible changes in the images and the perfusion- and function-calculated indices. A significant decrease in pixel intensity (14%) and contrast replenishment rate (66%) in left anterior descending coronary artery segments, in agreement with fluorescent microspheres measurements, coincided with a decrease in fractional area change (34%). For patients, respective perfusion and function indices were 61%, 51%, and 58% lower in segments where perfusion defects, regional wall-motion abnormalities, or both were noted in gray scale images. Color-encoded, contrast-enhanced power modulation allows simultaneous real-time imaging and quantitative analysis of myocardial perfusion and regional left ventricular function.

Since 1980, the principal form of crop loss assistance in the United States has been provided through the Federal Crop Insurance Program. The Federal Crop Insurance Act of 1980 was intended to replace disaster programs with a subsidized insurance program that farmers could depend on in the event of crop losses. Crop insurance was seen as preferable to disaster assistance because it was less costly and hence could be provided to more producers, was less likely to encourage moral hazard, and less likely to encourage producers to plant crops on marginal lands. Despite substantial growth in the program, the crop insurance program has failed to replace other disaster programs as the sole form of assistance. Over the past 20 years, producers received an estimated $15 billion in supplemental disaster payments in addition to $22 billion in crop insurance indemnities.

Introduction: Left ventricular (LV) assist device (LVAD) has emerged as a valuable option for patients with severe congestive heart failure both as bridge to transplantation or destination therapy. Speed optimization of LVAD is currently based on the position of the inter-ventricular septum, mitral regurgitation severity and aortic valve opening. Hypothesis: We hypothesized that 3D transthoracic echocardiography (3DE) would provide additional information on left and right ventricular (RV) volumes and shape, which could be valuable in determining optimal LVAD speed. Our aim was to assess the feasibility of combined 3D LV and RV analysis during an incremental RAMP study. Methods: Six consecutive patients undergoing a RAMP test were studied. Device speed was increased from 8000 to 12000 rpm in 400-rpm increments for axial-flow pumps (n=2) and from 2300 to 3200 rpm in 100 rpm increments for centrifugal-flow pumps (n=4). Transthoracic 3DE apical full-volume datasets of the LV and the RV were acquired (Philips) at every other step. RV and LV endocardial surfaces were reconstructed using commercial software (TomTec) and used to calculate ventricular volumes. Custom software was used to calculate LV shape indices of sphericity and conicity (a perfectly spherical/conical ventricle would result in 1.0 value). Results: Data acquisition and post-processing was feasible in 5/6 patients. In axial pumps (Figure), increments in LVAD speed were associated with gradually decreasing LV volume, while RV volume initially decreased to a minimum and then increased at higher speeds. These volumetric changes were associated with alterations in LV shape, with the LV becoming less spherical and more conical at higher speeds. With centrifugal pumps, increased speed was associated with similar changes in LV shape but with minimal changes in volumes. Conclusions: Acquisition of 3D datasets during RAMP studies is feasible and could become a valuable aid in optimizing LVAD pump speed.

Tyrosine availability can influence dopamine (DA) synthesis in highly electrophysiologically active DAergic neurons, such as those innervating the medial prefrontal cortex (MPFC). Whether tyrosine concentrations can also affect MPFC extracellular DA concentrations, measured in vivo, is not known. Since clozapine preferentially activates mesocortical DA neurons, we posited that tyrosine administration to a clozapine-pretreated rat would enhance the clozapine-induced augmentation of MPFC extracellular DA concentrations. Tyrosine alone (25-50mg/kg IP) did not affect mesocortical or striatal extracellular DA concentrations measured by in vivo microdialysis. Given 30 minutes after clozapine (10 mg/kg), tyrosine (50 mg/kg) significantly prolonged the clozapine-induced increase in MPFC extracellular DA concentrations but had no effect in the striatum. In contrast, tyrosine (50 mg/kg) significantly prolonged the haloperidol (1 mg/kg) induced increase in striatal extracellular DA concentrations but had no effect in the MPFC. These data constitute the first in vivo evidence that administration of tyrosine can selectively potentiate the clozapine-evoked increase in mesocortical extracellular DA concentrations.

