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PubMedDate not supplied

Stable microbubble test for predicting the occurrence of respiratory distress syndrome.

To predict the development of respiratory distress syndrome (RDS) in premature neonates who might benefit from early administration of surfactant, the clinical applicability of stable microbubble (SM) test was prospectively evaluated. Fifty-nine preterm neonates with the gestational ages of less than 37 weeks were studied. SM test was performed on gastric aspirates obtained within 30 minutes after birth. The number of microbubbles was correlated with later development of RDS. With a cut-off value of less than 10 microbubbles/mm2, the SM test showed a positive predictive value of 76.0% (19/25) and a negative predictive value of 97.1% (33/34), while sensitivity and specificity were 95.0% (19/20) and 84.6% (33/39), respectively. The overall accuracy was 88.1% (52/59). It was concluded that use of the SM test on gastric aspirates immediately after birth is a rapid, simple and reliable procedure for identifying those neonates with surfactant deficiency who may benefit from prophylactic surfactant therapy.

Gastric Juice↗
PubMed1997

Utility of Doppler-detectable microbubbles in the diagnosis and treatment of decompression sickness.

BACKGROUND: Doppler-detectable microbubbles (DMB) are frequently used to evaluate altitude decompression stress. However, the role of DMB in the therapy of decompression sickness (DCS) has not been examined. HYPOTHESIS: The ability of Doppler to detect microbubbles during decompression (Doppler test) may be used in the diagnosis of DCS, and to aid clinical decisions about treatment options for DCS. METHODS: We examined the data on DMB and symptoms from NASA Database on DCS (n = 516). The accuracy of Doppler test was obtained from the Receiver Operating Characteristic (ROC) for DMB (grades I through IV), and efficacy was obtained by calculating predictive or post-test probabilities. Threshold analysis was used to obtain the probabilities for testing and/or treatment decisions. RESULTS: The Doppler test was useful for both screening and confirming DCS, when different criteria (grade I for screening; grade IV for confirming) were used for a positive test. Calculation of predictive values and threshold analysis showed that: 1) early recompression was the therapy of choice when post-test probability of disease was > 0.25 in individuals with non-specific pain at altitude, and early recompression with 100% oxygen for 2 h at site level was optimal therapy when this probability was > 0.33; 2) hyperbaric therapy was optimal when post-test probability was > 0.04 in individuals with uncertain symptoms post-flight. CONCLUSIONS: The Doppler test was of greater utility in excluding DCS than confirming its presence, and was useful in making therapeutic decisions on DCS when confronted with non-specific symptoms at altitude.

Aerospace Medicine↗
PubMed2005

Novel site-specific systemic delivery of Rapamycin with perfluorobutane gas microbubble carrier reduced neointimal formation in a porcine coronary restenosis model.

Earlier studies demonstrated that perfluorobutane gas microbubble carrier (PGMC) adheres to injured arteries and enhances the drug uptake specifically into the cells of the denuded vessel segment. The purpose of this study was to investigate the effect of PGMC-based systemic delivery of Rapamycin on expression of p27 in vascular tissue and restenosis in porcine coronary arteries after stent implantation. Eight pigs underwent coronary stent implantation (three stents per animal). Five pigs were treated with i.v. injection of PGMC with 2 mg of Rapamycin and three animals served as control. Four hours postprocedure, three pigs were sacrificed and stented segments were analyzed by high-performance liquid chromatography (HPLC) and Western blot. In chronic experiments, five pigs (15 stent sites) were sacrificed at 28 days following intervention and vessels were perfusion-fixed. HPLC of the treated arteries demonstrated high drug concentration in the vessel tissue, and Western blot analysis showed elevated expression of p27 at 4 hr postprocedure. Histomorphometry revealed significantly reduced (by 40%) neointimal formation in the PGMC/Rapamycin group compared with controls (1.84 +/- 0.84 vs. 4.77 +/- 1.71 mm2, respectively; P < 0.001). In the porcine coronary model, site-specific systemic delivery of Rapamycin utilizing PGMC resulted in overexpression of p27 and a significant reduction of neointimal formation within the stented segments.

Animals↗
PubMed2003

Microbubble-enhanced sonoporation: efficient gene transduction technique for chick embryos.

