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.

An experimental characterization of elastographic spatial resolution: analysis of the trade-offs between spatial resolution and contrast-to-noise ratio.

An experimental study of the spatial resolution in elastography was conducted. Models that involved two cylindrical inclusions arranged as a wedge were used to characterize the axial and lateral resolution of the axial strain elastograms. A study of the dependence of the spatial resolution on several factors such as the algorithmic parameters, the applied strain and the modulus contrast was performed. The axial resolution was found to show a linear dependence with respect to the algorithmic parameters, namely the window length and the window shift used for strain estimation. The lateral resolution showed a weak dependence on the algorithmic parameters. A weak dependence of the spatial resolution on factors such as the modulus contrast and the applied strain was found. The trade-offs between the spatial resolution and the elastographic contrast-to-noise ratio (CNR(e)) were then analyzed. A nonlinear trade-off between the CNR(e) and the axial and lateral resolution was shown for conventional strain estimation techniques, with the CNR(e) improving at a more than linear rate with respect to a linear degradation in the resolution. This study provided an experimental framework for characterizing the spatial resolution in elastography and facilitating a comparison of the CNR(e) with spatial resolution.

Theoretical derivation of SNR, CNR and spatial resolution for a local adaptive strain estimator for elastography.

Conventional techniques in elastography estimate the axial strain as the gradient of the displacement (time-delay) estimates obtained using cross-correlation of pre- and temporally stretched postcompression radiofrequency (RF) A-line segments. The use of a constant stretch factor for stretching the postcompression A-line is not adequate in the presence of heterogeneous targets that are commonly encountered. This led to the development of several adaptive strain estimation techniques in elastography. Yet, a theoretical framework for the image quality of adaptive strain estimation has not been established. In this work, we develop theoretical expressions for the image quality [measured in terms of the signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR) and spatial resolution] of elastograms obtained using an adaptive strain estimator developed by Alam et al. (1998). We show a linear trade-off between the SNR and axial resolution of the strain elastogram with respect to the window length used for strain estimation. The CNR shows a quadratic tradeoff with the axial resolution with respect to the window length. The SNR, CNR and axial resolution are shown to improve with the ultrasonic bandwidth.

A quantitative comparison of modulus images obtained using nanoindentation with strain elastograms.

Tissue stiffness is generally known to be associated with pathologic changes. Ultrasound (US) elastography, on the other hand, is capable of imaging tissue strain, which may or may not be well-correlated with tissue stiffness. Hence, a quantitative comparison between the elastographic tissue strain images and the corresponding tissue modulus images needed to be performed to evaluate the usefulness of elastography in imaging tissue stiffnesss properties. Simulations were performed to demonstrate and quantify the similarities between modulus images and strain elastograms. This was followed by comparing nanoindenter-based modulus images with strain elastograms of thin slices of tissue-mimicking phantoms. Finally, some beef slices, canine prostates, ovine kidneys and breast cancers grown in mice were used to demonstrate the qualitative correspondence between modulus images and strain elastograms. The simulations and the experiments indicated that it is feasible to perform quantitative comparisons between strain images (using elastography) and modulus images on certain tissue structures and geometries. A good quantitative correspondence (correlation values of greater than 0.8) between structures in the modulus and strain images could be obtained at scales equal to or larger than 20 Qlambda (where Q is the quality factor defined as the ratio of the center frequency over the band width and lambda is the wavelength of the US system) modulus contrasts larger than 5, applied strains between 0.5% and 3% and window lengths for computing strain elastograms between 3 Qlambda and 5 Qlambda. The gelatin-phantom experiments showed lower values of correlation (values around 0.5) than with theory and simulations. The decrease in correlation was attributed to the presence of measurement noise in both strain elastography and modulus imaging, an increase of dimensionality of the problem (from 2-D to 3-D), local anisotropy, heterogeneity and nonstationarity. Experiments on real tissue slices showed further decrease in the correlation to around 0.3, possibly due to additional confounding factors such as time-dependent mechanical properties and geometrical distortions in the tissue during imaging. The work presented in this paper demonstrates that there is an intrinsic relationship between strain elastograms and the actual distribution of soft tissue elastic moduli, and bodes well for continued work in the area of elastography.

