Effect of contrast agent on the incidence and magnitude of ultrasound-induced lung hemorrhage in rats

OBJECTIVE: To test the hypothesis that inertial cavitation in the vasculature of the lung is not the physical mechanism responsible for ultrasound-induced lung hemorrhage. METHODS: A factorial design was used to study the effects of two types of injected agents (IA; 0.25 ml per rat of saline or Optison given intravenously) and two levels of pulsed ultrasound exposure (UE; in situ peak rarefactional pressures of 2.74 and 5.86 MPa; respective mechanical indices of 1.02 and 2.14) on the incidence and size of lung lesions. Ten 10-to-11-week-old Sprague-Dawley rats were exposed to pulsed ultrasound at each of the four combinations of IA and UE at a center frequency of 3.1 MHz, exposure duration of 10 s, pulse repetition frequency of 1,000 Hz and pulse duration of 1.2 micros. In addition, nine rats served as shams in which no lung hemorrhage occurred. RESULTS: Rats administered contrast agent prior to exposure did not have an increase in lesion occurrence or size compared to rats that received saline with no contrast agent. CONCLUSIONS: These results provide further evidence that the mechanism for production of lung hemorrhage is not inertial cavitation.     

Ring-shaped appearance in liver-specific image with Levovist: a characteristic enhancement pattern for hypervascular benign nodule in the liver of heavy drinkers.

BACKGROUND/AIMS: The aim was to clarify the features of contrast-enhanced ultrasound (CEUS) with Levovist for diagnosis of hypervascular benign nodules in the liver of heavy drinkers. PATIENTS AND METHODS: Seven heavy drinkers with hypervascular nodules in the liver were studied. Findings of CEUS with Levovist (wide-band Doppler, 7/7), contrast-enhanced computed tomography (CECT, 7/7) and magnetic resonance imaging (MRI, 5/7) were compared for one nodule in each patient. RESULTS: Diagnosis of all seven nodules on CECT was HCC, whereas pathological results were HCC for four nodules and benign lesion for three nodules. The former four showed compatible findings for HCC on CEUS (4/4) and MRI (2/4). However, the latter three showed characteristic liver-specific sonograms with a ring-shaped appearance--peripheral enhancement with a central non-enhanced area. Two of the three nodules showed decreased signal-intensity in the periphery on SPIO-enhanced MRI. CONCLUSIONS: The ring-shaped appearance on liver-specific sonograms with Levovist may be a useful sign for the differential diagnosis of hypervascular benign nodule from HCC in heavy drinkers.     

Assessment of hepatic fibrosis by analysis of the dynamic behaviour of microbubbles during contrast ultrasonography

Background/aims: Microbubble behaviour from the portal vein to the liver parenchyma may reflect haemodynamic changes because of hepatic fibrosis. The aim of this study was to determine the efficacy of contrast‐enhanced ultrasound (US) with Sonazoid^? for the assessment of the grade of hepatic fibrosis. Methods: This prospective study evaluated 117 patients with chronic liver disease (chronic hepatitis 85; cirrhosis 32) and 34 controls. All subjects received both contrast‐enhanced US with Sonazoid^? for 1 min after the agent injection and subsequent liver biopsy. Flow velocity and flow volume in the right portal vein, onset time of contrast enhancement in the right hepatic artery and right portal vein, maximum intensity ratio between the intra‐hepatic portal vein and liver parenchyma, and time interval between the onset time and the time of maximum intensity ratio were compared with the pathological findings. Results: Among the evaluated parameters, time interval between the onset time and the time of maximum intensity ratio showed the closest relationship with the grade of hepatic fibrosis: 4.21 ± 1.32 for controls (n=34), 5.58 ± 1.39 for F1 (n=31), 6.79 ± 1.77 for F2 (n=28), 8.85 ± 1.97 for F3 (n=26) and 14.3 ± 3.49 for cirrhosis (n=32); controls vs. F2, P=0.0004; F1 vs. F3, P<0.0001; F2 vs. F3, P=0.0177; F3 vs. cirrhosis, P<0.0001. The areas under the receiver operating characteristic curves of the time interval were 0.94, 0.96 and 0.98 for the diagnosis of marked fibrosis (≥F2), advanced fibrosis (≥F3) and cirrhosis respectively. Conclusions: Contrast‐enhanced US with Sonazoid^? may be a promising method for the indirect evaluation of hepatic fibrosis.     