Current policies and programs affecting the supply of food are examined and options assessed for changes that would help generate a food supply consistent with the US population eating according to the Dietary Guidelines for Americans. Potential policy and program changes are identified in three categories: eliminating existing domestic farm and trade program limitations on the US food supply; creating incentives or disincentives, such as taxes or subsidies, to produce foods consistent with the Dietary Guidelines; and influencing consumers directly to choose foods consistent with the Dietary Guidelines. Despite the trend toward liberalization, there remain a few changes in farm and trade policy that would increase consumption of under-consumed foods. Taxes and subsidies are difficult to apply without creating unintended adverse consequences, although removal of production input constraints may be effective. Strategies to influence consumer behavior have advantages over policies designed to affect supplies of foods. Rather than large program interventions, changes in consumer tastes and preferences would drive market forces to efficiently produce the needed food supply.

s S197 technically demanding HTx operation and that longer duration would have a higher incidence of post-operative vasoplegia. Methods: All patients who received a CF-LVAD for BTT at our center from 01/08-09/14 were evaluated (n= 116). Eighty (69%) patients underwent HTx, 12 (10%) died before HTx, and 24 (21%) remain listed for HTx and continue on LVAD support. Of the 80 transplanted patients, 29 (36%) were supported with an LVAD for ≤ 180 days (group 1) and 51 (64%) for > 180 days (group 2). Results: Mean time of LVAD support was 98±41 d for group 1 and 365±193 for group 2. Mean age for group 1 was 52±9 years vs 57±9 for group 2 (p= 0.02). Median operative time (473 vs 523 min), CPB time (205 vs. 219 min), aortic cross clamp time (119 vs 126 min) and intra-operative blood product transfusion (6 vs 6.3 units) did not differ between groups (p> 0.05). While median ICU time (88 vs 92 hrs) and the degree or duration of vasoconstrictor support after HTx were similar, there was a trend for prolonged ventilation (> 24h) in group 2 (24% vs 10%; p= 0.06). Median hospital length of stay was 9 d for both groups. Survival after HTx at 1 and 3 years was 93% for group 1 and 91% and 87% for group 2, respectively (Figure; Log rank p= 0.57). Conclusion: Shorter duration of CF-LVAD support does not appear to increase the technical difficulty of HTx operation and longer duration of support was not associated with a greater incidence of vasoplegia. Both groups had equivalent and excellent long-term survival.

The antinociception induced by beta-endorphin given supraspinally has been previously demonstrated to be mediated by the release of [Met5]enkephalin acting on delta-opioid receptors in the spinal cord. The present study was designed to determine what type of opioid receptors in the spinal cord is involved in beta-endorphin-induced antinociception in the rat. Antinociception was induced by beta-endorphin (0.6 nmol) given into nucleus raphe obscurus and was assessed by the tail-flick test in pentobarbital-anesthesized rats. Naltriben (0.6-6.0 nmol), a selective delta 2-opioid receptor antagonist, given intrathecally dose-dependently attenuated beta-endorphin-induced inhibition of the tail-flick response. On the other hand, 7-benzylidene naltrexone (2.1-64.3 nmol), CTOP (D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2, 0.09-2.8 nmol), or nor-binaltorphimine (1.4-40.8 nmol), selective delta 1-, mu-, and kappa-opioid receptor antagonists, respectively, did not block beta-endorphin-induced antinociception. The results of present study in rats are consistent with previous experiments in mice indicating that spinal delta 2-, but not delta 1-, mu- or kappa-opioid receptors are involved in beta-endorphin-induced inhibition of the tail-flick response.

The effects of subcutaneous morphine pellet-implantation on antinociception induced by intracerebroventricular (i.c.v.) administration of β -endorphin or morphine and intrathecal (i.t.) administration of morphine, [D-Pen 2 ,D-Pen 5 ]enkephalin (DPDPE), [D-Ala 2 ,NMePhe 4 ,Gly 5 -ol]enkephalin (DAMGO), serotonin or norepinephrine were studied in male ICR mice. The tail-flick and hot-plate responses were used for antinociceptive tests. The ED 50 values for i.c.v. administered morphine for antimociception in morphine pellet-implanted mice were increased from 3.3- and 2.2-fold at 0 h to 14.2- and 19.0-fold at 4 h and declined to 4.8- and 3.0-fold at 8 h after pellet removal in the tail-flick and hot-plate tests, respectively. On the other hand, the ED 50 values for i.c.v. administered β -endorphin for antinociception were only slightly increased (1.7- to 5.1-fold increases) throughout the same time course. The inhibition of the tail-flick response induced by i.t. injection of morphine, DPDPE and serotonin, but not norepinephrine or DAMGO, was attenuated in morphine pellet-implanted mice. These findings are consistent with previous studies indicating that different neuronal mechanisms are involved in morphine- and β -endorphin-induced antinociception.