Trade-offs between the axial resolution and the signal-to-noise ratio in elastography.

Elastography involves tracking the ultrasonic A-mode signals before and after mechanical compression of tissue to form a computed image of the local strains undergone by various tissue components. The quality of the strain estimates in elastography is typically quantified using factors such as the elastographic SNR (SNR(e)), contrast-to-noise ratio (CNR(e)), and the spatial resolution. These quality factors depend on the mechanical parameters (such as the applied strain and the boundary conditions), the acoustic parameters (such as the sonographic SNR, the center frequency, and the bandwidth), and the signal-processing parameters (such as the window length and the window separation). Theoretical developments in elastography have established functional relationships between the SNR(e) and CNR(e) and these parameters. Similarly, simulations have established empirical relationships between the axial resolution and the acoustic and signal-processing parameters. We find that a trade-off exists between the achievable SNR(e) (CNR(e)) and the axial resolution in elastography and that the trade-off occurs only with respect to the signal-processing parameters. Theoretical work on the spatial resolution accompanied with simulations and experiments were used to confirm such an observation. The trade-off between the SNR(e) (CNR(e)) and the resolution was found to be nonlinear, with large improvements in the SNR(e) being possible at the expense of small reductions in the axial resolution. All the quality factors improve with the acoustic parameters, which suggests the preferred use of transducers with high absolute bandwidths and center frequencies.

Tissue-mimicking oil-in-gelatin dispersions for use in heterogeneous elastography phantoms.

A ten-month study is presented of materials for use in heterogeneous elastography phantoms. The materials consist of gelatin with or without a suspension of microscopic safflower oil droplets. The highest volume percent of oil in the materials is 50%. Thimerosal acts as a preservative. The greater the safflower oil concentration, the lower the Young's modulus. Elastographic data for heterogeneous phantoms, in which the only variable is safflower oil concentration, demonstrate stability of inclusion geometry and elastic strain contrast. Young's modulus ratios (elastic contrasts) producible in a heterogeneous phantom are as high as 2.7. The phantoms are particularly useful for ultrasound elastography. They can also be employed in MR elastography, although the highest achievable ratio of longitudinal to transverse relaxation times is considerably less than is the case for soft tissues.

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.

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.

Analysis of an adaptive strain estimation technique in elastography.

Elastography is based on the estimation of strain due to tissue compression or expansion. Conventional elastography involves computing strain as the gradient of the displacement (time-delay) estimates between gated pre- and postcompression signals. Uniform temporal stretching of the postcompression signals has been used to reduce the echo-signal decorrelation noise. However, a uniform stretch of the entire postcompression signal is not optimal in the presence of strain contrast in the tissue and could result in loss of contrast in the elastogram. This has prompted the use of local adaptive stretching techniques. Several adaptive strain estimation techniques using wavelets, local stretching and iterative strain estimation have been proposed. Yet, a quantitative analysis of the improvement in quality of the strain estimates overconventional strain estimation techniques has not been reported. We propose a two-stage adaptive strain estimation technique and perform a quantitative comparison with the conventional strain estimation techniques in elastography. In this technique, initial displacement and strain estimates using global stretching are computed, filtered and then used to locally shift and stretch the postcompression signal. This is followed by a correlation of the shifted and stretched postcompression signal with the precompression signal to estimate the local displacements and hence the local strains. As proof of principle, this adaptive stretching technique was tested using simulated and experimental data.

Estimating the elastographic signal-to-noise ratio using correlation coefficients.