The gene transduction technique is a useful method to study gene functions that underlie vertebrate embryogenesis. In this study, a new gene transduction technique is reported using microbubble-enhanced sonoporation (hereafter referred to as sonoporation) to achieve ectopic and transient gene expression for several embryonic organs including embryonic chick limb bud mesenchymes. The technique proposed in this study has the advantages of 1) relatively simple gene transduction procedures, and 2) efficient exogenous gene transduction and expression with lower damages to embryos. Green fluorescent protein (GFP) or LacZ was misexpressed in limb bud mesenchymes by sonoporation, with the introduced expression transiently detected in the injected sites. Most of the transduced chick embryos survived without showing significant embryonic abnormalities or cell death after sonoporation. To demonstrate its efficacy for assessing the effect of transient gene transduction, the Shh (sonic hedgehog) was transduced into the developing chick limb bud. The transduced limb bud displayed limb malformations including partial digit duplication. Advantages and possible future applications in relation to this method are discussed.

Animals↗
PubMedDate not supplied

Ultrastructural biologic effects of sonography with pulse inversion and microbubble contrast in rabbit liver.

PURPOSE: This prospective study was conducted to evaluate the biologic effects of microbubble destruction with pulse-inversion harmonic imaging on rabbit liver parenchyma. METHODS: The livers of 6 albino rabbits were examined sonographically by a single investigator. Three rabbits underwent contrast-enhanced sonography, with scanning starting 5 seconds after injection by using pulse-inversion harmonic imaging with a mechanical index of 1.2. Four time-triggered images were recorded at a rate of 1 frame every 2 seconds. For comparison, 3 control rabbits had pulse-inversion harmonic imaging with a mechanical index of 1.2 only, without contrast medium. Immediately after sonography, the animals were killed and uninterrupted, thin serial sections of the liver from both groups were analyzed by energy-filtered transmission electron microscopy. RESULTS: The hepatic parenchyma of rabbits exposed to contrast agents had ultrastructural damage: mitochondria with fragmented crests; interrupted rough endoplasmic reticulum; enlarged intercellular spaces; highly vacuolized cytoplasmic areas; dilated sinusoids, sometimes with an irregular and interrupted endothelial wall; fragmented hepatocyte microvilli in dilated spaces of Disse; fragmented or missing microvilli in bile canaliculi; vacuolated and lysosome-deprived hepatic cytoplasm around the bile canaliculi; markedly injured or fragmented endothelium in larger vessels; and damaged basal membrane. Control-group results indicated that exposure to ultrasound alone did not cause ultrastructural damage to hepatic cells. CONCLUSIONS: Simultaneous exposure to contrast administration and pulse-inversion harmonic imaging with a high mechanical index causes ultrastructural damage in the rabbit liver.

Animals↗
PubMed2005

An efficient gene transfer method mediated by ultrasound and microbubbles into the kidney.

BACKGROUND: Safety issues are of paramount importance in clinical human gene therapy. From this point of view, it would be better to develop a novel non-viral efficient gene transfer method. Recently, it was reported that ultrasound exposure could induce cell membrane permeabilization and enhance gene expression. METHODS: In this study, we examined the potential of ultrasound for gene transfer into the kidney. First, we transfected rat left kidney with luciferase plasmid mixed with microbubbles, Optison, to optimize the conditions (duration of ultrasound and concentration of Optison). Then, 4, 7, 14 and 21 days after gene transfer, luciferase activity was measured. Next, localization of gene expression was assessed by measuring luciferase activity and green fluorescent protein (GFP) expression. Expression of GFP plasmid was examined under a fluorescence microscope at 4 and 14 days after gene transfer. Finally, to examine the side effects of this gene transfer method, biochemical assays for aspartate aminotransferase (AST), alanine aminotransferase (ALT), blood urea nitrogen (BUN) and creatinine (Cre) were performed. RESULTS: Optison and/or ultrasound significantly enhanced the efficiency of gene transfer and expression in the kidney. Especially, 70-80% of total glomeruli could be transfected. Also, a significant dose-dependent effect of Optison was observed as assessed by luciferase assay (Optison 25%: 12.5 x 10(5) relative light units (RLU)/g tissue; 50%: 31.3 x 10(5) RLU/g tissue; 100%: 57.9 x 10(5) RLU/g tissue). GFP expression could be observed in glomeruli, tubules and interstitial area. Results of blood tests did not change significantly after gene transfer. CONCLUSIONS: Overall, an ultrasound-mediated gene transfer method with Optison enhanced the efficiency of gene transfer and expression in the rat kidney. This novel non-viral method may be useful for gene therapy for renal disease.

