Comparison of contrast-enhanced multi-station MR angiography and digital subtraction angiography of the lower extremity arterial disease

PURPOSE: To compare diagnostic accuracy of multi-station, high-spatial resolution contrast-enhanced MR angiography (CE-MRA) of the lower extremities with digital subtraction angiography (DSA) as the reference standard in patients with symptomatic peripheral arterial occlusive disease. MATERIALS AND METHODS: Of 485 consecutive patients undergoing a run-off CE-MRA, 152 patients (86 male, 66 female; mean age, 71.6 years) with suspected peripheral arterial occlusive disease were included into our Institutional Review Board approved study. All patients underwent MRA and DSA of the lower extremities within 30 days. MRA was performed at 1.5 Tesla with a single bolus of 0.1 mmol/kg body weight of gadobutrol administered at a rate of 2.0 mL/s at three stations. Two readers evaluated the MRA images independently for stenosis grade and image quality. Sensitivity and specificity were derived. RESULTS: Sensitivity and specificity ranged from 73% to 93% and 64% to 89% and were highest in the thigh area. Both readers showed comparable results. Evaluation of good and better quality MRAs resulted in a considerable improvement in diagnostic accuracy. CONCLUSION: Contrast-enhanced MRA demonstrates good sensitivity and specificity in the investigation of the vasculature of the lower extremities. While a minor investigator experience dependence remains, it is standardizable and shows good inter-observer agreement. Our results confirm that the administration of Gadobutrol at a standard dose of 0.1 mmol/kg for contrast-enhanced runoff MRA is able to detect hemodynamically relevant stenoses. Use of contrast-enhanced MRA as an alternative to intra-arterial DSA in the evaluation and therapeutic planning of patients with suspected peripheral arterial occlusive disease is well justified. J. Magn. Reson. Imaging 2013;37:1427-1435. © 2012 Wiley Periodicals, Inc.

Enhancing Sensitivity In Natural Product Nmr: Exploring Optimal Non-Uniform Sampling

Recent optimizations of NMR spectroscopy have focused their attention on innovations in new hardware, such as novel probes and higher field strengths. Only recently has the potential to enhance the sensitivity of NMR through data acquisition strategies been investigated. This thesis has focused on the practice of enhancing the signal-to-noise ratio (SNR) of NMR using non-uniform sampling (NUS). After first establishing the concept and exact theory of compounding sensitivity enhancements in multiple non-uniformly sampled indirect dimensions, a new result was derived that NUS enhances both SNR and resolution at any given signal evolution time. In contrast, uniform sampling alternately optimizes SNR (t < 1.26T2) or resolution (t~3T2), each at the expense of the other. Experiments were designed and conducted on a plant natural product to explore this behavior of NUS in which the SNR and resolution continue to improve as acquisition time increases. Possible absolute sensitivity improvements of 1.5 and 1.9 are possible in each indirect dimension for matched and 2x biased exponentially decaying sampling densities, respectively, at an acquisition time of ¿T2. Recommendations for breaking into the linear regime of maximum entropy (MaxEnt) are proposed. Furthermore, examination into a novel sinusoidal sampling density resulted in improved line shapes in MaxEnt reconstructions of NUS data and comparable enhancement to a matched exponential sampling density. The Absolute Sample Sensitivity derived and demonstrated here for NUS holds great promise in expanding the adoption of non-uniform sampling.

Comparison of inversion recovery and contrast-enhanced T1-weighted fat-suppressed sequences for the staging of cervical lymphoma

In a retrospective analysis with two readers blinded to the clinical information, coronal short tau inversion recovery (STIR) images were compared to contrast-enhanced fat-saturated T1-weighted imaging (T1 CEfs) in 51 cases of cervical lymphoma. Interrater reliability was good to excellent. Although sensitivity and subjective quality of the STIR sequence were higher than those of the T1 CEfs sequence (sensitivity 85%/72%, respectively), specificity (82%/95%) as well as positive likelihood ratio (4.65/15.93) was much lower. Therefore, contrast-enhanced sequences should be included in the primary staging of lymphoma.