The inhibition of the tail-flick response induced by beta-endorphin given i.c.v. has been demonstrated to be mediated by the stimulation of epsilon- but not mu-, delta- or kappa-opioid receptors. beta-Endorphin given i.t. also inhibited the tail-flick response. The present studies were designed to determine what types of opioid receptors in the spinal cord were involved in i.t. beta-endorphin-induced tail-flick inhibition. Blockade of kappa-opioid receptors by coadministration of nor-binaltorphimine or Win 44,441-3 with beta-endorphin given i.t. dose dependently inhibited i.t. beta-endorphin-induced inhibition of the tail-flick response. Blockade of mu-opioid receptors by i.t. coadministration of D-Phe-Cys-Tyr-D-Try-Orn-Thr-Pen-Thr-NH2 with beta-endorphin blocked i.t. beta-endorphin-induced inhibition of the tail-flick response. I.t. injection of delta-opioid receptors antagonists, ICI 174,864 and naltrindole, or epsilon-opioid receptor antagonist, beta-endorphin-(1-27), did not affect inhibition of the tail-flick response induced by beta-endorphin given i.t. Blockade of alpha 2-adrenoceptors and 5-HT receptors by i.t. injection of yohimbine and methysergide, respectively, also did not affect inhibition of the tail-flick response induced by beta-endorphin given i.t. The results indicate that the inhibition of the tail-flick response induced by beta-endorphin given i.t. is mediated by the stimulation of kappa- and mu-opioid receptors but not delta- and epsilon-opioid receptors, alpha 2-adrenoceptors or 5-HT receptors.

By sensing intracellular energy levels, ATP-sensitive potassium (KATP) channels help regulate vascular tone, glucose metabolism, and cardioprotection. SUR2 mutant mice lack full-length KATP channels in striated and smooth muscle and display a complex phenotype of hypertension and coronary vasospasm. SUR2 mutant mice also display baseline cardioprotection and can withstand acute sympathetic stress better than normal mice. We now studied response to a form of chronic stress, namely that induced by 4 wk of daily exercise on SUR2 mutant mice. Control mice increased exercise capacity by 400% over the training period, while SUR2 mutant mice showed little increase in exercise capacity. Unexercised SUR2 mutant showed necrotic and regenerating fibers in multiple muscle skeletal muscles, including quadriceps, tibialis anterior, and diaphragm muscles. Unlike exercised control animals, SUR2 mutant mice did not lose weight, presumably due to less overall exertion. Unexercised SUR2 mutant mice showed a trend of mildly reduced cardiac function, measured by fractional shortening, (46 ± 4% vs. 57 ± 7% for SUR2 mutant and control, respectively), and this decrease was not exacerbated by chronic exercise exposure. Despite an improved response to acute sympathetic stress and baseline cardioprotection, exercise intolerance results from lack of SUR2 KATP channels in mice.

Aims Despite the potential of real-time three-dimensional (3D) echocardiography (RT3DE) to assess myocardial perfusion, there is no quantification method available for perfusion analysis from RT3DE images. Such method would require 3D regions of interest (ROI) to be defined and adjusted frame-by-frame to compensate for cardiac translation and deformation. Our aims were to develop and test a technique for automated identification of 3D myocardial ROI suitable for translation-free quantification of myocardial videointensity over time, MVI(t), from contrast-enhanced RT3DE images. Methods and results Twelve transthoracic RT3DE (Philips) data sets obtained in pigs during transition from no contrast to steady-state enhancement (Definity) were analysed using custom software. Analysis included: (i) semi-automated detection of left ventricular endo- and epicardial surfaces using level-set techniques in one frame to define a 3D myocardial ROI, (ii) rigid 3D registration to reduce translation and rotation, (iii) elastic 3D registration to compensate for deformation, and (iv) quantification of MVI(t) in the 3D ROI from the registered and non-registered data sets to assess the effectiveness of registration. For each MVI(t) curve we computed % variability during steady-state enhancement (100 × SD/mean) and goodness of fit (r2) to the indicator dilution equation MVI(t) = A[1−exp(−βt)]. Analysis of myocardial contrast throughout contrast inflow was feasible in all data sets. Three-dimensional registration improved MVI(t) curves in terms of both % variability (2.8 ± 1.8 to 1.5 ± 0.9%; P < 0.05) and goodness of fit (r2 from 0.79 ± 0.2 to 0.90 ± 0.1; P < 0.05). Conclusion This is the first study to describe a new technique for semi-automated volumetric quantification of myocardial contrast from RT3DE images that includes registration and thus provides the basis for 3D measurement of myocardial perfusion.