Dose-dependent response of tumor vasculature to radiation therapy in combination with Sunitinib depicted by three-dimensional high-frequency power Doppler ultrasound

Purpose

Large doses of radiation (8–20 Gy) preferentially target tumor vasculature. This vascular response is suggested to regulate tumor response to radiotherapy. Here, we investigate the relative contributions of direct cell killing by radiation versus tumor cell death due to radiation effects on the vasculature. We also examine Sunitinib’s mechanism of action as a tumor radiosensitizer.

Experimental Design

MDA-MB-231 xenografts were treated with radiation doses of 2–16 Gy alone, or in combination with bFGF (endothelial radio-protector) or Sunitinib as pharmacological modulators of the vasculature. Sunitinib was orally administered for 2 weeks at 30 mg/kg before radiotherapy; bFGF was intravenously injected 1 h prior to irradiation. Three-dimensional high-frequency power Doppler ultrasound was used to assess relative changes in tumor vasculature. Immunohistochemistry, clonogenic and tumor growth assays were used to quantify tumor response.

Results

Significant reductions in power Doppler signal of up to 50 % were observed for 8 and 16 Gy treatments, along with a dose-dependent increase in cell death. No significant change in power Doppler signal and minimal tumor cell death were noted for tumors treated with radiation and bFGF. Treatments where Sunitinib was combined with radiation demonstrated a significant increase in flow signal at doses equal or greater than 8 Gy. This was accompanied with a significant increase in cell death when compared to radiation or Sunitinib alone.

Conclusion

We confirm that tumor response to high doses of radiation is regulated by its vasculature. We also posit that the response observed when radiation is combined with Sunitinib is linked to a vascular “normalization” effect.     

Direct biochemical evidence for eNOS stimulation by bradykinin in the human forearm vasculature

Objective: Although it has been shown recently that acetylcholine (ACh)-induced vasodilation of forearm resistance vessels is predominantly mediated by nitric oxide, direct biochemical evidence for eNOS stimulation by bradykinin (BK) in the human arterial circulation is still lacking. Therefore, the present study was designed to test the hypothesis that in the human forearm vasculature eNOS stimulation significantly contributes to BK-induced vasodilation. Methods: BK was infused in the presence and absence of the NOS inhibitor L-NMMA (8 μmol/min) into the brachial artery of 16 healthy volunteers and the effects compared to muscarinergic eNOS stimulation following acetylcholine infusion. Forearm blood flow (FBF) was measured by venous occlusion plethysmography, and plasma nitrite (NO₂ ⁻), which represents a sensitive and specific marker of regional eNOS activity, was determined in the antecubital vein and brachial artery by flow injection analysis. Nitric oxide production was calculated as product of the veno-arterial difference of NO₂ ⁻ concentration times FBF. Results: Kininergic (BK: 20, 60, 200 ng/min) as well as muscarinergic (ACh: 1, 3, 10 μg/min) stimulation resulted in a dose-dependent increase in FBF and NO₂ ⁻ in each individual. The relationship between FBF and NO production upon BK infusion was comparable to that obtained with ACh (r = 0.98; n = 64, p < 0.01). Moreover, NOS inhibition reduced both flow responses and NO production (BK: 54 and 75 %; ACh: 57 and 72 %) to a similar extent. Conclusions: These data provide direct biochemical evidence for the involvement of eNOS in bradykinin-induced vasodilation of forearm resistance vessels in humans. Received: 30 July 2002, Returned for revision: 13 August 2002, Revision received: 13 September 2002, Accepted: 24 September 2002 Correspondence to: M. Kelm, M.D.     