Diagnostic efficacy of SonoVue, a second generation contrast agent, in the assessment of extracranial carotid or peripheral arteries using colour and spectral Doppler ultrasound: a multicentre study

The purpose of this study was to demonstrate the improvement in diagnostic quality and diagnostic accuracy of SonoVue microbubble contrast-enhanced ultrasound (CE-US) versus unenhanced ultrasound imaging during the investigation of extracranial carotid or peripheral arteries. 82 patients with suspected extracranial carotid or peripheral arterial disease received four SonoVue doses (0.3 ml, 0.6 ml, 1.2 ml and 2.4 ml) with Doppler ultrasound performed before and following each dose. Diagnostic quality of the CE-US examinations was evaluated off-site for duration of clinically useful contrast enhancement, artefact effects and percentage of examinations converted from non-diagnostic to diagnostic. Accuracy, sensitivity and specificity were assessed as agreement of CE-US diagnosis evaluated by an independent panel of experts with reference standard modality. The median duration of clinically useful signal enhancement significantly increased with increasing SonoVue doses (p< or =0.002). At the dose of 2.4 ml of SonoVue, diagnostic quality evaluated as number of inconclusive examinations significantly improved, falling from 40.7% at baseline down to 5.1%. Furthermore, SonoVue significantly (p<0.01) increased the accuracy, sensitivity and specificity of assessment of disease compared with baseline ultrasound. SonoVue increases the diagnostic quality of Doppler images and improves the accuracy of both spectral and colour Doppler examinations of extracranial carotid or peripheral arterial disease.

Quantitative stress echocardiography in coronary artery disease using contrast-based myocardial blood flow measurements: prospective comparison with coronary angiography

AIM: To test whether quantitative stress echocardiography using contrast-based myocardial blood flow (MBF, ml x min(-1) x g(-1)) measurements can detect coronary artery disease in humans. METHODS: 48 patients eligible for pharmacological stress testing by myocardial contrast echocardiography (MCE) and willing to undergo subsequent coronary angiography were prospectively enrolled in the study. Baseline and adenosine-induced (140 microg x kg(-1) x min(-1)) hyperaemic MBF was analysed according to a three-coronary-artery-territory model. Vascular territories were categorised into three groups with increasing stenosis severity defined as percentage diameter reduction by quantitative coronary angiography. RESULTS: Myocardial blood flow reserve (MBFR)-that is, the ratio of hyperaemic to baseline MBF, was obtained in 128 (89%) territories. Mean (SD) baseline MBF was 1.073 (0.395) ml x min(-1) x g(-1) and did not differ between territories supplied by coronary arteries with mild (<50% stenosis), moderate (50%-74% stenosis) or severe (>or=75% stenosis) disease. Mean (SD) hyperaemic MBF and MBFR were 2.509 (1.078) ml x min(-1) x g(-1) and 2.54 (1.03), respectively, and decreased linearly (r2 = 0.21 and r2 = 0.39) with stenosis severity. ROC analysis revealed that a territorial MBFR <1.94 detected >or=50% stenosis with 89% sensitivity and 92% specificity. CONCLUSION: Quantitative stress testing based on MBF measurements derived from contrast echocardiography is a new method for the non-invasive and reliable assessment of coronary artery disease in humans.

Renal artery assessment with nonenhanced steady-state free precession versus contrast-enhanced MR angiography