We developed a technique for automated identification of 3D myocardial ROI suitable for translation-free quantification of myocardial videointensity over time, MVI(t), from RT3DE images. Our software was tested on 12 ECG-triggered RT3DE datasets obtained in pigs during transient contrast inflow. Analysis included: (1) semi-automated detection of endo- and epicardial surfaces using level-set techniques to define a 3D myocardial ROI, (2) rigid 3D registration to reduce translation and rotation, (3) elastic 3D registration to compensate for deformation, and (4) quantification of MVI(t) with and without registration to assess its effectiveness. Analysis of myocardial contrast throughout contrast inflow was feasible in all datasets. 3D registration improved MVI(t) curves in terms of both % variability during steady-state enhancement: 2.8plusmn1.8% to 1.5plusmn0.9%, and goodness of fit to the indicator dilution equation MVI(t)=Aldr(1-exp(-betat)): r2 from 0.79plusmn0.2 to 0.90plusmn0.1. This is the first study to describe a new technique for semi-automated volumetric quantification of myocardial contrast from RT3DE images that includes registration and thus provides the basis for 3D measurement of myocardial perfusion.

Echocardiographic assessment of myocardial perfusion is currently achieved by measuring indices of contrast replenishment following destructive high-energy ultrasound impulses @ask-echo), We developed a technique for automated detection of perfusion defects based on quanritative analysis of parametric pelfusion images created from these indices. Parametric images were obtained a[ rest and during dipyridamole stress in 18 pts with suspected coronary artery disease. Each image was divided into 6 segments, and mean parameter value (MPV) was calculated for each segment. Changes in MPV from rest to stress were used to automatically detect stress-induced pe&sion defects. ROC analysis was used to optimize (1) the threshold for MPV stress-to-rest ratio, and (2) the minimal number of abnormal segments, required for the diagnosis of ischemia, using coronary stenosis > 70% as rhe "gold standard". The sensitivity, specificity and accuracy of the automated detection of ischemia were 63, 75 and 69% in the LAD, and 67,100 and 75% in the non-LAD territories. In conclusion, automated quantitative analysis of echocardiographic porumetric perjfusion images is feasible and m y be useful for objective detection of myocardial ischemia.

Echocardiographic quantification of myocardial perfusion, based on analysis of contrast replenishment foliowing destructive high-energy ultrasound impulses flash-echo). has multiple limitations. We present an alternative approach. based on analysis of conrrast replenishment afier brief interruptions of contrast infksion (ICI). Images were acquired in 8 isolated rabbit hearts at 3flow levels (baseline; 50% and 15%) during contrast infusion (Defnily) with flash-echo and, asfer ICI. Peak contrast inflow rate (PCIR) was calculated from ICI data and compared with Jash-echo dda. Clinical feasibiliQ was rested in 5 subjects with the ICI technique at rest and stress. In rabbit hearts, PCIR foilowed changes in coronary flow (p

Cardiac MRI diagnosis of regional LV dysfunction relies on subjective interpretation of cine images that suffers from wide inter-observer variability, especially when performed by readers not trained in the assessment of regional wall motion. We developed a method for objective, automated detection of regional wall motion abnormalities. Cine images (GE 1.5 T, FIESTA) were obtained in 6-10 short axis slices in 10 pts. Images were reviewed by an expert cardiologist whose grades were used as the gold standard. Images were then analyzed using custom software. In each slice, endocardial border was detected semiautomatically and divided into 6 segments. Regional fractional area change (RFAC) was computed and displayed as "bull's eyes". RFAC

