The anti-inflammatory target A(3) adenosine receptor is over-expressed in rheumatoid arthritis, psoriasis and Crohn's disease.

The Gi protein associated A(3) adenosine receptor (A(3)AR) was recently defined as a novel anti-inflammatory target. The aim of this study was to look at A(3)AR expression levels in peripheral blood mononuclear cells (PBMCs) of patients with autoimmune inflammatory diseases and to explore transcription factors involved receptor expression. Over-expression of A(3)AR was found in PBMCs derived from patients with rheumatoid arthritis (RA), psoriasis and Crohn's disease compared with PBMCs from healthy subjects. Bioinformatics analysis demonstrated the presence of DNA binding sites for nuclear factor-kappaB (NF-kappaB) and cyclic AMP-responsive element binding protein (CREB) in the A(3)AR gene promoter. Up-regulation of NF-kappaB and CREB was found in the PBMCs from patients with RA, psoriasis and Crohn's disease. The PI3K-PKB/Akt signaling pathway, known to regulate both the NF-kappaB and CREB, was also up-regulated in the patients' PBMCs. Taken together, NF-kappaB and CREB are involved with the over-expression of A(3)AR in patients with autoimmune inflammatory diseases. The receptor may be considered as a specific target to combat inflammation.

Elastographic image quality vs. tissue motion in vivo.

Elastography is a noninvasive method of imaging tissue elasticity using standard ultrasound equipment. In conventional elastography, axial strain elastograms are generated by cross-correlating pre- and postcompression digitized radio frequency (RF) echo frames acquired from the tissue before and after a small uniaxial compression, respectively. The time elapsed between the pre- and the postcompression frames is referred to as the interframe interval. For in vivo elastography, the interframe interval is critical because uncontrolled physiologic motion such as heartbeat, muscle motion, respiration and blood flow introduce interframe decorrelation that reduces the quality of elastograms. To obtain a measure of this decorrelation, in vivo experimental data (from human livers and thyroids) at various interframe intervals were obtained from 20 healthy subjects. To further examine the effect of the different interframe intervals on the elastographic image quality, the experimental data were also used in combination with elastographic simulation data. The deterioration of elastographic image quality was objectively evaluated by computing the area under the strain filter (SF) at a given resolution. The experimental results of this study demonstrate a statistical exponential behavior of the temporal decay of the echo signal cross-correlation amplitudes from the in vivo tissues due to uncontrollable motion. The results also indicate that the dynamic range and height of the SF are reduced at increased interframe intervals, suggesting that good objective image quality may be achieved provided only that a high frame rate is maintained in elastographic applications.

Effect of topical interferon-beta on recurrence rates in genital herpes: a double-blind, placebo-controlled, randomized study.

The aim of this randomized, double-blind placebo-controlled trial was to evaluate the effect of IFN-beta cream applied at the time of recurrent eruptions of genital herpes during 6 months on the overall rate of recurrence. Therapy was initiated at the clinic for the first treated recurrence, and thereafter by the patient for early treatment of eventual subsequent eruptions. Each recurrence was ascertained at the clinic in all 35 evaluable patients. The mean recurrence rate was significantly lower in the group using IFN-beta cream than in the placebo group (p = 0.03). Complete responders without recurrence for the duration of the trial were 36.4% of all patients and 46% among women versus 15.4 and 16.6% in the placebo groups, respectively. A total of 77.3% of all patients were defined as complete or partial responders, their average recurrences/year decreasing from 11 to 2.2 (p < 0.0001). The topical episodic IFN-beta treatment was well tolerated by patients and without side effects. It is concluded that IFN-beta cream application reduces the overall rate of recurrence of genital herpes.

Precision estimation and imaging of normal and shear components of the 3D strain tensor in elastography.

In elastography we have previously developed a tracking and correction method that estimates the axial and lateral strain components along and perpendicular to the compressor/scanning axis following an externally applied compression. However, the resulting motion is a three-dimensional problem. Therefore, in order to fully describe this motion we need to consider a 3D model and estimate all three principal strain components, i.e. axial, lateral and elevational (out-of-plane), for a full 3D tensor description. Since motion is coupled in all three dimensions, the three motion components have to be decoupled prior to their estimation. In this paper, we describe a method that estimates and corrects motion in three dimensions, which is an extension of the 2D motion tracking and correction method discussed before. In a similar way as in the 2D motion estimation, and by assuming that ultrasonic frames are available in more than one parallel elevational plane, we used methods of interpolation and cross-correlation between elevationally displaced RF echo segments to estimate the elevational displacement and strain. In addition, the axial, lateral and elevational displacements were used to estimate all three shear strain components that, together with the normal strain estimates, fully describe the full 3D normal strain tensor resulting from the uniform compression. Results of this method from three-dimensional finite-element simulations are shown.

