Within-subjects vs between-subjects co-variation of prepulse-elicited reaction and the diminution of startle to the succeeding pulse stimulus in the prepulse inhibition paradigm.

Prepulse inhibition (PPI) refers to the diminution of the startle reflex to a sudden and intense acoustic stimulus (pulse) when this startle-eliciting pulse is preceded shortly by a weaker prepulse stimulus. PPI is widely used in evaluating the effects of psychomimetic and antipsychotic drugs on sensorimotor gating, but individual differences in PPI expression have received scant attention. We have previously shown that mice and rats exhibiting stronger motor response to the prepulse also exhibit more PPI. It remains unexplored, however, if this between-subjects correlation may be similarly observed across trials from a within-subjects perspective. Here, we mapped the prepulse-elicited response to the diminution of the startle response to the succeeding pulse stimulus, trial-by-trial, across nine prepulse-pulse definitions with varying prepulse and pulse intensities. The resulting within-subjects correlation independently obtained in 113 adult C57BL6 mice revealed that trials registering a stronger prepulse reaction also recorded a larger startle response to the pulse stimulus, indicative of weaker PPI, especially when higher-intensity prepulses were paired with low-intensity pulses. The within- and between-subjects analyses have apparently yielded two contrasting relationships between the direct motor response to the prepulse and the inhibition of subsequent startle reaction induced by the same prepulse. One interpretation is that the within-subjects correlation reflects state-dependent variation, whereas the between-subjects correlation stems from trait-dependent individual variation. Finally, whether our present findings may depend on the nature of the prepulse reaction is further discussed.

Differential effects of low-magnitude high-frequency vibration on reloading hind-limb soleus and gastrocnemius medialis muscles in 28-day tail-suspended rats.

OBJECTIVES: Low-magnitude high-frequency vibration (LMHFV) was reported beneficial to muscle contractile functions in clinical and preclinical studies. This study aims to investigate the effects of LMHFV on myofibers, myogenic cells and functional properties of disused soleus (Sol) and gastrocnemius medialis (GM) during reloading. METHODS: Sprague Dawley rats were hind-limb unloaded for 28 days and assigned to reloading control (Ctrl) or LMHFV group (Vib). Sol and GM of both groups were harvested for fiber typing, proliferating myogenic cell counting and in vitro functional assessment. RESULTS: Myogenic cells proliferation was promoted by LMHFV in both Sol and GM (p<0.001 and p<0.05 respectively). Force generating capacity was not much affected (Vib=Ctrl, p>0.05) but fast-fiber favorable changes in fiber type switching (more type IIA but lower type I in Vib; p<0.05 and 0.01 respectively) and fiber hypertrophy (type I, Vib

Effects of exposure to altitude on men with coronary artery disease and impaired left ventricular function.

The effects of altitude on coronary patients with impaired left ventricular function are virtually unknown and the question arises whether an exposure to altitude poses a risk to such patients. Twenty-three patients with coronary artery disease (mean age 51 +/- 9 years; group H) with a mean ejection fraction of 39 +/- 6% were compared with 23 normal subjects (mean age 53 +/- 6 years; group N). Both groups underwent a maximal symptom-limited bicycle stress test at 1,000 m and 2 days later at 2,500 m. In both groups, exercise capacity decreased significantly (group H, 1,000 m 162 +/- 28 W, 2,500 m 155 +/- 28 W, p = 0.02; group N, 1,000 m 205 +/- 28 W, 2,500 m 198 +/- 25 W, p = 0.02). Maximal heart rate and blood pressure did not differ between 1,000 and 2,500 m; oxygen saturation at rest and during exercise remained unchanged. At 2,500 m, the test was terminated more often because of dyspnea, but the level of perceived exertion (Borg) was similar to that at 1,000 m. There were no complications or signs of ischemia. Thus, patients with coronary artery disease with impaired left ventricular function without residual ischemia have good tolerance to exposure to altitude. The effects in patients are comparable to those in a group of normal subjects and the risk for an adverse event is not increased.

Simultaneous measurement of myocardial oxygen consumption and blood flow using [1-carbon-11]acetate.