Cardiac magnetic resonance (MR) images are often reviewed by non-cardiologists who are not trained in the interpretation of regional left ventricular (LV) function. We hypothesized that the use of still-frame parametric MR images of wall motion could aid in the assessment of regional LV function.Dynamic, electrocardiogram-gated, steady-state free precession (FIESTA) short-axis images were obtained in 6 to 10 slices in 18 consecutive patients. Each loop was used to automatically generate a still-frame image, in which each pixel is assigned a value equal to the amplitude of cyclic variation in local intensity, resulting in higher intensity in pixels that change between blood and tissue during the cardiac cycle. The dynamic images were reviewed by an expert cardiologist who provided gold standard grades for regional wall motion and by four radiologists. Then the radiologists reviewed and graded the same MR images in combination with parametric images. Grades assigned to each segment in the two sessions were compared with the gold standard.According to expert interpretation, 6 patients had normal wall motion, and 12 had wall motion abnormalities. Parametric images showed a bright band in the area spanned by endocardial motion, with reduced brightness and thickness in areas of hypokinesis. The agreement between the radiologists' grades and the gold standard significantly improved by adding parametric images (from 77% to 81%), which also resulted in reduced interobserver variability (from 52% to 33%).Still-frame parametric images aid in the assessment of regional wall motion by non-cardiologists who are required to interpret cardiac images.

Transgenic mice displaying abnormalities in cardiac development and function represent a powerful new tool for understanding molecular mechanisms underlying normal cardiovascular function and the pathophysiological bases of human cardiovascular disease. Complete cardiac evaluation of phenotypic changes in mice requires the ability to noninvasively assess cardiovascular structure and function in a serial manner. However, the small mouse heart beating at rates in excess of 500 beats/min presents unique methodological challenges. Two-dimensional and Doppler echocardiography have been recently used as effective, noninvasive tools for murine imaging, because quality images of cardiac structures and valvular flows can be obtained with newer high-frequency transthoracic transducers. We will discuss the use of echocardiography for the assessment of 1) left ventricular (LV) chamber dimensions and wall thicknesses, 2) LV mass, 3) improved endocardial border delineation using contrast echocardiography, 4) LV contractility using ejection phase indices and load-independent indices, 5) vascular properties, and 6) LV diastolic performance. Evaluation of cardiovascular performance in closed chest mice is feasible in a variety of murine models using Doppler echocardiographic imaging.

Quantitative analysis of myocardial perfusion is currently based on manual tracing and frame-by-frame realignment of regions of interest. We developed a technique for semiautomated identification of myocardial regions from power modulation images as a potential tool for quantification of myocardial contrast enhancement. This approach was tested in 13 anesthetized pigs during continuous intravenous infusion of contrast at baseline, left anterior descending coronary artery occlusion, and reperfusion. Regional pixel intensity was calculated for each consecutive end-systolic frame after a high-energy ultrasound impulse, and fitted with an exponential function. Perfusion defects caused by occlusion of left anterior descending coronary artery were confirmed by a significant decrease in both postimpulse steady-state intensity and the initial rate of contrast replenishment (P.05), which were reversed with reperfusion. Automated measurements of myocardial intensity correlated highly with conventional manual tracing (r = 0.90 to 0.97), and resulted in improved signal-to-noise ratios. This technique allows translation-free quantification of regional myocardial perfusion, without the need for manual tracing.

We hypothesized that analysis of color-encoded, contrast-enhanced, power modulation images could allow simultaneous quantification of myocardial perfusion and regional LV wall motion. We studied 12 anesthetized pigs at baseline, during acute ischemia and subsequent reperfusion, as well as 8 patients post acute myocardial infarction. Color kinesis was used to color-encode endocardial motion during real-time perfusion imaging with high-energy ultrasound pulses. Wall motion was assessed by calculating regional fractional area changes. Translation-free perfusion analysis was performed in automatically identified myocardial regions of interest. Steady-state intensity and initial rate of contrast replenishment were calculated. In all animals, ischemia caused reversible changes in the images and the calculated perfusion and function indices. A significant decrease in pixel intensity (14%) and contrast replenishment rate (66%) in LAD-related segments coincided with a decrease in fractional area change (34%). In patients, respective perfusion and function indices were 61%, 51% and 58% lower in segments where perfusion defects and/or regional wall motion abnormalities were noted in grey-scale images. Color-encoded, contrast-enhanced power modulation allows simultaneous real-time quantification of myocardial perfusion and regional LV function.

