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ObjectivesEndothelial dysfunction in the fetuses of women with gestational diabetes mellitus (GDM) is associated with their subsequent cardiovascular events. Prenatal assessment of endothelial function in fetuses exposed to intrauterine hyperglycemic environment remains challenging. The aim of this study was to assess the fetal vascular endothelial function in GDM patients using color M-mode derived aortic propagation velocity (APV) and evaluate the correlation of APV with endothelial function biomarkers.MethodsThis observational cross-sectional study included 31 gestational diabetic mothers and 30 healthy pregnant mothers from August 2019 to January 2020. Clinical data were compared between the groups. Fetal APV was measured using color M-mode echocardiography at late gestation. Concentrations of endothelial biomarkers including von Willebrand Factor (vWF), vascular endothelial-cadherin and endothelin-1 in umbilical cord serum were assessed. Measurements between diabetic group and controls were compared.ResultsvWF was the only endothelial functional marker that differed between the two groups. Fetuses in the GDM group had significantly lower APV levels and higher vWF levels compared with the healthy controls (P < 0.05). There was a moderate but significant correlation between APV and vWF (r =−0.58, P < 0.001). There were no associations between APV and ventricular wall thickness or umbilical artery pulsatility index.ConclusionsColor M-mode propagation velocity of aorta is a non-invasive, practical method that correlates well with GDM and fetal endothelial function. This novel metric could contribute to recognizing early vascular functional alterations and hence represents a potential strategy for early risk factor surveillance and risk modification.

Objectives To analyze the imaging manifestations of common fetal oral masses by ultrasound combined with magnetic resonance imaging (MRI) and to discuss their differential diagnoses. Methods A retrospective study of 6 fetuses with oral masses was performed at a tertiary referral center. The imaging features of prenatal ultrasonography and MRI in the diagnosis of fetal oral masses were analyzed. Results Histopathological examination and/or postpartum ultrasound revealed lymphangioma malformation in 2 fetuses, and mucosal retention cyst, mature teratoma, immature teratoma, and cranial meningocele in 1 fetus, respectively. The teratoma had a characteristic sonographic appearance. In our study, the 4 cases of cystic masses did not have an abnormal vessel architecture. Supplemental MRI revealed a mass effect at the level of the hypopharynx, and in 2 cases with polyhydramnios, the mass obstructed the fetuses' upper airway. Thus, ex-utero intrapartum therapy surgery was performed to secure the newborn's airway. Conclusions Oral fetal tumors represent rare congenital malformations. This study shows that a prenatal diagnosis of oral masses is feasible by ultrasound examination. MRI can further confirm the results of ultrasonography and clearly show the relationship between the mass and the hypopharynx. Ultrasonography combined with MRI could, to a large extent, facilitate early detection and appropriate treatment and improve outcome.

Echocardiographic molecular imaging techniques are beginning to be applied to evaluate preclinical efficacy of new drugs. In a large clinical trial, anti-interleukin-1β (IL-1β) immunotherapy reduced atherosclerotic events, yet treatment effects were modest, and the mechanisms of action were not fully elucidated. We tested the hypothesis that echocardiographic molecular imaging can assess changes in vascular thromboinflammatory status in response to anti-IL-1β therapy.In wild-type and atherosclerotic mice deficient for the low-density lipoprotein-receptor and Apobec-1, closed-chest myocardial infarction (MI) was performed to mimic high-risk clinical cohorts. Control animals had sham surgery. Post-MI animals were randomized to either no therapy or anti-IL-1β immunotherapy, which was continued weekly. At post-MI day 3 or 21, in vivo ultrasound molecular imaging of aortic VCAM-1, P-selectin, von Willebrand factor A1-domain, and platelet GPIbα in the thoracic aorta was performed. Aortic histology and NF-κB activity were assessed in atherosclerotic mice.In both atherosclerotic and wild-type mice, MI produced a several-fold increase (P .05) in aortic molecular signals for P-selectin, VCAM-1, von Willebrand factor, and GPIbα. In atherosclerotic mice, signal remained elevated at day 21. Anti-IL-1β therapy completely abolished the post-MI increase in signal for all endothelial targets (P .05 vs nontreated) at day 3 and 21. In atherosclerotic mice, MI triggered an increase in aortic plaque growth and macrophage content, a decrease in plaque collagen, and elevated aortic NF-κB (P .05 for all changes). All of these remote plaque adverse changes were inhibited by anti-IL-1β therapy.Echocardiographic molecular imaging of the vascular endothelium can quantify the beneficial effects of therapies designed to suppress the proatherosclerotic arterial thromboinflammatory effects of alarmins such as IL-1β. This approach could potentially be used to evaluate the biologic variables that influence response in preclinical studies, and possibly to select patients most likely to benefit from therapy.