PURPOSE: To prospectively assess the diagnostic accuracy of nonenhanced three-dimensional (3D) steady-state free precession (SSFP) magnetic resonance (MR) angiography for detection of renal artery stenosis (RAS), with breath-hold contrast material-enhanced MR angiography performed as the reference standard. MATERIALS AND METHODS: The study was local ethics committee approved; all patients gave written informed consent. Fifty-three patients (30 male, 23 female; mean age, 58 years) with arterial hypertension and suspected of having RAS were examined with 1.5-T 3D SSFP renal MR angiography. Stenosis grade, maximal visible vessel length, and subjective image quality were compared. Sensitivity, specificity, accuracy, and negative predictive value (NPV) were calculated on artery-by-artery and patient-by-patient bases. The significance of the results was assessed with the paired two-sided t test for continuous variables and with the marginal homogeneity test for categorical variables. Cohen kappa statistics were used to estimate interobserver agreement. RESULTS: One hundred eight renal arteries with 20 significant (>or=50%) stenoses were detected with contrast-enhanced MR angiography. At artery-by-artery analysis, sensitivity, specificity, accuracy, and NPV of nonenhanced SSFP MR angiography for RAS detection were 100%, 93%, 94%, and 100%, respectively, for observer 1 and 95%, 95%, 95%, and 99%, respectively, for observer 2. Corresponding patient-by-patient values were 100%, 92%, 94%, and 100%, respectively, for observer 1 and 100%, 95%, 96%, and 100%, respectively, for observer 2. Overestimation of stenosis grade with SSFP MR angiography resulted in six and four false-positive findings for readers 1 and 2, respectively. Mean maximal visible lengths of the renal arteries were 69.9 mm at contrast-enhanced MR angiography and 61.1 mm at SSFP MR angiography (P<.001). Both techniques yielded good to excellent image quality. CONCLUSION: Slab-selective inversion-prepared 3D SSFP MR angiography had high sensitivity, specificity, accuracy, and NPV for RAS detection, without the need for contrast material. However, RAS severity was overestimated in some patients.

Myocardial contrast echocardiography for the distinction of hypertrophic cardiomyopathy from athlete's heart and hypertensive heart disease

BACKGROUND: Myocardial contrast echocardiography (MCE) is able to measure in vivo relative blood volume (rBV, i.e., capillary density), and its exchange frequency b, the constituents of myo-cardial blood flow (MBF, ml min-1 g-1). This study aimed to assess, by MCE, whether left ventricular hypertrophy (LVH) in hypertrophic cardiomyopathy (HCM) can be differentiated from LVH in triathletes (athlete's heart, AH) or from hypertensive heart disease patients (HHD). METHODS: Sixty individuals, matched for age (33 +/- 10 years) and gender, and subdivided into four groups (n = 15) were examined: HCM, AH, HHD and a group of sedentary individuals without LVH (S). rBV (ml ml-1), b (min-1) and MBF, at rest and during adenosine-induced hyperaemia, were derived by MCE in mid septal, lateral and inferior regions. The ratio of MBF during hyperaemia and MBF at rest yielded myocardial blood flow reserve (MBFR). RESULTS: Septal wall rBV at rest was lower in HCM (0.084 +/- 0.023 ml ml-1) than in AH (0.151 +/- 0.024 ml ml-1, p <0.01) and in S (0.129 +/- 0.026 ml ml-1, p <0.01), but was similar to HHD (0.097 +/- 0.016 ml ml-1). Conversely, MBFR was lowest in HCM (1.67 +/- 0.93), followed by HHD (2.8 +/- 0.93, p <0.01), by S (3.36 +/- 1.03, p <0.001) and by AH (4.74 +/- 1.46, p <0.0001). At rest, rBV <0.11 ml ml-1 accurately distinguished between HCM and AH (sensitivity 99%, specificity 99%), similarly MBFR < or =1.8 helped to distinguish between HCM and HHD (sensitivity 100%, specificity 77%). CONCLUSIONS: rBV at rest, most accurately distinguishes between pathological LVH due to HCM and physiological, endurance-exercise induced LVH.

Retinoic acid reduces glucocorticoid sensitivity in C2C12 myotubes by decreasing 11beta-hydroxysteroid dehydrogenase type 1 and glucocorticoid receptor activities

Vitamin A is a nutrient with remarkable effects on adipose tissue and skeletal muscles, and plays a role in controlling energy balance. Retinoic acid (RA), the carboxylic form of vitamin A, has been associated with improved glucose tolerance and insulin sensitivity. In contrast, elevated glucocorticoids have been implicated in the development of insulin resistance and impaired glucose tolerance. Here, we investigated whether RA might counteract glucocorticoid effects in skeletal muscle cells by lowering 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1)-dependent local glucocorticoid activation and/or activation of glucocorticoid receptor (GR). We found a dose-dependent down-regulation of 11beta-HSD1 mRNA expression and activity upon incubation of fully differentiated mouse C2C12 myotubes with RA. In addition, RA inhibited GR transactivation by an 11beta-HSD1-independent mechanism. The presence of RA during myogenesis did not prevent myotube formation but resulted in relatively glucocorticoid-resistant myotubes, exhibiting very low 11beta-HSD1 expression and GR activity. The use of selective retinoic acid receptor (RAR) and retinoid X receptor ligands provided evidence that these effects were mediated through RARgamma. Importantly, short hairpin RNA against RARgamma abolished the effect of RA on 11beta-HSD1 and GR. In conclusion, we provide evidence for an important role of RA in the control of glucocorticoid activity during myogenesis and in myotubes. Disturbances of the nutrient and hormonal regulation of glucocorticoid action in skeletal muscles might be relevant for metabolic diseases.