Our goal was to test the feasibility of using power modulation, a new echocardiographic imaging technique, for combined quantitative assessment of myocardial perfusion and regional LV function. Coronary balloon occlusions were performed in 18 anesthetized pigs. Images were obtained during iv contrast infusion at baseline, during coronary occlusion and reperfusion, and analyzed using custom software. At each phase, regional myocardial perfusion was assessed by calculating mean pixel intensity and the rate of contrast replenishment following high-power ultrasound impulses. LV function was assessed by calculating regional fractional area change. All ischemic episodes caused delectable and reversible changes in perfusion and function. Perfusion defects were visualized in real time and confirmed by a significant decrease in pixel intensity in the LAD territory following balloon inflation and reduced rate of contrast replenishment. Fractional area change significantly decreased in ischemic segments, and was restored with reperfusion. Power modulation allows simultaneous on-line assessment of myocardial perfusion and regional LV wall motion.

We tested the feasibility of improved evaluation of left ventricular (LV) wall motion using still-frame-parametric images of local video intensity oscillations. In 8 anesthetized pigs, baseline parametric images showed bright hands in the area spanned by endocardial motion, which gradually decreased in brightness and thickness in the territory of the occluded coronary artery. In 30 patients with contrast-enhanced echocardiograms, "gold standard" for wall motion was determined from independent interpretations of dynamic images made by three experienced reviewers. Dynamic images were independently classified by 3 inexperienced and 3 intermediate experience level readers. Interpretation was then repeated in combination with parametric images. Compared with the "gold standard", evaluation of wall motion correlated with the readers' experience and was significantly improved by adding parametric images.

There is no method to objectively evaluate left ventricular (LV) function from contrast-enhanced images. We tested the feasibility of evaluating regional LV function by using power modulation imaging. In protocol 1, 9 anesthetized closed-chest pigs were studied. Images were obtained during contrast infusion at baseline, during LAD occlusion and reperfusion. In protocol 2, images were obtained in 20 patients (14 wall-motion abnormalities; 6 controls) during contrast enhancement. Off-line, frame-by-frame, semiautomated endocardial border detection was followed by color encoding of endocardial motion, followed by segmentation and calculation of regional fractional area changes. In all animals, coronary occlusions resulted in hypokinesis and decreased fractional area changes in LAD-related segments only, which were reversed during reperfusion. In patients, wall-motion analysis was in agreement with an expert reader of dynamic images in 92.5% segments, with interobserver variability of 12.5%. Color encoding of endocardial motion from contrast-enhanced power modulation images allows accurate quantitative assessment of regional LV function. (J Am Soc Echocardiogr 2002;15:118-28.)

Background: Conventional echocardiographic assessment of left ventricular wall motion is based on visual interpretation of dynamic images, which depends on readers' experience. We tested the feasibility of evaluating endocardial motion using still-frame parametric images. Methods and Results: In protocol 1, integrated backscatter images were obtained in 8 anesthetized pigs at baseline, 5, and 60 seconds after left anterior descending coronary occlusion and during reperfusion. Images from 1 cardiac cycle were analyzed offline to create a parametric image of local video intensity oscillations. Ischemia-induced changes were quantified by segmenting the parametric images and calculating regional pixel-intensity profiles. In protocol 2, parametric images were obtained from contrast-enhanced echocardiograms in 30 patients (18 with wall-motion abnormalities; 12 control subjects). "Gold standard" for wall motion was determined from independent interpretations of dynamic images made by 3 experienced reviewers. Dynamic images were independently classified by 3 inexperienced and 3 intermediate-level readers. Interpretation was then repeated in combination with parametric images. Parametric images showed a bright band in the area spanned by endocardial motion, which gradually decreased in brightness and thickness in the left anterior descending territory during coronary occlusion in all animals. In patients, the agreement with the gold standard correlated with the readers' experience (68% inexperienced, 87% intermediate) and significantly improved by adding parametric images (83% and 91%, respectively). Conclusion: Parametric imaging provides a still-frame display of regional endocardial motion, sensitive to track ischemia-induced abnormalities. When combined with dynamic images, this technique improves the accuracy of the interpretation of wall motion, especially by less experienced echocardiographers. (J Am Soc Echocardiogr 2002;15:926-34.)