In conventional elastography, strain is estimated from the gradient of the displacement (time-delay) estimates. The displacement estimates involve estimating the peak location of the cross-correlation function between matching pre- and post-compression A-lines. Bias errors in estimating the peak location of the cross-correlation function, amplified by the gradient operation on the displacement estimates (needed for the computation of the strain), could result in values of elastographic signal-to-noise ratio (SNR(e)) that exceed the theoretical upper bounds, thereby hindering a consistent interpretation of this parameter. These algorithmic errors have not been accounted for by the theory. We propose the use of the measured correlation coefficients in the theoretical SNR(e) expressions to estimate the SNR(e), rather than computing them directly from the elastograms. This methodology results in values of SNR(e) that are lower than the theoretical upper bounds, thereby avoiding the problems associated with computing SNR(e) directly from the elastograms. Using simulated models of uniformly elastic phantoms, a proof of principle of such an SNR(e) measure is shown.

Elastographic imaging using staggered strain estimates.

Conventional techniques in elastography estimate strain as the gradient of the displacement estimates obtained through crosscorrelation of pre- and postcompression rf A-lines. In these techniques, the displacements are estimated over overlapping windows and the strains are estimated as the gradient of the displacement estimates over adjacent windows. The large amount ofnoise at high window overlaps may result in poor quality elastograms, thus restricting the applicability of conventional strain estimation techniques to low window overlaps, which, in turn, results in a small number of pixels in the image. To overcome this restriction, we propose a multistep strain estimation technique. It computes the first elastogram using nonoverlapped windows. In the next step, the data windows are shifted by a small distance (small fraction of window size) and another elastogram is produced. This is repeated until the cumulative shift equals/exceeds the window size and all the elastograms are staggered to produce the final elastogram. Simulations and experiments were performed using this technique to demonstrate significant improvement in the elastographic signal-to-noise ratio (SNRe) and the contrast-to-noise ratio (CNRe) at high window overlaps over conventional strain estimation techniques, without noticeable loss of spatial resolution. This technique might be suitable for reducing the algorithmic noise in the elastograms at high window overlaps.

Poroelastography: imaging the poroelastic properties of tissues.

In the field of elastography, biological tissues are conveniently assumed to be purely elastic solids. However, several tissues, including brain, cartilage and edematous soft tissues, have long been known to be poroelastic. The objective of this study is to show the feasibility of imaging the poroelastic properties of tissue-like materials. A poroelastic material is a material saturated with fluid that flows relative to a deforming solid matrix. In this paper, we describe a method for estimating the poroelastic attributes of tissues. It has been analytically shown that during stress relaxation of a poroelastic material (i.e., sustained application of a constant applied strain over time), the lateral-to-axial strain ratio decreases exponentially with time toward the Poisson's ratio of the solid matrix. The time constant of this variation depends on the elastic modulus of the solid matrix, its permeability and its dimension along the direction of fluid flow. Recently, we described an elastographic method that can be used to map axial and lateral tissue strains. In this study, we use the same method in a stress relaxation case to measure the time-dependent lateral-to-axial strain ratio in poroelastic materials. The resulting time-sequenced images (poroelastograms) depict the spatial distribution of the fluid within the solid at each time instant, and help to differentiate poroelastic materials of distinct Poisson's ratios and permeabilities of the solid matrix. Results are shown from finite-element simulations.

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-transfer efficiency for continuously varying tissue moduli: simulation and phantom validation.

This study consisted of two parts. In the first part, the contrast-transfer efficiency (CTE) in elastography was extended to account for continuous changes of modulus distribution. It was shown that, for a finite size background, the strain contrast approaches the modulus contrast in the case of Gaussian distributions. Thus, an increase in the CTE was obtained. For a fixed background size, it was shown that the CTE increases as the SD of the Gaussian distribution increases. This property was explained by the redistribution of strain concentrations at the inclusion/background interface. In the second part of the study, the CTE was verified experimentally. Six gelatin/agar/water-based phantoms embedding inclusions with modulus contrast varying between +/- 6 dB were manufactured. It was shown that the modulus at the interface inclusion/background was continuous and, in turn, resulted in an increase of the CTE as compared to the known case of a sharp boundary. The continuous inclusion/background interface was explained by the existence of an osmotic pressure gradient.