Parametric vs nonparametric measurements in tissues with nonlinear frequency dependent attenuation.

The relationship between the attenuation parameters of tissue and the linear regression slope derived from nonparametric estimates of tissue attenuation is investigated. It was found that if the attenuation in the tissue possesses a nonlinear frequency dependence, the linear regression slope parameter becomes dependent on center frequency and on the bandwidth of the measurement. Moreover, it was found that the slope estimate is numerically close to the parameter derived from parametric attenuation measurements in such cases.

Experimental corroboration of the nonstationary strain estimation errors in elastography.

The nonstationary variation in the noise performance of the cross-correlation-based strain estimator due to frequency-dependent attenuation and lateral and elevational signal decorrelation have been addressed theoretically in recent papers using the strain-filter approach. In this paper, we present the experimental verification and corroboration of the nonstationary effects on the strain estimation results. The accuracy and precision of the strain estimate deteriorates with lateral position in the elastogram, due to the lateral motion of tissue scatterers, and with depth, due to frequency-dependent attenuation. The results illustrate that the best strain-estimation noise performance is obtained in the focal zone of the transducer and around the axis of symmetry of the phantom.

A zero-crossing strain estimator for elastography.

A novel zero-crossing tracking strain estimator (ZCT) has been developed for elastography. This technique is based on tracking the zero-crossings between the pre- and postcompression A-lines, and does not require global or adaptive A-line stretching. For multicompression elastography, ZCT can be implemented as a tracking scheme, where a temporal track of the zero-crossings between successive radiofrequency (RF) A-lines is obtained, or as an averaging scheme, where a cumulation of the interframe strains is performed, to yield high elastographic signal-to-noise ratio (SNR). Other advantages of the scheme include fast processing and its potential to be implemented in hardware. The limitations of the technique are the need for small compression steps due to lack of robustness when large compression steps (> 3% applied compression) are used. Simulations and experiments were performed to illustrate its utility as an alternative strain-estimation technique. This technique provides lower SNR but higher contrast-to-noise ratio (CNR) than the conventional strain-estimation techniques in elastography.

Diffraction correction methods for pulse-echo acoustic attenuation estimation.

We describe computer simulations and water tank experiments for the estimation of the attenuation coefficient in scattering media. The efficacies of the Axial Beam Translation (ABT) and Inverse Diffraction Filtering (IDF) methods in reducing diffraction errors in such estimates are compared throughout the radiation field of a plane transducer. The effect of phase aberration due to the body wall and the effect of the scattering properties of the media are considered. Consistent improvement in the estimation due to ABT is demonstrated as well as unreliable improvement due to IDF which is sensitive to the presence of phase aberration and to changes in scattering.

Estimating tissue strain from signal decorrelation using the correlation coefficient.

A simple relationship between the correlation coefficient and the applied strain, applicable only at low strains, is presented in this article. This relationship is derived for a Gaussian modulated cosine point spread function. The performance of the strain estimator is analyzed using a theoretical expression for the correlation coefficient along with simulation and experimental results. Both the theoretical and simulation results diverge from the ideal relationship between the strain and the correlation coefficient as the applied strain is increased. Simulation results illustrate that the strain estimate obtained using the correlation coefficient is a biased estimate with a large variability. Experimental results, however, illustrate that strain estimation using the 1-D correlation coefficient estimate is applicable only at high signal-to-noise ratios in the radiofrequency signal and in the absence of lateral and elevational signal decorrelation.

Correction of diffraction errors in attenuation estimation with Dynamic Beam Translation.

We describe computer simulations for the estimation of the attenuation coefficient in scattering media using the Dynamic Beam Translation (DBT) method. DBT refocuses a variable aperture transducer to maintain the focal characteristics of the transducer at different depths in order to reduce diffraction errors. The efficacy of DBT is evaluated for transducers with different focal powers and under the influence of phase aberration due to the body wall. DBT shows robustness in the elimination of diffraction errors and resistance to the effects of aberration.