Background Echocardiographic contrast media have been used to assess myocardial perfusion and to enhance endocardial definition for improved assessment of left ventricular (LV) function. These methodologies, however, have been qualitative or have required extensive offline image analysis. Power modulation is a recently developed imaging technique that provides selective enhancement of microbubble-generated reflections. Our goal was to test the feasibility of using power modulation for combined quantitative assessment of myocardial perfusion and regional LV function in an animal model of acute ischemia. Methods and Results Coronary balloon occlusions were performed in 18 anesthetized pigs. Transthoracic power modulation images (Agilent 5500) were obtained during continuous intravenous infusion of the contrast agent Definity (DuPont) at baseline and during brief coronary occlusion and reperfusion and were analyzed with custom software. At each phase, myocardial perfusion was assessed by calculation, in 6 myocardial regions of interest, of mean pixel intensity and the rate of contrast replenishment after high-power ultrasound impulses. LV function was assessed by calculation of regional fractional area change from semiautomatically detected endocardial borders. All ischemic episodes caused detectable and reversible changes in perfusion and function. Perfusion defects, validated with fluorescent microspheres, were visualized in real time and confirmed by a significant decrease in pixel intensity in the left anterior descending coronary artery territory after balloon inflation and reduced rate of contrast replenishment. Fractional area change decreased significantly in ischemic segments and was restored with reperfusion. Conclusions Power modulation allows simultaneous online assessment of myocardial perfusion and regional LV wall motion, which may improve the echocardiographic diagnosis of myocardial ischemia.

One of the key characteristics of agriculture is the inherent production risks facing producers from adverse weather, pests, and diseases. These risks have been used to justify government intervention in the form of disaster assistance payments, emergency loans, livestock feed assistance programs, crop insurance, and other subsidized assistance schemes. Yet while government intervention to provide assistance has been widely supported in the United States, the form of assistance has been much debated.

Dilated cardiomyopathy (DC) is a leading cause of cardiovascular morbidity, and nonpharmacological therapies, such as exercise training, have been suggested. The effects of exercise on left ventricular (LV) function and mortality remain controversial. Using a recently described murine model of DC, which involves a dominant-negative form of the cAMP response element binding protein (CREB) transcription factor (CREBA133) under the control of the cardiac myocyte-specific α-myosin heavy chain promoter, we sought to assess the effects of moderate-intensity exercise training on LV performance and mortality. Thirty-two transgenic mice were subjected to exercise training and compared with sedentary controls. There was progressive enlargement in LV dimensions in both the sedentary and exercise-trained mice. LV performance was progressively impaired, and exercise training did not prevent this decline. The sedentary CREBA133 mice displayed a significantly increased rate of death, and exercise training did not prevent or delay this excess mortality. The CREBA133 murine model of inherited DC demonstrated progressive ventricular dilatation and dysfunction with increased mortality, which was not altered with 12 wk of moderate-intensity exercise training.

The antinociception induced by beta-endorphin given supraspinally has been previously demonstrated to be mediated by the stimulation of epsilon-, but not mu-, delta- or kappa-opioid receptors in rats and mice. The present study was designed to determine what types of opioid receptors in the spinal cord are involved in the antinociception induced by intrathecally (i.t.) administered beta-endorphin. Antinociception was assessed by the tail-flick test in male Sprague-Dawley rats. CTOP (0.9-6.6 nmol), a selective mu-opioid receptor antagonist, or nor-BNI(13.6-95.3 nmol), a selective kappa-opioid receptor antagonist, given i.t. dose-dependently reversed i.t. administered beta-endorphin-induced inhibition of the tail-flick response. On the other hand, naltrindole (6.6-44.4 nmol), a selective delta-opioid receptor antagonist, or beta-endorphin (1-27) (1-6.7 nmol), a selective epsilon-opioid receptor antagonist given i.t., did not antagonize the inhibition of the tail-flick response induced by i.t. administered beta-endorphin. The results are consistent with the previous study in mice [Tseng LF and Collins KA (1992) Eur J Pharmacol 214: 59-65] that the antinociception induced by beta-endorphin given i.t. is mediated by the stimulation of mu- and kappa-, but not delta- and epsilon-opioid receptors.