Molecular analysis of TNF sensitivity in normal and Ha-{\it ras\/} transformed murine fibroblasts

Tumor necrosis factor (TNF) is known to have antiproliferative effects on a wide variety of tumor cells but proliferative effects on normal cells. However, the molecular basis for such differences in the action of TNF are unknown. The overall objectives of my research are to investigate the role of oncogenes in TNF sensitivity and delineate some of the molecular mechanisms involved in TNF sensitivity and resistance. To accomplish these objectives, I transfected TNF-resistant C3H mouse embryo fibroblasts (10T1/2) with an activated Ha-ras oncogene and determined whether these cells exhibit altered sensitivity to TNF. The results indicated that 10T1/2 cells transfected with an activated Ha-ras oncogene (10T-EJ) not only produced tumors in nude mice but also exhibited extreme sensitivity to cytolysis by TNF. In contrast, 10T1/2 cells transfected with the pSV2-neo gene alone were resistant to the cytotoxic effects of TNF. I also found that TNF-induced cell death was mediated through apoptosis. The differential sensitivity of 10T1/2 and 10T-EJ cell lines to TNF was not due to differences in the number of TNF receptors on their cell surface. In addition, TNF-resistant revertants isolated from Ha-ras-transformed, TNF-sensitive cells still expressed the same amount of p21 as TNF-sensitive cells and were still tumorigenic, suggesting that Ha-ras-induced transformation and TNF sensitivity may follow different pathways. Interestingly, TNF-resistant but not sensitive cells expressed higher levels of bcl-2, c-myc, and manganese superoxide dismutase (MnSOD) mRNA following exposure to TNF. However, TNF treatment resulted in a marginal induction of p53 mRNA in both TNF-sensitive and resistant cells. Based on these results I can conclude that (i) Ha-ras oncogene induces both transformation and TNF sensitivity, (ii) TNF-induced cytotoxicity involves apoptosis, and (iii) TNF-induced upregulation of bcl-2, c-myc, and MnSOD genes is associated with TNF resistance in C3H mouse embryo fibroblasts. ^

Detecting determinism with improved sensitivity in time series: Rank-based nonlinear predictability score

The rank-based nonlinear predictability score was recently introduced as a test for determinism in point processes. We here adapt this measure to time series sampled from time-continuous flows. We use noisy Lorenz signals to compare this approach against a classical amplitude-based nonlinear prediction error. Both measures show an almost identical robustness against Gaussian white noise. In contrast, when the amplitude distribution of the noise has a narrower central peak and heavier tails than the normal distribution, the rank-based nonlinear predictability score outperforms the amplitude-based nonlinear prediction error. For this type of noise, the nonlinear predictability score has a higher sensitivity for deterministic structure in noisy signals. It also yields a higher statistical power in a surrogate test of the null hypothesis of linear stochastic correlated signals. We show the high relevance of this improved performance in an application to electroencephalographic (EEG) recordings from epilepsy patients. Here the nonlinear predictability score again appears of higher sensitivity to nonrandomness. Importantly, it yields an improved contrast between signals recorded from brain areas where the first ictal EEG signal changes were detected (focal EEG signals) versus signals recorded from brain areas that were not involved at seizure onset (nonfocal EEG signals).

MR Angiography at 3 Tesla to Assess Proximal Internal Carotid Artery Stenoses: Contrast-Enhanced or 3D Time-of-Flight MR Angiography?