实时超声造影评价狗肝微波凝固坏死效果的实验研究

目的探讨实时灰阶谐波超声造影评估活体狗肝微波凝固坏死范围的价值：方法取杂种狗9只，在超声引导下行微波凝固肝组织12处，在不同时间后予常规灰阶超声和实时灰阶超声造影及取大体病理标本测量凝固灶大小。计算体积（分别为V1、V2和V3）。结果（1）V2与V3相关性好（r=0．93，P〈0．01），V1与V3的相关性（r=0．61。P〈0．05）较V2与V3明显为差；（2）即时（30～60min）超声造影因凝固灶内尚存有水蒸气，其效果稍差；3～7d造影，凝固灶周边有环状增强，病理示炎性包裹所致；15d后超声造影能够较好的反映凝固灶的大小。结论常规灰阶超声不能真实显示微波凝阎坏死灶的大小，而实时超声造影能较准确地反映，故可做为临床肝癌微波治疗后的疗效判断的有效手段；微波治疗15d后行超声造影其清晰度更佳。     

A meta-analysis of the risk of total cardiovascular events of isosmolar iodixanol compared with low-osmolar contrast media

BackgroundThe iso-osmolar contrast agent iodixanol may be associated with a lower incidence of cardiac events than low-osmolar contrast media (LOCM), but previous trials have yielded mixed results.ObjectiveTo compare the risk of total cardiovascular events of the iso-osmolar contrast medium, iodixanol, to LOCM.MethodsMedical literature databases were searched to identify comparisons between iodixanol and LOCM with cardiovascular events as a primary endpoint. A random-effects model was used to obtain pooled odds ratio (OR) for within-hospital and 30-day events.ResultsA total of 2 prospective cross-sectional studies and 11 randomized controlled trials (RCTs) (covering 6859 subjects) met our criteria. There was no significant difference in the incidence of within-hospital and 30-day cardiovascular events when iodixanol was compared with LOCM, with pooled OR of 0.72 (95%CI 0.49–1.06, p = 0.09) and 1.19 (95%CI 0.70–2.02, p = 0.53), respectively. Subgroup analysis showed no relative difference when iodixanol was compared with ioxaglate (OR = 0.92, 95%CI 0.50–1.70, p = 0.80) and iohexol (OR = 0.75, 95%CI 0.48–1.17, p = 0.21). However, a reduction in the within-hospital cardiovascular events was observed when iodixanol was compared with LOCM in the RCT subgroup (OR = 0.65, 95%CI 0.44–0.96, p = 0.03). Sensitivity analyses revealed that three studies had a strong impact on the association of within-hospital cardiovascular events between iodixanol and LOCM. Meta-regression analysis failed to account for heterogeneity. No publication bias was detected.ConclusionsThis meta-analysis demonstrates that there is no conclusive evidence that iodixanol is superior to LOCM overall with regard to fewer cardiovascular events.     

Contrast-enhanced power Doppler sonography of knee synovitis in rheumatoid arthritis: assessment of therapeutic response

The aim of this study was to evaluate the ability of power Doppler sonography (PDS) with ultrasound contrast agent to assess the synovial perfusion changes induced by intra-articular steroid injection therapy in the knee joints of patients with rheumatoid arthritis (RA). Eighteen RA patients (16 women, 2 men) with a history and signs of active knee synovitis were studied. Tenderness was evaluated using Thompsons modified index of synovitis activity. All patients underwent joint aspiration followed by intra-articular injection of 40 mg of triamcinolone hexacetonide. Gray-scale ultrasonography and PDS with an intravenous ultrasound contrast agent (Levovist) examinations were carried out before and 3 weeks after the intra-articular steroid injection. The calculation of the time–intensity curves provided a quantitative estimation of the synovial perfusion. The median values of the index of synovitis activity decreased significantly from 7.0 (95% confidence interval (CI) 6.0–8.0) to 3.0 (95% CI 2.0–4.0) (p<0.01) 3 weeks after the intra-articular steroid injection. All patients showed a reduction of PDS signal after intra-articular steroid therapy and the baseline and follow up median values of the area underlying time–intensity curves were 7.48 (95% CI 5.79–8.73) and 2.45 (95% CI 1.92–3.61), respectively. The comparison between baseline and follow-up median values of the area under the curves showed a statistically significant reduction of PDS findings (p<0.01). At follow-up examinations the changes in the index score of the synovitis activity were significantly correlated to the changes in the values of the area underlying time–intensity curves (r=0.785; p<0.01). A significant correlation was also observed between baseline values of the area underlying time–intensity curves and C-reactive protein (CRP) (r=0.548; p=0.023). In conclusion, PDS with an intravenous ultrasound contrast agent has been shown to be able to detect changes in synovial perfusion after intra-articular steroid injection and may be an additional useful method in the evaluation of synovial inflammation and in the assessment of the therapeutic response.Abbreviations DMARD Disease-modifying anti-rheumatic drugs - NSAID Non-steroidal anti-inflammatory drugs - PDS Power Doppler sonography - RA Rheumatoid arthritis - RF Rheumatoid factor - US Ultrasonography     