The antinociceptive effects induced by beta-endorphin and morphine given supraspinally have been previously demonstrated to be mediated by the activation of different neural mechanisms. The present experiments were to examine the effects of intraventricular administration of beta-endorphin and morphine in mechanical paw-withdrawal and thermal tail-flick nociceptive tests in rats of 2-28 days of age. 2-4-day-old neonates were not responsive to i.c.v. injection of beta-endorphin or morphine for the inhibition of the tail-flick response. The thermal antinociceptive responses induced by beta-endorphin and morphine started to develop in 7-14-day-old rats and continued to increase at 21-28 days. The inhibition of the mechanical paw-withdrawal response to beta-endorphin was already present in 2-day-old rats and morphine in 4-day-old rats. The mechanical antinociception progressively increased and reached a plateau at 7 days of age for beta-endorphin and 28 days of age for morphine. beta-Endorphin was found to be more efficacious than morphine in producing mechanical antinociception. The results demonstrate that beta-endorphin- and morphine-induced antinociception to mechanical and thermal stimuli develops differently and are consistent with the hypothesis that two descending pain inhibitory systems activated by beta-endorphin and morphine are differentially developed.

An antisense oligodeoxynucleotide (A-oligo) to delta-opioid receptor mRNA was utilized to block the expression of mouse delta-opioid receptor in the spinal cord of male ICR mice. Intrathecal treatment with A-oligo (1.6-163 pmol) dose-dependently attenuated the antinociception induced by i.t. administered DPDPE ([D-Pen2,5]enkephalin) or [D-Ala2]deltorphin II, delta-opioid receptor agonist, without affecting the antinociception induced by DAMGO ([D-Ala2-MePhe4,Gly(ol)5]enkephalin) or U50,488H, respective mu- or kappa-opioid receptor agonists. Scrambled sense oligodeoxynucleotide (163 pmol) was ineffective against the tail-flick inhibition induced by DPDPE,[D-Ala2]deltorphin, DAMGO or U50,488H. The studies confirm previous pharmacological studies at the molecular level indicating a distinct delta-opioid receptor for antinociception in the spinal cord.

The antinociception induced by supraspinally administered beta-endorphin is mediated by the release of Met-enkephalin and subsequent stimulation of delta-opioid receptors from the spinal cord in mice. Repeated intrathecal administration of an antisense oligodeoxynucleotide against delta-opioid receptors selectively attenuated i.c.v. administered beta-endorphin-induced antinociception without any effect on the antinociception induced by mu-opioid receptor agonists, morphine and DAMGO, or kappa-opioid receptor agonists, U50,488H. A random sequence oligodeoxynucleotide was inactive against beta-endorphin-induced antinociception. The study confirms previous findings that the antinociception induced by beta-endorphin is mediated by the stimulation of the delta-opioid receptors in the spinal cord.

The antinociception induced by beta-endorphin given intracerebroventricularly (i.c.v.) has been previously demonstrated to be mediated by the release of Met-enkephalin and subsequent stimulation of delta receptors in the spinal cord for antinociception. The present study was designed to determine what type of opioid receptor, delta 1 or delta 2, in the spinal cord is involved in i.c.v. beta-endorphin-induced antinociception. Antinociception was assessed by the tail-flick test in male ICR mice. NTB (0.2-20 nmol) and NTI (0.22-2.2 nmol), selective delta 2 receptor antagonists, given intrathecally (i.t.) dose-dependently attenuated i.c.v. beta-endorphin-induced inhibition of the tail-flick response. On the other hand, BNTX (0.02-2.2 nmol), a selective delta 1 receptor antagonist, given i.t., did not block i.c.v. beta-endorphin-induced antinociception. The tail-flick inhibition induced by DAMGO, a mu receptor agonist, or U50,488H, a kappa receptor agonist, was not blocked by i.t. BNTX, NTB or NTI. It is concluded that delta 2 but not delta 1 receptors in the spinal cord are involved in i.c.v. beta-endorphin-induced antinociception.