Alanine Transaminase↗
PubMed2004

Local delivery of E2F decoy oligodeoxynucleotides using ultrasound with microbubble agent (Optison) inhibits intimal hyperplasia after balloon injury in rat carotid artery model.

Since restenosis after angioplasty still remains a major clinical problems, inhibition of neointimal formation is an important subject. In this study, we focused on the transcription factor, E2F, that plays a pivotal role in the transactivation of cell-cycle regulatory genes, and also we developed a newly delivery system of decoy oligodeoxynucleotides (ODN). We transfected E2F decoy ODN mixed with an echo-contrast microbubble agent (Optison) into rat carotid artery balloon-injured model by using therapeutic ultrasound (US) to inhibit neointimal formation. Two weeks after transfection, the intimal to medial area ratio in E2F decoy+Optison+US group was significantly decreased (P < 0.01). Inhibition of cell growth was also confirmed by PCNA staining. No apparent toxicity such as inflammation could be detected in blood vessels transfected with E2F decoy ODN with Optison and ultrasound. Overall, the present studies demonstrated a novel non-viral ODN transfer method into blood vessels. A novel therapeutic strategy using E2F decoy ODN with Optison using ultrasound may be useful to inhibit restenosis in clinical practice without a viral vector.

Angioplasty, Balloon, Coronary↗
PubMed2005

A novel method for the intracellular delivery of siRNA using microbubble-enhanced focused ultrasound.

Short interfering RNA (siRNA) has attracted much attention for clinical use in various diseases. However, its delivery, especially through the cell membrane, continues to present a challenge. Advances in ultrasound- and ultrasound contrast-agent technologies have made it possible to change transiently the permeability of the cell membrane and, using a focused ultrasound transducer, to narrow and focus the ultrasound energy on a small target, thereby avoiding damage to surrounding tissue. In this in vitro study, we demonstrate that it is possible to deliver siRNA intracellularly via microbubble-enhanced focused ultrasound. Although further optimization is necessary, our novel method for siRNA transduction represents a powerful tool for using siRNA in vivo and possibly in the clinical setting.

Animals↗
PubMed2004

Targeted ultrasound imaging using microbubbles.

Targeted ultrasound imaging uses acoustically active contrast agents bearing a ligand on the surface that binds to a function-specific molecule. These ultrasound contrast agents are typically gas-filled microbubbles, nongaseous liposomes, or lipid-encapsulated perfluorocarbon emulsions. Binding of the contrast agent to the target results in persistent contrast enhancement during ultrasound imaging. This approach has been applied to the ultrasound imaging of pathophysiologic processes such as inflammation associated with ischemia reperfusion, heart transplant rejection, atherosclerotic plaque, thrombus, and apoptosis.

Animals↗
PubMed2004

Different behaviors of microbubbles in the liver: time-related quantitative analysis of two ultrasound contrast agents, Levovist and Definity.

The differences in time-related changes of liver images were compared quantitatively between Levovist and Definity. A total of 40 rabbits were assigned to eight groups according to the timing of taking enhanced liver images at 1, 3, 5, 7, 9, 11, 13 and 15 min by intermittent harmonic imaging using Levovist or Definity (30 microL/kg) and another 40 rabbits for Definity (50 microL/kg). Intensity changes between before and after enhancement in the portal vein (I-PV) and liver parenchyma (I-LP) were analyzed. I-PV was greater than I-LP at the 1- and 3-min phases of enhancement and I-LP became greater than I-PV with Levovist after 5 min. However, I-PV was higher than I-LP in all phases with Definity. Different time-intensity curves of these two agents will indicate discrete behaviors of microbubble hemodynamics in the liver; Levovist becomes accumulated in the liver, whereas Definity acts as a blood pool contrast agent, without accumulation.