Characterization of elastographic noise using the envelope of echo signals.

A theoretical formulation characterizing the noise performance of strain estimation using envelope signals is presented for the cross-correlation based strain estimator in elastography, using a modified strain filter approach. The strain filter describes the relationship among the elastographic signal-to-noise ratio (SNRe), sensitivity, contrast-to-noise ratio and dynamic range for a given resolution in the elastogram, as determined by the cross-correlation window length and window overlap. Theoretical results indicate that the envelope strain filter noise performance (SNRe level) is about half that obtained in the ratio frequency (RF) case (fo = 7.5 MHz). Simulation results corroborate the trend predicted using the strain filter. Experimental SNRe vs. strain plots presented in this article illustrate the same trend as the theoretical results. These plots allow a quantitative comparison of the elastograms obtained with RF and envelope signal processing. For small strains, the performance obtained using RF signals is superior to that obtained for envelope signals (since jitter errors are smaller due to the utilization of phase information in RF signals). However, for large tissue strains, envelope analysis provides an accurate estimate of the tissue strain (since envelope signal decorrelation is smaller than RF signal decorrelation at large strains). An algorithm that combines the low-noise characteristics of the cross-correlation analysis using RF signals at small strains and envelope signals for estimation of large tissue strains is proposed to improve the dynamic range in the elastogram.

An analysis of elastographic contrast-to-noise ratio.

We present a theoretical formalism and simulation results that allow the incorporation of the elastic contrast properties of tissues with simple geometries into the elastographic noise models developed previously. This analysis results in the computation of the elastographic contrast-to-noise ratio (CNRe). The CNRe in elastography is an important quantity that is related to the detectability of a lesion or inhomogeneity. In this paper, the upper bound on the elastographic CNRe is derived for both a one-dimensional (1-D) and 2-D analytic plane-strain tissue model. The CNRe in the elastogram depends on the contrast-transfer efficiency (CTE) for both the 1-D and 2-D geometries discussed in this paper. The 1-D model is used to characterize layered structures and the 2-D model is derived for circular inclusion within a background of uniform elasticity. A previously derived classical analytic solution of the elasticity equations, for a circular inclusion embedded in an infinite medium and subjected to a uniaxial compression, is used to compute the upper bound of the CNRe. Monte Carlo simulations illustrate the close correspondence between the theoretical and simulation results.

A new elastographic method for estimation and imaging of lateral displacements, lateral strains, corrected axial strains and Poisson's ratios in tissues.

A major disadvantage of the current practice of elastography is that only the axial component of the strain is estimated. The lateral and elevational components are basically disregarded, yet they corrupt the axial strain estimation by inducing decorrelation noise. In this paper, we describe a new weighted interpolation method operating between neighboring RF A-lines for high precision tracking of the lateral displacement. Due to this high lateral-tracking precision, quality lateral elastograms are generated that display the lateral component of the strain tensor. These precision lateral-displacement estimates allow a fine correction for the lateral decorrelation that corrupts the axial estimation. Finally, by dividing the lateral elastogram by the axial elastogram, we are able to produce a new image that displays the distribution of Poisson's ratios in the tissue. Results are presented from finite-element simulations and phantoms as well as in vitro and in vivo experiments.

Limits on the contrast of strain concentrations in elastography.

Using an analytic solution of the elasticity equation derived for a cylindrical inclusion, it is shown that the contrast of the strain concentrations is limited for both hard and soft lesions. This means that, beyond a given elastic modulus contrast, the strain concentrations remain virtually constant.

The nonstationary strain filter in elastography: Part I. Frequency dependent attenuation.

The accuracy and precision of the strain estimates in elastography depend on a myriad number of factors. A clear understanding of the various factors (noise sources) that plague strain estimation is essential to obtain quality elastograms. The nonstationary variation in the performance of the strain filter due to frequency-dependent attenuation and lateral and elevational signal decorrelation are analyzed in this and the companion paper for the cross-correlation-based strain estimator. In this paper, we focus on the role of frequency-dependent attenuation in the performance of the strain estimator. The reduction in the signal-to-noise ratio (SNRs) in the RF signal, and the center frequency and bandwidth downshift with frequency-dependent attenuation are incorporated into the strain filter formulation. Both linear and nonlinear frequency dependence of attenuation are theoretically analyzed. Monte-Carlo simulations are used to corroborate the theoretically predicted results. Experimental results illustrate the deterioration in the precision of the strain estimates with depth in a uniformly elastic phantom. Theoretical, simulation and experimental results indicate the importance of high SNRs values in the RF signals, because the strain estimation sensitivity, elastographic SNRe and dynamic range deteriorate rapidly with a decrease in the SNRs. In addition, a shift in the strain filter toward higher strains is observed at large depths in tissue due to the center frequency downshift.