The third-generation tyrosine kinase inhibitor (TKI) ponatinib has been associated with high rates of acute ischemic events. The pathophysiology responsible for these events is unknown. We hypothesized that ponatinib produces an endothelial angiopathy involving excessive endothelial-associated von Willebrand factor (VWF) and secondary platelet adhesion. In wild-type mice and ApoE−/− mice on a Western diet, ultrasound molecular imaging of the thoracic aorta for VWF A1-domain and glycoprotein-Ibα was performed to quantify endothelial-associated VWF and platelet adhesion. After treatment of wild-type mice for 7 days, aortic molecular signal for endothelial-associated VWF and platelet adhesion were five- to sixfold higher in ponatinib vs sham therapy (P < .001), whereas dasatinib had no effect. In ApoE−/− mice, aortic VWF and platelet signals were two- to fourfold higher for ponatinib-treated compared with sham-treated mice (P < .05) and were significantly higher than in treated wild-type mice (P < .05). Platelet and VWF signals in ponatinib-treated mice were significantly reduced by N-acetylcysteine and completely eliminated by recombinant ADAMTS13. Ponatinib produced segmental left ventricular wall motion abnormalities in 33% of wild-type and 45% of ApoE−/− mice and corresponding patchy perfusion defects, yet coronary arteries were normal on angiography. Instead, a global microvascular angiopathy was detected by immunohistochemistry and by intravital microscopy observation of platelet aggregates and nets associated with endothelial cells and leukocytes. Our findings reveal a new form of vascular toxicity for the TKI ponatinib that involves VWF-mediated platelet adhesion and a secondary microvascular angiopathy that produces ischemic wall motion abnormalities. These processes can be mitigated by interventions known to reduce VWF multimer size.

// Pintong Huang 1 , Ying Zhang 1 , Jian Chen 2 , Weihui Shentu 1 , Yu Sun 3 , Zhijian Yang 3 , Tingbo Liang 2 , Shuyuan Chen 4 and Zhaoxia Pu 1 1 Department of Ultrasonography, The Second Affiliated Hospital of Zhejiang University College of Medicine, Hangzhou, Zhejiang Province, P. R. China 2 Department of Surgery, The Second Affiliated Hospital Zhejiang University College of Medicine, Hangzhou, Zhejiang Province, P. R. China 3 Origin Biosciences Inc., Nanjing, Jiangsu Province, P. R. China 4 Baylor Research Institute, Baylor University Medical Center at Dallas, Texas, USA Correspondence to: Pintong Huang, email: // Keywords : ultrasonic cavitation; microbubbles; tumor vasculature; pancreatic cancer; therapy Received : February 14, 2015 Accepted : April 22, 2015 Published : May 08, 2015 Abstract Ultrasonic cavitation is a novel potential approach for cancer treatment. We optimized the techniques of ultrasonic cavitation to enhance antitumor efficacy in a mouse model with human pancreatic cancer. A polydisperse MB contrast agent formulation (TS-P) with a mean number diameter of 1.9 μm was depleted in small diameter particles by differential centrifugation, producing an “up-sized” size distribution (TS-PL) possessing a mean diameter of 2.9 μm. Mice bearing the XPA-1-RFP pancreatic tumor were treated daily for 3 consecutive days with either up-sized or standard MB. Both treatment cohorts exhibited a significant reduction in tumor volume relative to the untreated control cohort ( P < 0.05), and TS-PL group has significantly reduction in tumor volume (1215.1± 324.7 mm 3 ) compared with standard TS-P group (2131.2±753.4 mm 3 ) ( P < 0.05). The treatment with TS-PL resulted in more tumor cell necrosis and apoptosis than with TS-P. Decreased expression of CD31 and MVD was observed histologically in tumors treated with TS-PL relative to TS-P. This study demonstrates that tuning the size distribution of existing contrast agent products, specifically to reduce the concentration of small MB, is required for enhanced anti-tumor cavitation activity.