Animals↗
PubMed2005

Erythrocytes, as well as microbubble contrast agents, are important factors in improving thermal and therapeutic effects of high-intensity focused ultrasound.

Erythrocytes, as well as microbubble contrast agents, are important factors in improving thermal effect of high-intensity focused ultrasound (US), or HIFU, and increasing the coagulation volume produced by HIFU irradiation. In vitro experiments used human plasma with various concentrations of human erythrocytes in combination with or without Levovist. In vivo experiments used eight Japan white rabbits with three degrees of anemia. Using a 2.17-MHz transducer, HIFU was applied for 60 s, and the temperature rise and the volume of coagulation necrosis was evaluated. There was a significant correlation between the HIFU-induced temperature rise and hematocrit, with a correlation coefficient of 0.998 (p=0.0001). Although the temperature rise was smaller at low hematocrit, it was significantly increased by adding Levovist in the suspension (p<0.01). The mean volume of coagulation necrosis was significantly greater in the rabbits with higher hematocrits (p<0.01), and that in the moderate anemia group was significantly increased by using Levovist (p<0.01).

Anemia↗
PubMed2005

Pressure-dependent attenuation with microbubbles at low mechanical index.

It has previously been shown that the attenuation of ultrasound (US) by microbubble contrast agents is dependent on acoustic pressure (Chen et al. 2002). Although previous studies have modelled the pressure-dependence of attenuation in single bubbles, this paper investigates this subject by considering a bulk volume of bubbles together with other linear attenuators. Specifically, a new pressure-dependent attenuation model for an inhomogeneous volume of attenuators is proposed. In this model, the effect of the attenuation on US propagation is considered. The model was validated using experimental measurements on the US contrast agent Sonovue. The results indicate, at low acoustic pressures, a linear relationship between the attenuation of Sonovue, measured in dB, and the insonating acoustic pressure.

Humans↗
PubMed2005

An ultrasonic microbubble semi-intermodulated imaging technique.

The performance of contrast imaging technique is critically influenced by some factors, such as spatial resolution, agent-to-tissue ratio, lifetime of contrast agents and attenuation effect. By using a transducer with higher frequency and higher bandwidth of transmitted signals, the spatial resolution can be improved. Similarly, a better signal-to-interference ratio (SIR) can improve the agent-to-tissue ratio, a lower transmission pressure can prolong the lifetime of contrast agents and a lower center frequency can diminish the attenuation effect. We extend the two-frequency analytic solutions of to approximate the short-pulse responses of microbubbles in a low-amplitude field. Based on their results, there is an expected component near 0 Hz in the spectrum of bubble echoes excited by a short pulse of ultrasound. Here, this component is called the low-frequency response; and it is shown to have a special bandwidth-dependent property and to have potential applications in imaging. We have established the procedure of semi-intermodulated (low-frequency) imaging and the effects of the attenuation effect on imaging resolution, SIR, and signal-to-noise ratio are also analyzed. The obtained experimental images demonstrate that the SIR in semi-intermodulated imaging is better than that in fundamental imaging under various attenuation conditions.

Contrast Media↗
PubMed2005

Targeting vascular endothelium with avidin microbubbles.

Targeting microbubbles (MBs) to specific vascular beds enables contrast ultrasound to be used for molecular imaging. There are several methods for attaching targeting moieties to the surface of MBs. In the present study, we demonstrate that avidin (Av) can be incorporated into the shell of perfluorocarbon-exposed sonicated dextrose albumin (PESDA) MBs (Av-PESDA-MBs) and serve as an anchor that links Av-PESDA-MBs to biotinylated monoclonal antibodies (mAbs). This novel linking strategy was used to conjugate Av-PESDA-MBs to mAbs specific for endoglin (CD105) or a control IgG. MBs targeted to CD105 specifically bound to endothelial cells, but not to fibroblasts, in vitro but Av-PESDA-MBs conjugated with the control IgG did not specifically target either cell type. We conclude that Av-PESDA-MBs represent a novel and attractive tool to conjugate MBs with biotinylated mAbs for the purposes of vascular targeting and molecular imaging.

Animals↗
PubMed2005

Ultrasound-microbubble-induced neovascularization in mouse skeletal muscle.