Use of contrast enhancement for the assessment of left ventricular function

Endocardial visualization is essential for accurate interpretation of regional wall thickening abnormalities, which constitute the diagnostic hallmark of coronary artery disease, and for reproducible assessment of left ventricular (LV) ejection fraction. Unfortunately, in many cardiac patients, poor image quality does not allow consistent visualization, let alone automated detection, of the endocardial boundary in all segments throughout the cardiac cycle. Continuing efforts directed towards improving endocardial visualization made by both echocardiographic imaging equipment manufacturers and researchers have recently produced new objective, quantitative approaches for the assessment of global and regional LV function. Although these developments have not been integrated into routine clinical practice, they may have a positive impact on endocardial visualization and, thus, eventually improve the ability to accurately and objectively evaluate LV performance. In this review, we discuss some of the latest developments in the use of contrast for the evaluation of LV function.     

Progesterone enhancement of lysergic acid diethylamide and levo-5-hydroxytryptophan stimulation of the copulatory response in the female rat

Copulatory behavior in the ovariectomized rat, i.e. the lordosis response (LR) on being mounted by a male, can be induced by administration of either estrogen alone or estrogen followed by progesterone. LR has been shown to be inhibited by lysergic acid diethylamide (LSD) in certain doses (greater than or equal to 50 micrograms/kg) and by Levo-5-hydroxytryptophan (L-5-HTP) (greater than or equal to 2.5 mg/kg). This effect was recently found to be enhanced by increasing doses of progesterone. In contrast, small doses of LSD (5-30 micrograms/kg) have been shown to increase LR activated by estrogen alone. The effects of various hormone treatments on the stimulatory action of LSD were tested in the present study. When the lordosis behavior was activated by estradiol benzoate (EB) alone (25 or 7 X 2 micrograms/kg), LR increased 10 min after injection of LSD in a dose of 10 micrograms/kg. There were no detectable effects in animals treated with estrogen alone when the dose of LSD was lowered to 1 microgram/kg. LSD in the latter dose gave an increased response, however, when LR was activated by EB (5 micrograms/kg) in combination with progesterone (4.0 mg/rat). An analogous study was conducted with L-5-HTP, after pretreatment with pargyline and R04-4602. Small doses of L-5-HTP (0.25 and 0.05 mg/kg) stimulated the LR and the influence of progesterone was the same as for small doses of LSD. Possible mechanisms underlying the observed influence of progesterone on serotonergic mechanisms involved in the lordosis behavior are discussed.     

Localization and determination of infarct size by Gd-Mesoporphyrin enhanced MRI in dogs

Background: Accurate localization and sizing of a myocardial infarction are necessary for clinical decision making and even more in research. Gd-Mesoporphyrin enhanced magnetic resonance imaging (MRI) was recently shown to specifically delineate necrosis in liver tumors, renal and muscle necrosis and myocardial infarction in rats. In this study, we investigated this technique's potential to accurately delineate myocardial infarction in a larger animal species, the dog. Methods: Myocardial infarction was induced in 8 dogs by ligation of the left anterior descending coronary artery, 4 of which were reperfused after 3 hr. Gd-Mesoporphyrin (0.05 mmol/kg) was injected intravenously 210 min after the onset of ischemia (n = 6) or after 24 hr in 2 dogs with non-reperfused infarctions. MRI was performed 10 hr. after administration of Gd-Mesoporphyrin. In vivo MRI consisted of EKG-triggered, respiratory gated T1-weighted spin echo and segmented turboFLASH long and short axis measurements. Post-mortem, a spin echo short axis measurement was repeated. Infarct size was determined planimetrically by TTC staining of left ventricular slices. Results: In all instances, there was a very close qualitative agreement between the MRI and TTC defined myocardial infarction. Quantitatively, the linear regression from post-mortem MRI to TTC determined infarct size yielded a result very close to the line of identity (regression coefficient: 0.980 ± 0.026, p<0.000001, adjusted R² = 0.964). Conclusion: We conclude that Gd-Mesoporphyrin enhanced MRI is a promising tool for the accurate delineation of myocardial infarction.     