UNLABELLED: [1-Carbon-11]acetate has been used as a tracer for oxidative metabolism with PET. The aim of this study was to validate, in humans, a previously proposed two-compartment model for [1-11C]acetate for the noninvasive measurement of myocardial oxygen consumption (MVO2) and myocardial blood flow (MBF) with PET. METHODS: Twelve healthy volunteers were studied with [13N]ammonia, [1-11C]acetate and PET. Myocardial oxygen consumption was invasively determined by the Fick method from arterial and coronary sinus O2 concentrations and from MBF obtained by [13N]ammonia PET. RESULTS: Directly measured MVO2 ranged from 5.2 to 11.1 ml/100g/min, and MBF ranged from 0.48 to 0.88 ml/g/min. Oxidative flux through the tricarboxylic acid cycle, reflected by the rate constant k2, which correlated linearly with measured MVO2 [k2 = 0.0071 + 0.0074(MVO2); r = 0.74, s.e.e. = 0.015]. With this correlation, MVO2 could be estimated from the model-derived k2 value by MVO2 = 135(k2) - 0.96. The slope of this relationship was close to that previously obtained in rats and implies that the tricarboxylic acid cycle intermediate metabolite pool sizes are comparable. The net extraction (K1) of [1-11C]acetate, measured by PET, from blood into myocardium correlated closely with MBF by K1 = 0.15 + 0.73(MBF) (r = 0.93, s.e.e. = 0.033) and, thus, provided noninvasively obtainable measures of blood flow. CONCLUSION: The proposed compartment model for [1-11C]acetate fits the measured kinetics well and, with proper calibration, allows estimation of absolute MVO2 rather than only an index of oxidative metabolism. Furthermore, [1-11C]acetate-derived estimates of MBF are feasible.

Compartment model for measuring myocardial oxygen consumption using [1-11C]acetate.

UNLABELLED: Although [1-11C]acetate has been validated as a PET tracer for myocardial oxygen consumption (MVO2) in animals and humans, mono- and biexponential fitting of the tissue time-activity curve yields only estimates of MVO2. This study attempts to develop and validate a simple tracer kinetic model in vivo for estimation of regional MVO2. METHODS: Twenty-seven experiments were performed in 12 anesthetized dogs with [1-11C]acetate and serial PET images under different MBF and MVO2 (baseline, ischemia, xylazine, dobutamine and dipyridamole). Estimates of MVO2 were obtained from dynamic [1-11C]acetate PET and model fitting. MBF was measured by radiolabeled microspheres, and MVO2 was calculated by the Fick method using arterial and coronary blood samples. RESULTS: The proposed model fitted equally well for all study conditions with a multiple correlation coefficient of 0.985 +/- 0.026. Estimated MVO2 correlated linearly with measured MVO2 (y = 0.033 + 0.690x, r = 0.92, s.e. of estimates = 0.020). CONCLUSION: This study indicates that MVO2 can be assessed with PET and [1-11C]acetate over a wide range with a simple tracer kinetic model.

Effects of dobutamine stimulation on myocardial blood flow, glucose metabolism, and wall motion in normal and dysfunctional myocardium.

BACKGROUND: This investigation examines the effects of inotropic stimulation on myocardial blood flow (MBF) and glucose metabolism (MRGlc) in dysfunctional myocardium through the use of positron emission tomography (PET). METHODS AND RESULTS: Nineteen patients with chronic coronary artery disease and 12 normal volunteers were studied with 13N-ammonia, 18F-deoxyglucose, and PET and with two-dimensional echocardiography at baseline and during intravenous dobutamine (5 to 10 micrograms/kg per minute). At rest, MBF in mismatch regions (n = 10) averaged 0.53 +/- 0.19 mL/g per minute and increased by 41.4 +/- 46.6% (P = .01) during dobutamine, whereas in match regions (n = 16) MBF was 0.28 +/- 0.09 mL/g per minute at rest without an increase during dobutamine (26.4 +/- 47.3%; NS). Myocardium with normal rest MBF was classified as normal remote (normal wall motion, n = 8) or abnormal remote (abnormal wall motion, n = 11). Dobutamine raised MBF similarly in normal subjects and in normal remote regions (by 82 +/- 85% and 84 +/- 42%, P < .01) but by only 33 +/- 34% in abnormal remote regions. MRGlc declined by 49 +/- 28% (P < .005) with dobutamine in the normal subjects, remained unchanged in normal and abnormal remote regions of the patients, but increased in mismatch and match regions (by 49 +/- 74% and 46 +/- 77%; P < .05). Wall motion improved with dobutamine only in mismatch and abnormal remote regions but not in match regions. CONCLUSIONS: Blood flow-metabolism mismatch patterns are not consistently associated with a fixed downregulation of MBF; the increased contractile work in response to dobutamine stimulation is associated with an increase in MBF and a greater reliance on glucose utilization, possibly reflecting acute ischemia or alterations in substrate selection by chronically dysfunctional myocardium. Importantly, functionally impaired though normally perfused myocardium frequently exists in chronic coronary artery disease patients and may represent repetitively stunned or, more likely, remodeled left ventricular myocardium.