Ultrasound-microbubble (US-MB) interactions stimulate neovascularization in rat gracilis muscle (GM). We examined microvascular remodeling (MVR) in GMs of C57BL/6 and balb/C mice following ultrasonic MB destruction. A range of MB dosages were administered IV, and exposed GMs received US. Muscles harvested 3, 7 and 14 d posttreatment were stained for vascular markers and assessed for changes in microvessel number, diameter and length. Muscles receiving a low MB dose (LMBD) and US showed significant increases in microvascular density after 3 d, returning to sham levels after one week. A MB dose producing maximum capillary disruptions was then established. This high MB dose (HMBD) facilitated significant MVR in C57BL/6 mice after one week. Balb/C GMs exhibited neovascularization 3 d, but not 7 or 14 d, following US-HMBD treatment. We conclude that HMBD in C57BL/6 mice induces a more sustained neovascularization response compared to balb/C or LMBD-treated C57BL/6 muscles; however, this response is still impermanent.

Animals↗
PubMed2006

Transfection effect of microbubbles on cells in superposed ultrasound waves and behavior of cavitation bubble.

The combination of ultrasound and ultrasound contrast agents (UCAs) is able to induce transient membrane permeability leading to direct delivery of exogenous molecules into cells. Cavitation bubbles are believed to be involved in the membrane permeability; however, the detailed mechanism is still unknown. In the present study, the effects of ultrasound and the UCAs, Optison on transfection in vitro for different medium heights and the related dynamic behaviors of cavitation bubbles were investigated. Cultured CHO-E cells mixed with reporter genes (luciferase or beta-gal plasmid DNA) and UCAs were exposed to 1 MHz ultrasound in 24-well plates. Ultrasound was applied from the bottom of the well and reflected at the free surface of the medium, resulting in the superposition of ultrasound waves within the well. Cells cultured on the bottom of 24-well plates were located near the first node (displacement node) of the incident ultrasound downstream. Transfection activity was a function determined with the height of the medium (wave traveling distance), as well as the concentration of UCAs and the exposure time was also determined with the concentration of UCAs and the exposure duration. Survival fraction was determined by MTT assay, also changes with these values in the reverse pattern compared with luciferase activity. With shallow medium height, high transfection efficacy and high survival fraction were obtained at a low concentration of UCAs. In addition, capillary waves and subsequent atomized particles became significant as the medium height decreased. These phenomena suggested cavitation bubbles were being generated in the medium. To determine the effect of UCAs on bubble generation, we repeated the experiments using crushed heat-treated Optison solution instead of the standard microbubble preparation. The transfection ratio and survival fraction showed no additional benefit when ultrasound was used. These results suggested that cavitation bubbles created by the collapse of UCAs were a key factor for transfection, and their intensities were enhanced by the interaction of the superpose ultrasound with the decreasing the height of the medium. Hypothesizing that free cavitation bubbles were generated from cavitation nuclei created by fragmented UCA shells, we carried out numerical analysis of a free spherical bubble motion in the field of ultrasound. Analyzing the interaction of the shock wave generated by a cavitation bubble and a cell membrane, we estimated the shock wave propagation distance that would induce cell membrane damage from the center of the cavitation bubble.

Acoustics↗
PubMed2006

Microbubble disappearance-time is the appropriate timing for liver-specific imaging after injection of Levovist.

Contrast enhancement in the portal vein was repeatedly observed at 1 min intervals with wide-band Doppler ultrasonography in 152 consecutive patients (132 with liver cirrhosis and HCC, 20 controls), 5 min after the injection of Levovist. The duration time of contrast enhancement in the portal vein (microbubble disappearance-time; MD-T) was measured in all patients and contrast-enhanced appearances were compared between the 5 min phase and MD-T phase in 68 HCC nodules. MD-T in patients with liver cirrhosis (572.4 +/- 117.9 s) was significantly longer than in controls (481.6 +/- 89.3 s, p < 0.05). MD-T was prolonged in patients with Child B and C compared with Child A (p < 0.05). The contrast-enhanced appearances between the two phases were different in 30 of 68 HCC nodules (44.1%), showing positive enhancement in the 5 min phase and negative enhancement in the MD-T phase. The proposed MD-T may become an essential factor for the evaluation of liver-specific sonograms.

Adult↗