This study investigated the efficacy of concurrent delivery of an anti-angiogenic drug and ultrasonic cavitation therapy in a mouse model of human colon cancer. A biotinylated form of the anti-angiogenic drug Endostar was conjugated to a streptavidin-coated microbubble (MB). Mice bearing subcutaneous tumors (HT29) were divided into 4 groups. Group 1 served as an untreated control. Group 2 served as a cavitation control and received naked microbubbles and sham ultrasonic cavitation (MB + sham cavitation). Group 3 received naked microbubbles and ultrasonic cavitation (MB + cavitation). Group 4 received Endostar loaded microbubbles and ultrasonic cavitation (Endostar-MB + cavitation). Ultrasonic cavitation was performed using a high-power custom built sonicator. Contrast-enhanced ultrasound imaging (CEUS) was used to measure tumor blood flow before and after ultrasonic cavitation. In vivo fluorescence imaging was performed to monitor changes in tumor volume. Immunohistochemistry was performed to assess CD31, VEGFR-2 and alpha-v beta-3 integrin expression within the tumor. Apoptosis of the tumor cells was determined by TUNEL assay, and ultrastructural changes within the tumor were examined by electron microcopy. Ultrasonic cavitation with Endostar-MB demonstrated a significantly greater inhibition of tumor blood flow on day 7 and tumor growth on day 16 compared with naked MB and control groups. The Endostar-MB treated mice showed significantly decreased expression VEGFR-2 and alpha-v beta-3 integrin, and increased apoptosis of tumor cells and degradation of the tumor ultrastructure. Our findings indicated that the anti-vascular and anti-tumor effects of ultrasonic cavitation could be potentiated by simultaneously delivering an anti-angiogenic drug in colon cancer.

In order to evaluate the left ventricular remodeling in patients with myocardial infarction after revascularization with intravenous real-time myocardial contrast echocardiography (RT-MCE), intravenous RT-MCE was performed on 20 patients with myocardial infarction before coronary revascularization. Follow-up echocardiography was performed 3 months after coronary revascularization. Segmental wall motion was assessed using 18-segment LV model and classified as normal, hypokinesis, akinesis and dyskinesis. Myocardial perfusion was assessed by visual interpretation and divided into 3 conditions: homogeneous opacification=1; partial or reduced opacification or subendocardial contrast defect=2; contrast defect=3. Myocardial perfusion score index (MPSI) was calculated by dividing the total sum of contrast score by the total number of segments with abnormal wall motion. Twenty patients were classified into 2 groups according to the MPSI: MPSIor=1.5 as good myocardial perfusion, MPSI1.5 as poor myocardial perfusion. To assess the left ventricular remodeling, the following comparisons were carried out: (1) Comparisons of left ventricular ejection fraction (LVEF), left ventricular end-systolic volume (LVESV) and left ventricular end-diastolic volume (LVEDV) before and 3 months after revascularization in two groups; (2) Comparisons of LVEF, LVESV and LVEDV pre-revascularization between two groups and comparisons of these 3 months post-revascularization between two groups; (3) Comparisons of the differences in LVEF, LVESV and LVEDV between 3 months post-and pre-revascularization (DeltaLVEF, DeltaLVESV and DeltaLVEDV) between two groups; (4) The linear regression analysis between DeltaLVEF, DeltaLVESV, DeltaLVEDV and MPSI. The results showed that the LVEF obtained 3 months after revascularization in patients with MPSI1.5 was obviously lower than that in those with MPSIor=1.5. The LVEDV obtained 3 months post-revascularization in patients with MPSI1.5 was obviously larger than that in those with MPSIor=1.5 (P=0.002 and 0.04). The differences in DeltaLVEF and DeltaLVEDV between patients with MPSI1.5 and those with MPSIor=1.5 were significant (P=0.002 and 0.001, respectively). Linear regression analysis revealed that MPSI had a negative correlation with DeltaLVEF and a positive correlation with DeltaLVESV, DeltaLVEDV (P=0.004, 0.008, and 0.016, respectively). It was concluded that RT-MCE could accurately evaluate the left ventricular remodeling in patients with myocardial infarction after revascularization.