Reproducibility of measurements of regional resting and hyperemic myocardial blood flow assessed with PET.

UNLABELLED: PET with 13N-ammonia permits the noninvasive quantification of myocardial blood flow (MBF) in humans. The present study was done to assess the reproducibility of quantitative blood flow measurements at rest and during pharmacologically induced hyperemia in healthy individuals. METHODS: Thirty healthy volunteers (26 men, 4 women) were studied. Paired measurements of MBF at rest (n = 21), during adenosine (n = 15) and during dipyridamole (n = 7) were performed using a two-compartment model for 13N-ammonia PET. The mean difference between baseline and follow-up blood flow (% difference) was calculated to assess reproducibility. RESULTS: No significant difference was observed between resting blood flow at baseline or follow-up (15.8% +/- 15.8%; p = ns). Baseline and follow-up resting blood flow were linearly correlated (r = 0.63, p < 0.005). Normalization of resting blood flow to the rate pressure product improved the reproducibility significantly (15.8% +/- 15.8% versus 10.1% +/- 10.5%, p < 0.05). Baseline and follow-up hyperemic myocardial blood flow did not differ (11.8% +/- 9.4%; p = ns) and were linearly correlated (r = 0.69, p < 0.0005). CONCLUSION: MBF at rest can be measured reproducibly with 13N-ammonia PET. The individual response to pharmacologic stress appears to be relatively consistent. Thus, serial blood flow measurements with 13N-ammonia PET can be used to quantify the effect of various interventions on MBF and vasodilatory reserve.

Coronary vasodilatory capacity is impaired in patients with dilated cardiomyopathy.

Increases in wall stress because of left ventricular enlargement and/or alterations in coronary vasomotor tone might affect myocardial blood flow and vasodilatory capacity in patients with dilated cardiomyopathy. To test this hypothesis myocardial blood flow was measured at rest and during intravenous administration of dipyridamole (0.56 mg/kg) using dynamic nitrogen 13-ammonia positron emission tomography (two-compartment model) in 10 patients with dilated cardiomyopathy (mean left ventricular ejection fraction 28 +/- 8% 1 woman, 9 men; 47 +/- 13 years of age). Ten age and gender matched healthy volunteers served as controls. Coronary artery disease was ruled out by coronary angiography and left ventricular hypertrophy by two dimensional-echocardiography. Baseline heart rate (70 +/- 13 v 64 +/- 12 bpm), systolic blood pressure (111 +/- 20 v 114 +/- 12 mm Hg) and rate pressure product (7,686 +/- 1264 v 7,306 +/- 1,645) were similar in patients and controls. During dipyridamole administration, the rate pressure product increased similarly in both groups. Myocardial blood flow at rest did not differ between groups of patients and volunteers (0.69 +/ -0.27 v 0.67 +/- 0.17 mL/g/min) but correlated with the rate pressure product only in controls (myocardial blood flow, 0.18 + 0.000068214; rate pressure product, .67; P < .05). Hyperemic myocardial blood flow was lower in patients (1.57 +/- 0.39 v 1.92 +/- 0.31 mL/g/min, p < .05, whereas myocardial flow reserve did not differ between groups of patients and controls (2.57 +/- 1.15 v 3.02 +/- 0.94). Coronary vasodilatory capacity is reduced in patients with severe nonischemic cardiomyopathy. Increases in extravascular compressive forces or increased serum catecholamine levels, which in turn induce coronary vasoconstriction, might account for this finding.

Effect of caffeine on myocardial blood flow at rest and during pharmacological vasodilation.

