Moderate Exercise Modulates Inflammatory Responses and Improves Survival in a Murine Model of Acute Pneumonia.

OBJECTIVES: An association between physical inactivity and worse outcome during infectious disease has been reported. The effect of moderate exercise preconditioning on the immune response during an acute pneumonia in a murine model was evaluated. SETTING: Laboratory experiments. SUBJECTS: C57BL6/j male mice. INTERVENTIONS: Six-week-old C57BL/6J mice were divided in two groups: an exercise group and a control group. In the exercise group, a moderate, progressive, and standardized physical exercise was applied for 8 weeks. It consisted in a daily treadmill training lasting 60 minutes and with an intensity of 65% of the maximal theoretical oxygen uptake. Usual housing recommendation were applied in the control group during the same period. After 8 weeks, pneumonia was induced in both groups by intratracheal instillation of a fixed concentration of a Klebsiella pneumoniae (5 × 103 colony-forming unit) solution. MEASUREMENTS AND MAIN RESULTS: Mice preconditioned by physical exercise had a less sever onset of pneumonia as shown by a significant decrease of the Mouse Clinical Assessment Severity Score and had a significantly lower mortality compared with the control group (27% vs. 83%; p = 0.019). In the exercise group, we observed a significantly earlier but transient recruitment of inflammatory immune cells with a significant increase of neutrophils, CD4+ cells and interstitial macrophages counts compared with control group. Lung tumor necrosis factor-α, interleukin (IL)-1ß, IL-6, and IL-10 were significantly decreased at 48 hours after pneumonia induction in the exercise group compared with the control group. CONCLUSIONS: In our model, preconditioning by moderate physical exercise improves outcome by reducing the severity of acute pneumonia with an increased but transient activation of the innate immune response.

Feasibility and Safety of Sildenafil to Repair Brain Injury Secondary to Birth Asphyxia (SANE-01): A Randomized, Double-blind, Placebo-controlled Phase Ib Clinical Trial.

OBJECTIVE: To test feasibility and safety of administering sildenafil in neonates with neonatal encephalopathy (NE), developing brain injury despite therapeutic hypothermia (TH). STUDY DESIGN: We performed a randomized, double-blind, placebo-controlled phase Ib clinical trial between 2016 and 2019 in neonates with moderate or severe NE, displaying brain injury on day-2 magnetic resonance imaging (MRI) despite TH. Neonates were randomized (2:1) to 7-day sildenafil or placebo (2 mg/kg/dose enterally every 12 hours, 14 doses). Outcomes included feasibility and safety (primary outcomes), pharmacokinetics (secondary), and day-30 neuroimaging and 18-month neurodevelopment assessments (exploratory). RESULTS: Of the 24 enrolled neonates, 8 were randomized to sildenafil and 3 to placebo. A mild decrease in blood pressure was reported in 2 of the 8 neonates after initial dose, but not with subsequent doses. Sildenafil plasma steady-state concentration was rapidly reached, but decreased after TH discontinuation. Twelve percent of neonates (1/8) neonates died in the sildenafil group and 0% (0/3) in the placebo group. Among surviving neonates, partial recovery of injury, fewer cystic lesions, and less brain volume loss on day-30 magnetic resonance imaging were noted in 71% (5/7) of the sildenafil group and in 0% (0/3) of the placebo group. The rate of death or survival to 18 months with severe neurodevelopmental impairment was 57% (4/7) in the sildenafil group and 100% (3/3) in the placebo group. CONCLUSIONS: Sildenafil was safe and well-absorbed in neonates with NE treated with TH. Optimal dosing needs to be established. Evaluation of a larger number of neonates through subsequent phases II and III trials is required to establish efficacy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.govNCT02812433.

Ultrasound Shear Wave Attenuation Imaging for Grading Liver Steatosis in Volunteers and Patients With Non-alcoholic Fatty Liver Disease: A Pilot Study.