PURPOSE The aim of this study was to compare the diagnostic accuracy of 3D time-of-flight (TOF-MRA) and contrast-enhanced (CE-MRA) magnetic resonance angiography at 3 T for detection and quantification of proximal high-grade stenosis using multidetector computed tomography angiography (MDCTA) as reference standard. METHODS The institutional ethics committee approved this prospective study. A total of 41 patients suspected of having internal carotid artery (ICA) stenosis underwent both MDCTA and MRA. CE-MRA and TOF-MRA were performed using a 3.0-T imager with a dedicated eight-element cervical coil. ICA stenoses were measured according to the North American Symptomatic Carotid Endarterectomy Trial criteria and categorized as 0-25 % (minimal), 25-50 % (mild), 50-69 % (moderate), 70-99 % (high grade), and 100 % (occlusion). Sensitivity and specificity for the detection of high-grade ICA stenoses (70-99 %) and ICA occlusions were determined. In addition, intermodality agreement was assessed with κ-statistics for detection of high-grade ICA stenoses (70-99 %) and ICA occlusions. RESULTS A total of 80 carotid arteries of 41 patients were reviewed. Two previously stented ICAs were excluded from analysis. On MDCTA, 7 ICAs were occluded, 12 ICAs presented with and 63 without a high-grade ICA stenosis (70-99 %). For detecting 70-99 % stenosis, both 3D TOF-MRA and CE-MRA were 91.7 % sensitive and 98.5 % specific, respectively. Both MRA techniques were highly sensitive (100 %), and specific (CE-MRA, 100 %; TOF-MRA, 98.7 %) for the detection of ICA occlusion. However, TOF-MRA misclassified one high-grade stenosis as occlusion. Intermodality agreement for detection of 70-99 % ICA stenoses was excellent between TOF-MRA and CE-MRA [κ = 0.902, 95 % confidence interval (CI) = 0.769-1.000], TOF-MRA and MDCTA (κ = 0.902, 95 % CI = 0.769-1.000), and CE-MRA and MDCTA (κ = 0.902, 95 % CI = 0.769-1.000). CONCLUSION Both 3D TOF-MRA and CE-MRA at 3 T are reliable tools for detecting high-grade proximal ICA stenoses (70-99 %). 3D TOF-MRA might misclassify pseudo-occlusions as complete occlusions. If there are no contraindications for CE-MRA, CE-MRA is recommended as primary MR imaging modality.

Evaluation of treatment response after chemoembolisation (TACE) in hepatocellular carcinoma using real time image fusion of contrast-enhanced ultrasound (CEUS) and computed tomography (CT)--preliminary results.

OBJECTIVE To evaluate treatment response of hepatocellular carcinoma (HCC) after transarterial chemoembolization (TACE) with a new real-time imaging fusion technique of contrast-enhanced ultrasound (CEUS) with multi-slice detection computed tomography (CT) in comparison to conventional post-interventional follow-up. MATERIAL AND METHODS 40 patients with HCC (26 male, ages 46-81 years) were evaluated 24 hours after TACE using CEUS with ultrasound volume navigation and image fusion with CT compared to non-enhanced CT and follow-up contrast-enhanced CT after 6-8 weeks. Reduction of tumor vascularization to less than 25% was regarded as "successful" treatment, whereas reduction to levels >25% was considered as "partial" treatment response. Homogenous lipiodol retention was regarded as successful treatment in non-enhanced CT. RESULTS Post-interventional image fusion of CEUS with CT was feasible in all 40 patients. In 24 patients (24/40), post-interventional image fusion with CEUS revealed residual tumor vascularity, that was confirmed by contrast-enhanced CT 6-8 weeks later in 24/24 patients. In 16 patients (16/40), post-interventional image fusion with CEUS demonstrated successful treatment, but follow-up CT detected residual viable tumor (6/16). Non-enhanced CT did not identify any case of treatment failure. Image fusion with CEUS assessed treatment efficacy with a specificity of 100%, sensitivity of 80% and a positive predictive value of 1 (negative predictive value 0.63). CONCLUSIONS Image fusion of CEUS with CT allows a reliable, highly specific post-interventional evaluation of embolization response with good sensitivity without any further radiation exposure. It can detect residual viable tumor at early state, resulting in a close patient monitoring or re-therapy.