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.

Clinical significance of markedly elevated serum creatine kinase levels in patients with acne on isotretinoin.

Muscle-related complaints and high creatine kinase (CK) blood levels have been reported in 16-51% of patients with acne treated with isotretinoin. It has been suggested that this retinoid and exercise have a synergistic effect on muscle. The presence of marked hyperCKemia during the treatment raises concern about rhabdomyolysis. The objective of this report was to evaluate the incidence, course and clinical significance of severe hyperCKemia in isotretinoin therapy for acne. Out of 442 patients on isotretinoin, we reviewed 7 patients (1.58%) with CK values above 5,000 IU/l. Only two of them had myalgia. Physical activity or intramuscular injection prior to blood testing was reported in 6 patients. CK values returned to normal within 2 weeks and all subjects except 2, completed treatment. In conclusion, marked hyperCKemia with or without muscle-related complaints in isotretinoin-treated patients with acne is a benign phenomenon.

Tradeoffs in elastographic imaging.

This paper presents the tradeoffs in elastographic imaging. Elastography is viewed as a new imaging modality and presented in terms of three fundamental concepts that constitute the basis for the elastographic imaging process. These are the tissue elastic deformation process, the statistical analysis of strain estimation and the image characterization. The first concept involves the use of the contrast transfer efficiency (CTE) that describes the mapping of a distribution of local tissue elastic moduli into a distribution of local longitudinal tissue strains. The second concept defines the elastographic system and the relationship between ultrasonic and signal processing parameters. This process is described in terms of a stochastic framework (the strain filter) that provides upper and practical performance bounds and their dependence on the various system parameters. Finally, the output image, the elastogram, is characterized by its image parameters, such as signal-to-noise ratio, contrast-to-noise ratio, dynamic range and resolution. Finite-element simulations are used to generate examples of elastograms that are confirmed by the theoretical prediction tools.

Nonlinear stress-strain relationships in tissue and their effect on the contrast-to-noise ratio in elastograms.

The practice of elastography is generally limited to small applied compressions (typically 1%), under the assumption of a linear stress-strain relationship in biological tissue. However, the recent reports of larger applied compressions and precompression levels to increase the strain contrast violate the above assumption. The nonlinear stress-strain relationships in different breast tissue types significantly alter the contrast in elastography, especially for large applied compression. The moduli of normal fibrous and glandular breast tissue (along with cancerous lesions) are strain-dependent, with tissue stiffness increasing with applied compression. In this paper, we illustrate that the strain-dependence of the modulus has a significant impact on the elastographic contrast and on the contrast-to-noise ratio, and may even cause a reversal of the contrast in certain situations. This paper also emphasizes the effect of the precompression strain level on the strain contrast.

Psoriatic arthritis: interrelationships between skin and joint manifestations related to onset, course and distribution.

To assess the relationships between skin and joint disease, 70 patients with psoriatic arthritis were consecutively evaluated. Data were obtained regarding age, sex, duration of disease, age at onset, and flares of both skin and joint disease. Rheumatological assessment included morning stiffness, number of swollen, tender and deformed joints, involvement of distal interphalangeal joints (DIP), presence of dactylitis, Achilles tendinitis, and clinical lumbar and cervical involvement. Skin assessment included recording of the distribution of skin lesions and nail involvement, and grading of psoriasis severity using the PASI. The scalp was the most frequently involved site. Significant correlation was found between the PASI score and the number of deformed joints and Schober's test. The scalp score was found to correlate with the number of swollen joints, deformed joints, sausage finger and DIP involvement. Synchronous flares of skin and joint were significantly more frequent in the patients with onset of skin and joint diseases within the same year. Likewise, these patients showed a highly significant association between the PASI score and the number of tender, swollen and deformed joints, Schober's test and cervical involvement, whereas no such associations were found among patients with separate onset of skin and joint diseases.