OBJECTIVE: The aims of the work described here were to assess shear wave attenuation (SWA) in volunteers and patients with non-alcoholic fatty liver disease (NAFLD) and compare its diagnostic performance with that of shear wave dispersion (SWD), magnetic resonance imaging (MRI) proton density fat fraction (PDFF) and biopsy. METHODS: Forty-nine participants (13 volunteers and 36 NAFLD patients) were enrolled. Ultrasound and MRI examinations were performed in all participants. Biopsy was also performed in patients. SWA was used to assess histopathology grades as potential confounders. The areas under curves (AUCs) of SWA, SWD and MRI-PDFF were assessed in different steatosis grades by biopsy. Youden's thresholds of SWA were obtained for steatosis grading while using biopsy or MRI-PDFF as the reference standard. RESULTS: Spearman's correlations of SWA with histopathology (steatosis, inflammation, ballooning and fibrosis) were 0.89, 0.73, 0.62 and 0.31, respectively. Multiple linear regressions of SWA confirmed the correlation with steatosis grades (adjusted R2 = 0.77, p < 0.001). The AUCs of MRI-PDFF, SWA and SWD were respectively 0.97, 0.99 and 0.94 for S0 versus ≥S1 (p > 0.05); 0.94, 0.98 and 0.78 for ≤S1 versus ≥S2 (both MRI-PDFF and SWA were higher than SWD, p < 0.05); and 0.90, 0.93 and 0.68 for ≤S2 versus S3 (both SWA and MRI-PDFF were higher than SWD, p < 0.05). SWA's Youden thresholds (Np/m/Hz) (sensitivity, specificity) for S0 versus ≥S1, ≤S1 versus ≥S2 and ≤S2 versus S3 were 1.05 (1.00, 0.92), 1.37 (0.96, 0.96) and 1.51 (0.83, 0.87), respectively. These values were 1.16 (1.00, 0.81), 1.49 (0.91, 0.82) and 1.67 (0.87, 0.92) when considering MRI-PDFF as the reference standard. CONCLUSION: In this pilot study, SWA increased with increasing steatosis grades, and its diagnostic performance was higher than that of SWD but equivalent to that of MRI-PDFF.

Sex-Specific Cerebral Blood Flow Alterations in Youth Operated for Congenital Heart Disease.

Background Lower cerebral blood flow (CBF) has previously been documented preoperatively in neonates with congenital heart disease (CHD). However, it remains unclear if these CBF deficits persist over the life span of CHD survivors following heart surgery. When exploring this question, it is critical to consider the sex differences in CBF that emerge during adolescence. Therefore, this study aimed to compare global and regional CBF between postpubertal youth with CHD and healthy peers and examine if such alterations are related to sex. Methods and Results Youth aged 16 to 24 years who underwent open heart surgery for complex CHD during infancy and age- and sex-matched controls completed brain magnetic resonance imaging, including T1-weighted and pseudo-continuous arterial spin labeling acquisitions. Global gray matter CBF and regional CBF in 9 bilateral gray matter regions were quantified for each participant. Compared with female controls (N=27), female participants with CHD (N=25) presented with lower global and regional CBF. In contrast, there were no differences in CBF between male controls (N=18) and males with CHD (N=17). Concurrently, female controls had higher global and regional CBF compared with male controls, with no differences in CBF between female and male participants with CHD. CBF was lower in individuals with a Fontan circulation. Conclusions This study provides evidence of altered CBF in postpubertal female participants with CHD despite undergoing surgical intervention during infancy. Alterations to CBF could have implications for later cognitive decline, neurodegeneration, and cerebrovascular disease in women with CHD.

Altered resting state functional connectivity in youth with congenital heart disease operated during infancy.

Congenital heart disease (CHD) has been associated with structural brain growth and long-term developmental impairments, including deficits in learning, memory, and executive functions. Altered functional connectivity has been shown to be altered in neonates born with CHD; however, it is unclear if these early life alterations are also present during adulthood. Therefore, this study aimed to compare resting state functional connectivity networks associated with executive function deficits between youth (16 to 24 years old) with complex CHD (mean age = 20.13; SD = 2.35) who underwent open-heart surgery during infancy and age- and sex-matched controls (mean age = 20.41; SD = 2.05). Using the Behavior Rating Inventory of Executive Function-Adult Version questionnaire, we found that participants with CHD presented with poorer performance on the inhibit, initiate, emotional control, working memory, self-monitor, and organization of materials clinical scales than healthy controls. We then compared the resting state networks theoretically corresponding to these impaired functions, namely the default mode, dorsal attention, fronto-parietal, fronto-orbital, and amygdalar networks, between the two groups. Participants with CHD presented with decreased functional connectivity between the fronto-orbital cortex and the hippocampal regions and between the amygdala and the frontal pole. Increased functional connectivity was observed within the default mode network, the dorsal attention network, and the fronto-parietal network. Overall, our results suggest that youth with CHD present with disrupted resting state functional connectivity in widespread networks and regions associated with altered executive functioning.

Human iPSC model reveals a central role for NOX4 and oxidative stress in Duchenne cardiomyopathy.

Duchenne muscular dystrophy (DMD) is a progressive muscle disorder caused by mutations in the Dystrophin gene. Cardiomyopathy is a major cause of early death. We used DMD-patient-specific human induced pluripotent stem cells (hiPSCs) to model cardiomyopathic features and unravel novel pathologic insights. Cardiomyocytes (CMs) differentiated from DMD hiPSCs showed enhanced premature cell death due to significantly elevated intracellular reactive oxygen species (ROS) resulting from depolarized mitochondria and increased NADPH oxidase 4 (NOX4). CRISPR-Cas9 correction of Dystrophin restored normal ROS levels. ROS reduction by N-acetyl-L-cysteine (NAC), ataluren (PTC124), and idebenone improved hiPSC-CM survival. We show that oxidative stress in DMD hiPSC-CMs was counteracted by stimulating adenosine triphosphate (ATP) production. ATP can bind to NOX4 and partially inhibit the ROS production. Considering the complexity and the early cellular stress responses in DMD cardiomyopathy, we propose targeting ROS production and preventing detrimental effects of NOX4 on DMD CMs as promising therapeutic strategy.