The myocardial viability after myocardial infarction was evaluated by intravenous myocardial contrast echocardiography. Intravenous real-time myocardial contrast echocardiography was performed on 18 patients with myocardial infarction before coronary revascularization. Follow-up echocardiography was performed 3 months after coronary revascularization. Segmental wall motion was assessed using 18-segment LV model and classified as normal, hypokinesis, akinesis and dyskinesis. Viable myocardium was defined by evident improvement of segmental wall motion 3 months after coronary revascularization. Myocardial perfusion was assessed by visual interpretation and divided into 3 conditions: homogeneous opacification; partial or reduced opacification or subendocardial contrast defect; contrast defect. The former two conditions were used as the standard to define the viable myocardium. The results showed that 109 abnormal wall motion segments were detected among 18 patients with myocardial infarction, including 47 segments of hypokinesis, 56 segments of akinesis and 6 segments of dyskinesis. The wall motion of 2 segments with hypokinesis before coronary revascularization which showed homogeneous opacification, 14 of 24 segments with hypokinese and 20 of 24 segments with akinese before coronary revascularization which showed partial or reduced opacification or subendocardial contrast defect was improved 3 months after coronary revascularization. In our study, the sensitivity and specificity of evaluation of myocardial viability after myocardial infarction by intravenous real-time myocardial contrast echocardiography were 94.7% and 78.9%, respectively. It was concluded that intravenous real-time myocardial contrast echocardiography could accurately evaluate myocardial viability after myocardial infarction.

The aim of this study was to compare the accuracy of multi-detector computed tomography (MDCT) with double contrast-enhanced ultrasound (DCEUS), in which intravenous microbubbles are used alongside oral contrast-enhanced ultrasound, in determining the gross classification of patients with gastric carcinoma (GC). Altogether, 239 patients with GC proved by histology after endoscopic biopsy were included in this study. DCEUS and MDCT were performed pre-operatively. The diagnostic accuracies of DCEUS and MDCT in determining the gross classification were calculated and compared. The overall accuracy of DCEUS in determining the gross appearance of GC was higher than that of MDCT (84.9% vs. 79.9%, p

The present study evaluated the application of three dimensional echocardigraphy (3DE) in the diagnosis of atrial septal defect (ASD) and the measurement of its size by 3DE and compared the size with surgical findings. Two-dimensional and real-time three dimensional echocardiography (RT3DE) was performed in 26 patients with atrial septal defect, and the echocardiographic data were compared with the surgical findings. Significant correlation was found between defect diameter by RT3DE and that measured during surgery (r=0.77, P

Loss of synchronous contraction between or within the right and left ventricle (RV, LV) leads to adverse ventricular function. We used real time three-dimensional echocardiography (RT3DE) for evaluation of severity of interventricular dyssynchrony and function in a porcine heart model.Six fresh in vitro porcine hearts were used to create a controlled model of LV and RV dyssynchrony using two sets of pulsatile pumps. Synchronized and dyssynchronized pump settings were used with two different dyssynchronized settings: LV filled first and RV filled first.There was good correlation between actual measurement and RT3DE for interventricular time difference (r = 0.95, P0.0001) and stroke volume (SV) for LV and RV (0.89, 0.85; P0.0001, respectively). RT3DE data showed a small but significant underestimation for actual volume (P0.05). The intra- and interobserver variabilities are 2.9 +/- 1.5% and 3.1 +/- 5.4% for LV and RV SVs, and 1.7 +/- 2.4% and 2.2 +/- 3.2% for time differences by RT3DE. There was significant difference in RV SV between synchrony and dyssynchrony when the RV filled first (P0.05), but not in other groups. The same pattern was found in RT3DE derived SVs (synchrony versus dyssynchrony with RV filled first, P0.05).There is no compromise in LV SV during interventricular dyssynchrony; but RV SV was significantly diminished when the RV filled first. RT3DE is a feasible, robust and reproducible method to identify interventricular dyssynchrony and to evaluate ventricular SVs.