UNLABELLED: Stress testing with intravenous injection of dipyridamole is frequently used for noninvasive detection of coronary artery disease (CAD) with PET or SPECT. Dietary intake of caffeinated food, beverages or medication might alter both resting and dipyridamole-induced hyperemic blood flow, thereby compromising the diagnostic sensitivity of dipyridamole stress testing. METHODS: To quantify the effect on myocardial blood flow at rest and during intravenous injection of dipyridamole, 12 healthy volunteers (mean age 27 +/- 6 yr) with low risk for CAD were studied with dynamic PET and a tracer kinetic model for 13N-ammonia after 24 hr of caffeine abstinence and after caffeine intake. RESULTS: Caffeine tended to increase the rate pressure product from 6873 +/- 1494 to 7566 +/- 1102 (p = 0.051), whereas resting myocardial blood flow remained unchanged (0.61 +/- 0.13 versus 0.58 +/- 0.07 ml/g/min, p = ns). The heart rate response to dipyridamole was inversely related to serum caffeine levels. Hyperemic blood flow (2.01 +/- 0.46 versus 1.31 +/- 0.0.38 ml/g/min; p < 0.001) and flow reserve (3.4 +/- 0.8 versus 2.3 +/- 0.7; p < 0.001) were inversely related to the caffeine dose. Coronary vascular resistance at rest tended to increase (132 +/- 32 versus 147 +/- 25 mmHg/ml/g/min; p = 0.06), whereas minimal coronary vascular resistance was significantly higher after caffeine (41 +/- 9 to 69 +/- 25 mmHg/ml/g/min; p < 0.01). CONCLUSION: Caffeine intake alters the coronary vasomotor tone at rest, which might lower the threshold for ischemic events in patients with CAD. It reduces hyperemic blood flow and flow reserve and the dipyridamole-induced increase in heart rate in a dose-dependent fashion. These findings emphasize the importance of carefully screening patients for intake of caffeinated food, beverages or medication prior to dipyridamole stress testing.

Effect of short-term cardiovascular conditioning and low-fat diet on myocardial blood flow and flow reserve.

BACKGROUND: Cardiovascular conditioning reduces resting myocardial oxygen demand by lowering systolic blood pressure and heart rate. Lower myocardial oxygen demand at rest would be expected to be associated with a decrease in resting myocardial blood flow and, consequently, an increase in myocardial flow reserve as the ratio of hyperemic to resting blood flow. However, the effect of controlled exercise together with a low-lipid diet on myocardial blood flow and flow reserve has not been examined in humans. METHODS AND RESULTS: Myocardial blood flow at rest and after dipyridamole-induced hyperemia (0.56 mg/kg i.v.) was quantified with [13N]ammonia and positron emission tomography in 13 volunteers before and upon completion of a 6-week program of cardiovascular conditioning and a low-fat diet. Exercise capacity and serum lipid profiles were also assessed at the start and finish of the program. Eight normal volunteers of similar age not participating in the conditioning program served as a control group. Cardiovascular conditioning lowered the resting rate-pressure product (8859 +/- 2128 versus 7450 +/- 1496, P < .001), serum cholesterol (217 +/- 36 versus 181 +/- 26 mg/dL), LDL cholesterol (140 +/- 32 versus 114 +/- 24 mg/dL), and triglycerides (145 +/- 53 versus 116 +/- 33 mg/dL, all P < .05). Exercise tolerance (metabolic equivalent of the task, METs) improved significantly from 10.0 +/- 3.0 to 14.4 +/- 3.6 (P < .01). Resting blood flow decreased (0.78 +/- 0.18 versus 0.69 +/- 0.14 mL.g-1.min-1, P < .05), whereas hyperemic blood flow increased (2.06 +/- 0.35 versus 2.25 +/- 0.40 mL.g-1.min-1, P < .05), resulting in an improved myocardial flow reserve (2.82 +/- 1.07 versus 3.39 +/- 0.91, P < .05). Overall, the myocardial flow reserve was significantly related to exercise performance (METs). In the control group, no changes in resting rate-pressure product, serum cholesterol levels, exercise performance, resting or hyperemic myocardial blood flow, or flow reserve were observed. CONCLUSIONS: Short-term cardiovascular conditioning together with a low-fat diet results in an improved myocardial flow reserve by lowering resting blood flow and increasing coronary vasodilatory capacity. These changes are associated with an improved exercise capacity and may offer a protective effect in patients with coronary artery disease.

Effects of modified pharmacologic stress approaches on hyperemic myocardial blood flow.

UNLABELLED: Pharmacologic stress testing with 0.56 mg/kg of intravenous dipyridamole is frequently used to noninvasively detect coronary artery disease (CAD). However, high-dose dipyridamole (0.80 mg/kg) or the combination of standard-dose dipyridamole (0.56 mg/kg) with the isometric handgrip maneuver might evoke a greater coronary hyperemic response. METHODS: To evaluate the effect of modified pharmacologic stress tests, myocardial blood flow as quantified in 11 male subjects (mean age: 27 +/- 7 yr) during standard-dose dipyridamole (0.56 mg/kg), high-dose dipyridamole (0.80 mg/kg) and standard-dose dipyridamole combined with the isometric handgrip exercise using dynamic PET and a two-compartment model for 13N-ammonia. RESULTS: Systolic blood pressure, heart rate and rate pressure product remained unchanged from standard to high-dose dipyridamole but increased with the addition of the isometric handgrip. Myocardial blood flow was unchanged from standard to high-dose dipyridamole but was lower with the addition of the isometric handgrip. CONCLUSION: The hyperemic response induced by standard-dose dipyridamole cannot be further enhanced by high-dose dipyridamole. The addition of the isometric handgrip exercise results in a modest, but significant decline in hyperemic blood flow possibly due to increased extravascular resistive forces or an increase in a mediated coronary vasoconstriction associated with exercise.