On the enhancement of oncolytic effect of laser radiation by means of fast electrons.

Non-inbred albino mice were inoculated subcutaneously or intraperitoneally with Ehrlich carcinoma cells pre-exposed in vitro either to different doses of laser radiation or to fast electrons alone, or to both agents. The statistical data on the latency of tumors, their weights (subcutaneous inoculation) and the survival time in group "laser + electrons" (intraperitoneal inoculation) were found to differ considerably from those for the mice inoculated with the ascitic tumor cells pre-exposed either to laser radiation or fast electrons alone. The enhancement of the oncolytic effect of laser radiation combined with fast electrons is gained through the addition of the effects of each of these agents.     

Contrast-enhanced gray-scale harmonic ultrasound in the efficacy assessment of ablation treatments for hepatocellular carcinoma.

BACKGROUND: The aim of this study was to compare contrast-enhanced gray-scale harmonic ultrasound with multiphasic spiral computed tomography in the assessment of treatment efficacy of non-surgically treated HCC. METHODS: We studied 56 HCCs treated by percutaneous ethanol injection (31 cases), radiofrequency ablation (three cases), trans-arterial chemoembolization (12 cases), and combined treatment (10 cases). The efficacy of therapies was blindly assessed by multiphasic computed tomography and gray-scale harmonic ultrasound with a second-generation contrast agent (sulfur hexafluoride). RESULTS: On computed tomography 30 tumors (53.6%) showed complete necrosis, while 26 lesions (45.4%) were still viable. On contrast-enhanced ultrasound examination 33/56 nodules (58.9%) had no contrast enhancement in the arterial phase, while 23/56 lesions (41.1%) were still vascularized. All the nodules assessed as completely necrotic on computed tomography did not show arterial enhancement on contrast-enhanced ultrasound and diagnostic agreement was found in 53/56 cases (94.6%) (P<0.001). Contrast-enhanced ultrasound demonstrated relative sensitivity and specificity of 87.0% and 98.4%. CONCLUSIONS: Contrast-enhanced harmonic ultrasound is promising in the efficacy evaluation of ablation treatments for HCC. Nodules vascularized in the arterial phase on contrast harmonic ultrasound should be considered still viable and addressed to additional treatment without further evaluation.     

Is nonionic isotonic iohexol the contrast agent of choice for quantitative myocardial videodensitometry?

Summary All currently used contrast media in coronary angiography induce a considerable hyperemic response interfering with the interpretation of circulation times derived from myocardial time-density curves. Aim of this study therefore, was to find a contrast agent with minimal hyperemic response. For this purpose 2, 4 and 6 ml of the nonionic isotonic low iodinated contrast agent iohexol (Omnipaque 140®) and 6 ml of a similarly low iodinated but still hypertonic solution of the ionic diatrizoate (Urographin 30%®) were administered into the left coronary artery of 8 anesthetized instrumented dogs. Heart rate was held constant by atrial pacing and left ventricular pressure, left ventricular dP/dt and mean and phasic coronary blood flow were recorded. To test the hypothesis that the hyperemic response to nonionic contrast media is partly due to an increase in inotropic state mediated by CA⁺⁺ion influx, all measurements were repeated 30 minutes after intracoronary administration of 0.5 mg verapamil. For iohexol the increase in coronary blood flow was small but significant: 12±7%, 25±11% and 38±16% for the 2, 4 and 6 ml administrations, respectively (mean±s.d; p<0.01). For the diluted diatrizoate the increase in coronary blood flow was 65±23%. Increases for currently used contrast agents are on the order of 200–300%. After verapamil, the hyperemic response to iohexol decreased significantly to 9±5%, 20±8% and 29±12% for the 2, 4 and 6 ml administrations, respectively (p<0.01). The reaction to diatrizoate was not affected by verapamil. Moreover, there was a significant positive correlation between the increase in coronary blood flow and left ventricular dP/dt max under all conditions for all but one dog.We conclude that the isotonic, low iodinated nonionic contrast agent iohexol has only a moderate influence on coronary blood flow, which can be further attenuated by verapamil. By this approach, a more reliable assessment of circulation times from myocardial time-density curves obtained by digital subtraction angiography and videodensitometry becomes possible.     