A Model Study of the Circulation in the Pearl River Estuary (PRE) and Its Adjacent Coastal Waters: 2. Sensitivity Experiments

The Princeton Ocean Model is used to study the circulation in the Pear River Estuary (PRE) and the adjacent coastal waters in the winter and summer seasons. Wong et al. [2003] compares the simulation results with the in situ measurements collected during the Pearl River Estuary Pollution Project (PREPP). In this paper, sensitivity experiments are carried out to examine the plume and the associated frontal dynamics in response to seasonal discharges and monsoon winds. During the winter, convergence between the seaward spreading plume water and the saline coastal water sets up a salinity front that aligns from the northeast to the southwest inside the PRE. During the summer the plume water fills the PRE at the surface and spreads eastward in the coastal waters in response to the prevailing southwesterly monsoon. The overall alignment of the plume is from the northwest to the southeast. The subsurface front is similar to that in the winter and summer except that the summer front is closer to the mouth and the winter front closer to the head of the estuary. Inside the PRE, bottom flows are always toward the head of the estuary, attributed to the density gradient associated with the plume front. In contrast, bottom flows in the shelf change from offshore in winter to onshore in summer, reflecting respectively the wintertime downwelling and summertime upwelling. Wind also plays an essential role in controlling the plume at the surface. An easterly wind drives the plume westward regardless winter or summer. The eastward spreading of the plume during the summer can be attributed to the southerly component of the wind. On the other hand, the surface area of the plume is positively proportional to the amount of discharge.

Transfer of the HIV-1 cyclophilin-binding site to simian immunodeficiency virus from Macaca mulatta can confer both cyclosporin sensitivity and cyclosporin dependence

HIV-1 specifically incorporates the peptidyl prolyl isomerase cyclophilin A (CyPA), the cytosolic receptor for the immunosuppressant cyclosporin A (CsA). HIV-1 replication is inhibited by CsA as well as by nonimmunosuppressive CsA analogues that bind to CyPA and interfere with its virion association. In contrast, the related simian immunodeficiency virus SIVmac, which does not interact with CyPA, is resistant to these compounds. The incorporation of CyPA into HIV-1 virions is mediated by a specific interaction between the active site of the enzyme and the capsid (CA) domain of the HIV-1 Gag polyprotein. We report here that the transfer of HIV-1 CA residues 86–93, which form part of an exposed loop, to the corresponding position in SIVmac resulted in the efficient incorporation of CyPA and conferred an HIV-1-like sensitivity to a nonimmunosuppressive cyclosporin. HIV-1 CA residues 86–90 were also sufficient to transfer the ability to efficiently incorporate CyPA, provided that the length of the CyPA-binding loop was preserved. However, the resulting SIVmac mutant required the presence of cyclosporin for efficient virus replication. The results indicate that the presence or absence of a type II tight turn adjacent to the primary CyPA-binding site determines whether CyPA incorporation enhances or inhibits viral replication. By demonstrating that CyPA-binding-site residues can induce cyclosporin sensitivity in a heterologous context, this study provides direct in vivo evidence that the exposed loop between helices IV and V of HIV-1 CA not merely constitutes a docking site for CyPA but is a functional target of this cellular protein.

Molecular basis for the exquisite sensitivity of Mycobacterium tuberculosis to isoniazid

The exceptional sensitivity of Mycobacterium tuberculosis to isonicotinic acid hydrazide (INH) lacks satisfactory definition. M. tuberculosis is a natural mutant in oxyR, a central regulator of peroxide stress response. The ahpC gene, which encodes a critical subunit of alkyl hydroperoxide reductase, is one of the targets usually controlled by oxyR in bacteria. Unlike in mycobacterial species less susceptible to INH, the expression of ahpC was below detection limits at the protein level in INH-sensitive M. tuberculosis and Mycobacterium bovis strains. In contrast, AhpC was detected in several series of isogenic INH-resistant (INHr) derivatives. In a demonstration of the critical role of ahpC in sensitivity to INH, insertional inactivation of ahpC on the chromosome of Mycobacterium smegmatis, a species naturally insensitive to INH, dramatically increased its susceptibility to this compound. These findings suggest that AhpC counteracts the action of INH and that the levels of its expression may govern the intrinsic susceptibility of mycobacteria to this front-line antituberculosis drug.