The effects of digitization on the elastographic signal-to-noise ratio.

In elastography, the tissue under investigation is compressed and the resulting strain is estimated from the gradient of the displacement (time-delay) estimates. The displacements are typically estimated by cross-correlating the radiofrequency (RF) ultrasound signals of the pre- and postcompressed tissue. One of the parameters used to quantify the resulting quality of the elastogram is the elastographic signal-to-noise ratio (SNR(e)). For a uniformly elastic target (a single elastic modulus), the dependence of the SNR(e) on the applied strain has a bandpass characteristic that has been termed the strain filter. Theoretical expressions for the upper bound on the strain filter were developed earlier. Yet, simulated as well as experimental strain filters derived from uniformly elastic phantoms deviate from these upper bounds. The failure to achieve the upper bounds could be partially attributed to the fact that, in both simulations and experiments, the RF signals used to compute the TDEs are sampled and quantized. Using simulated models of uniformly elastic phantoms, a study of the dependence of the strain filter on the quantization and sampling rates was performed. The results indicated that the strain filter improves with both the sampling rate and the quantization, as expected. A theoretical analysis was done to incorporate quantization as a derating factor to the strain filter.

The measurement of attenuation in nonlinearly attenuating media by the zero crossing method.

A closed form expression relating the zero crossing density to the material parameters of media with nonlinear frequency dependent attenuation is derived for the case of Gaussian excitation. This expression indicates that for tissues which exhibit a small degree of such nonlinearity, significant errors in the determination of the material parameter result if the nonlinearity is ignored. This result is similar to that shown earlier [Narayana and Ophir (1983) Ultrasound in Med. & Biol. 9, 357-361] for frequency shift techniques.

Correlation of ultrasonic attenuation with pathologic fat and fibrosis in liver disease.

The attenuation coefficient in two groups (n1 = 70; n2 = 59) of pathologically graded in vitro human liver specimens was measured over a frequency range from 1.25-8.0 MHz and fitted to a power law model. The slopes of the power law curves at 5 MHz were correlated with pathological scores for fat in Group I, which consisted of normal and fatty livers (no fibrosis); they were also correlated with the pathological score for fibrosis in Group II, which consisted of normal and fibrotic livers (no intracellular fat). Significant (p less than 0.002) differences were found between the two groups. The fatty liver group exhibited approximately a 0.23 +/- 0.06 dB cm-1 MHz-1 (fat grade)-1 behavior (mean +/- s.d.), while the fibrotic liver group exhibited approximately a 0.11 +/- 0.01 dB cm-1 MHz-1 (fibrosis grade)-1 behavior. These results may explain some of the conflicting literature in this area, and suggest that attenuation may in principle be used for screening for liver disease, but not for differentiation between fatty and fibrotic conditions.

Phase aberration effects in elastography.

In sonography, phase aberration plays a role in the corruption of sonograms. Phase aberration does not have a significant impact on elastography, if statistically similar phase errors are present in both the pre- and postcompression signals. However, if the phase errors are present in only one of the pre- or postcompression signal pairs, the precision of the strain estimation process will be reduced. In some cases, increased phase errors may occur only in the postcompression signal due to changes in the tissue structure with the applied compression. Phase-aberration effects increase with applied strain and may be viewed as an image quality derating factor, much like frequency-dependent attenuation or undesired lateral tissue motion. In this paper, we present a theoretical and simulation study of the effects of phase aberration on the elastographic strain-estimation process, using the strain filter approach.

Contrast agents in diagnostic ultrasound.

We review the field of contrast agents in diagnostic ultrasound. The progress in the development of various classes of contrast agents such as free and encapsulated gas bubbles, colloidal suspensions, emulsions, and aqueous solutions is described. The mechanisms for production of backscatter contrast, as well as attenuation contrast and speed of sound contrast are explained. Finally, the potential advantages and disadvantages of various classes of contrast agents are compared.