Quantification of the extent and severity of perfusion defects in canine myocardium by PET polar mapping.

UNLABELLED: This study validates perfusion defect extent and severity as derived by PET polar maps in vivo against measurements derived from radiolabeled microspheres. METHODS: In seven open-chest dogs, either the left anterior descending (n = 11) or left circumflex coronary artery (n = 13) were ligated sequentially from distal to proximal. After each occlusion, gated PET images were acquired with 13N-ammonia (20 mCi) while radiolabeled microspheres were administered into the left atrium. The transaxial PET images were reoriented into left ventricular short-axis cuts, including the apex, and polar maps were generated from circumferential activity profiles. PET polar maps were then compared with polar maps derived from microspheres after normal databases for 13N-ammonia and for microspheres were established. Nitrogen-13 or microsphere activities of less than 1.5 s.d. below the mean were defined as hypoperfused. RESULTS: The extent (percent of left ventricular mass) and mean severity of the hypoperfused myocardium in the postmortem microsphere measurements ranged from 3% to 69% and 3% to 58%, respectively. The estimated extent by summed PET and by microspheres correlated by y = 4.95 + 0.95x (r = 0.91, s.e.e. = 0.085, p < 0.001) and mean severity by y = 5.52 + 0.87x (r = 0.85, s.e.e. = 0.101, p < 0.001). The extent and severity were similar for summed and gated PET studies. CONCLUSION: The current study validated a polar map approach that provides accurate, quantitative assessment of the extent and severity of myocardial perfusion defects in vivo. Gating did not yield an improved correlation between PET and microsphere measurements. Thus, ungated PET images can be used to assess accurately the extent and severity of perfusion defects.

Effect of H3PO4 concentration on bond strength.

Prior to bonding, the enamel surface of the tooth is normally etched using a solution of 37%-50% phosphoric acid (H3PO4) for 60 seconds. The purpose of this study was to evaluate the tensile bond strength, debonding interface distribution and enamel surface detachment of various concentrations of H3PO4 solution, from 2% to 80%, applied for 15 seconds. Statistically significant differences in bond strength were found among the various concentrations tested: concentrations in the 10% to 60% range produced greater bond strengths than both the weaker and stronger concentrations. The weaker the bond strength, the greater the debonding interface between resin and enamel. The greater the bond strength, the greater the debonding interface between the bracket and resin. Enamel detachment occurred as the H3PO4 concentration rose above 30%. To obtain greater bond strength and less enamel detachment, 10%-30% concentrations of phosphoric acid for 15 seconds etching are suggested for clinical bonding.

A refined method for quantification of myocardial oxygen consumption rate using mean transit time with carbon-11-acetate and dynamic PET.

The utility of the mean transit time equation was investigated for estimation of the myocardial clearance rate constant of 11C-acetate, which is proportional to myocardial oxygen consumption rates. The mean transit time approach was also employed to generate parametric images of the clearance rate constant of 11C-acetate with dynamic PET imaging in 20 normal human studies. Input function delays and cutoff errors due to the truncation of the myocardial tissue time-activity curve at a finite time were corrected. The clearance rate constants estimated by mean transit time correlated well with the estimates by conventional monoexponential fitting (15 min (truncation time): Y = 0.01 + 0.94X, correlated coefficient (r) = 0.99; 16 min: Y = 0.03 + 0.94X, r = 0.98; 20 min: Y = 0.03 + 0.84X, r = 0.99). The clearance rate constants estimated by the mean transit time approach also correlated well (r = 0.94) with the measured rate-pressure products. The quality and noise level of parametric images of the clearance rate constants generated by mean transit time are improved over those generated by monoexponential fitting. Additional advantages of the mean transit time approach compared to the standard monoexponential fitting method for estimating myocardial clearance rate constant of 11C-acetate include ease of input function delay correction, less sensitivity to the shape of the input function and elimination of subjective data selection of the linear portion of the clearance data on a semilog plot. Thus, this approach is expected to facilitate objective quantitative analysis of indices of myocardial oxygen consumption.