This study was aimed to evaluate the relationship between carotid atherosclerotic plaque stability and the clinical symptoms in patients with carotid atherosclerotic plaques by using contrast-enhanced ultrasonography. Fifty patients with carotid atherosclerotic plaques were enrolled and examined with contrast-enhanced ultrasonography. The correlation of contrast agent enhancement of the carotid atherosclerotic plaques and the clinical symptoms was analyzed. The results showed that among the 50 patients, plaques were enhanced in the 23 patients with obvious clinical symptoms. In 27 patients without apparent clinical symptoms, plaques were enhanced sparsely in 15 patients and not enhanced in 12 patients. It was suggested that contrast-enhanced ultrasonography could be used for the examination of the microcirculation in carotid atherosclerotic plaques on real-time basis and serve as a new noninvasive approach for the assessment of stability of carotid atherosclerotic plaques.

OBJECTIVES: We sought to determine the feasibility and reproducibility of real-time 3-dimensional echocardiography (RT3DE) for evaluation of cardiac volume, mass, and function and to characterize maturational changes of these measurements in human fetuses. METHODS: Eighty pregnant women in the 2(nd) and 3(rd) trimesters (59 with normal fetuses and 21 with fetuses with congenital heart disease [CHD]) were enrolled. We acquired RT3DE images using a matrix-array transducer. RT3DE measurements of volume, mass, stroke volume (SV), combined cardiac output (CCO), and ejection fraction (EF) were obtained. Images were scored and analyzed by two blinded independent observers. Inter- and intraobserver variabilities and correlations between fetal cardiac indices and gestational age were determined. RESULTS: Fifty-two of 59 normal data sets (88%) and 9 of 21 CHD data sets (43%) were feasible for analysis. In normal fetuses, the right ventricle (RV) is larger than the left ventricle (LV) (P

Although about 30% of gastric cancers have distant metastasis at the time of initial diagnosis, metastatic tumor embolus in the main blood vessels is not common, especially in the main artery. The report presents, for the first time, an extremely rare clinical case of a metastatic embolus in the common carotid artery (CCA) from primary gastric cancer. Metastatic embolus from the primary tumor should be considered when patients present with gastric cancer accompanied by intravascular emboli. The patient should be actively examined further so as to allow early detection and treatment.

ObjectivesWe hypothesized that noninvasive molecular imaging of activated von Willebrand factor (vWF) on the vascular endothelium could be used to detect a high-risk atherosclerotic phenotype.BackgroundPlatelet-endothelial interactions have been linked to increased inflammatory activation and prothrombotic state in atherosclerosis. These interactions are mediated, in part, by platelet glycoprotein (GP) Ibα, suggesting that dysregulated endothelial vWF is a marker for high-risk atherosclerotic disease.MethodsMicrobubbles targeted to activated vWF were prepared by surface conjugation of recombinant GPIbα. Flow-chamber studies were used to evaluate attachment of targeted microbubbles to immobile platelet aggregates bearing activated vWF. Contrast-enhanced ultrasound (CEU) molecular imaging of the aorta from mice was performed: 1) ex vivo after focal crush injury and blood perfusion; and 2) in vivo in mice with advanced atherosclerosis produced by deletion of the low-density lipoprotein receptor and ApoBec-1 editing peptide (LDLR–/–/ApoBec-1–/–).ResultsIn flow-chamber studies, tracer attachment to vWF was >10-fold greater for microbubbles bearing GPIbα compared with control microbubbles (p < 0.01). In the ex vivo aortic injury model, CEU signal enhancement for vWF-targeted microbubbles occurred primarily at the injury site and was 4-fold greater than at noninjured sites (p < 0.05). In LDLR–/–/ApoBec-1–/– mice, inflammatory cell infiltrates and dense vWF expression on the intact endothelium were seen in regions of severe plaque formation. Scanning electron microscopy demonstrated widespread platelet-endothelial interaction and only few sites of endothelial erosion. On CEU, signal enhancement for vWF-targeted microbubbles was approximately 4-fold greater (p < 0.05) in LDLR–/–/ApoBec-1–/– compared with wild-type mice. En face aortic microscopy demonstrated regions where platelet adhesion and microbubble attachment colocalized.ConclusionsMolecular imaging using GPIbα as a targeting moiety can detect the presence of activated vWF on the vascular endothelium. This strategy may provide a means to noninvasively detect an advanced prothrombotic and inflammatory phenotype in atherosclerotic disease.