Analysis of morphological vascular changes of hepatocellular carcinoma by microflow imaging using contrast-enhanced sonography.

Aim: To determine whether the findings of microflow imaging (MFI), composed of a flash replenishment and a maximum intensity holding sequence, using contrast-enhanced sonography, correlate with the degree of histological differentiation of hepatocellular carcinoma (HCC). Methods: This study was approved by the institutional review board; patients gave informed consent. The samples comprised of 61 nodules histologically diagnosed as HCC: 20 well-differentiated, 26 moderately-differentiated, and 15 poorly-differentiated HCC. SonoVue was used as the ultrasound (US) contrast agent. The US equipment used was a SSA-770 A with the imaging mode set at MFI. MFI is an imaging method combining flash replenishment imaging and maximum intensity holding. Two independent readers (readers 1 and 2) classified the microflow images into four patterns: (i) normal pattern; (ii) cotton pattern; (iii) vascular pattern; and (iv) dead wood pattern. The results were compared with the degree of histopathological differentiation of the HCC. Results: In each of the 61 HCC, blood vessels in the tumor were clearly resolved down to their fine branches. With regard to the relationship between imaging patterns and thehistological findings, it was found (with high percentages) that the normal and cotton patterns were associated with well-differentiated HCC, that the vascular pattern was associated with moderately-differentiated HCC, and that the dead wood pattern was associated with poorly-differentiated HCC. If HCC with the normal and cotton patterns were assessed as well differentiated and those with the vascular or dead wood pattern were assessed as moderately or poorly differentiated, the sensitivity, specificity, and accuracy of these assessments were found to be 85%, 92.7%, and 90%, respectively, for reader 1, and 85%, 82.9%, and 83.6%, respectively, for reader 2. Conclusion: The angioarchitecture and hemodynamics of HCC could be evaluated in detail using MFI. The results of this study demonstrate the feasibility of a non-invasive preoperative diagnosis of the histological differentiation of HCC using MFI.     

Rapid enhancement of visual cortical response discriminability by microstimulation of the frontal eye field

Visual attention provides a means of selecting among the barrage of information reaching the retina and of enhancing the perceptual discriminability of relevant stimuli. Neurophysiological studies in monkeys and functional imaging studies in humans have demonstrated neural correlates of these perceptual improvements in visual cortex during attention. Importantly, voluntary attention improves the discriminability of visual cortical responses to relevant stimuli. Recent work aimed at identifying sources of attentional modulation has implicated the frontal eye field (FEF) in driving spatial attention. Subthreshold microstimulation of the FEF enhances the responses of area V4 neurons to spatially corresponding stimuli. However, it is not known whether these enhancements include improved visual-response discriminability, a hallmark of voluntary attention. We used receiver-operator characteristic analysis to quantify how well V4 responses discriminated visual stimuli and examined how discriminability was affected by FEF microstimulation. Discriminability of responses to stable visual stimuli decayed over time but was transiently restored after microstimulation of the FEF. As observed during voluntary attention, the enhancement resulted only from changes in the magnitude of V4 responses and not in the relationship between response magnitude and variance. Enhanced response discriminability was apparent immediately after microstimulation and was reliable within 40 ms of microstimulation onset, indicating a direct influence of FEF stimulation on visual representations. These results contribute to the mounting evidence that saccade-related signals are a source of spatial attentive selection.