Robust arterial input function surrogate measurement from the superior sagittal sinus complex signal for fast dynamic contrast-enhanced MRI in the brain.

PURPOSE: Accurately estimating the arterial input function for dynamic contrast-enhanced MRI is challenging. An arterial input function is typically determined from signal magnitude changes related to a contrast agent, often leading to underestimation of peak concentrations. Alternatively, signal phase recovers the accurate peak concentration for straight vessels but suffers from high noise. A recent method proposed to fit the signal in the complex plane by combining the advantages of the previous 2 methods. The purpose of this work is to refine this complex-based method to determine the venous output function (VOF), an arterial input function surrogate, from the superior sagittal sinus. METHODS: We propose a state-of-the-art complex-based method that includes direct compensation for blood inflow and signal phase correction accounting for the curvature of the superior sagittal sinus, generally assumed collinear with B0 . We compared the magnitude-, phase-, and complex-based VOF determination methods against various simulated biases as well as for 29 brain metastases patients. RESULTS: Angulation of the superior sagittal sinus relative to B0 varied widely within patients, and its effect on the signal phase caused an underestimation of peak concentrations of up to 65%. Correction significantly increased the VOF peak concentration for the phase- and complex-based VOFs in the cohort. The phase-based method recovered accurate peak concentrations but lacked precision in the tail of the VOF. Our complex-based VOF completely recovered the effect of inflow and resulted in a high-peak concentration with limited noise. CONCLUSION: The new complex-based method resulted in high-quality VOF robust against superior sagittal sinus curvature and variations in patient positioning.

MRI-based R2* mapping in patients with suspected or known iron overload.

PURPOSE: R2* relaxometry is a quantitative method for assessment of iron overload. The purpose is to analyze the cross-sectional relationships between R2* in organs across patients with primary and secondary iron overload. Secondary analyses were conducted to analyze R2* according to treatment regimen. METHODS: This is a retrospective, cross-sectional, institutional review board-approved study of eighty-one adult patients with known or suspected iron overload. R2* was measured by segmenting the liver, spleen, bone marrow, pancreas, renal cortex, renal medulla, and myocardium using breath-hold multi-echo gradient-recalled echo imaging at 1.5 T. Phlebotomy, transfusion, and chelation therapy were documented. Analyses included correlation, Kruskal-Wallis, and post hoc Dunn tests. p < 0.01 was considered significant. RESULTS: Correlations between liver R2* and that of the spleen, bone marrow, pancreas, and heart were respectively 0.49, 0.33, 0.27, and 0.34. R2* differed between patients with primary and secondary overload in the liver (p < 0.001), spleen (p < 0.001), bone marrow (p < 0.01), renal cortex (p < 0.001), and renal medulla (p < 0.001). Liver, spleen, and bone marrow R2* were higher in thalassemia than in hereditary hemochromatosis (all p < 0.01). Renal cortex R2* was higher in sickle cell disease than in hereditary hemochromatosis (p < 0.001) and in thalassemia (p < 0.001). Overall, there was a trend toward lower liver R2* in patients assigned to phlebotomy and higher liver R2* in patients assigned to transfusion and chelation therapy. CONCLUSION: R2* relaxometry revealed differences in degree or distribution of iron overload between organs, underlying etiologies, and treatment.

Intravoxel incoherent motion diffusion-weighted MRI for the characterization of inflammation in chronic liver disease.

OBJECTIVE: To evaluate the diagnostic performance of intravoxel incoherent motion (IVIM) diffusion-weighted imaging (DWI) for grading hepatic inflammation. METHODS: In this retrospective cross-sectional dual-center study, 91 patients with chronic liver disease were recruited between September 2014 and September 2018. Patients underwent 3.0-T MRI examinations within 6 weeks from a liver biopsy. IVIM parameters, perfusion fraction (f), diffusion coefficient (D), and pseudo-diffusion coefficient (D*), were estimated using a voxel-wise nonlinear regression on DWI series (10 b-values from 0 to 800 s/mm2). The reference standard was histopathological analysis of hepatic inflammation grade, steatosis grade, and fibrosis stage. Intraclass correlation coefficients (ICC), univariate and multivariate correlation analyses, and areas under receiver operating characteristic curves (AUC) were assessed. RESULTS: Parameters f, D, and D* had ICCs of 0.860, 0.839, and 0.916, respectively. Correlations of f, D, and D* with inflammation grade were ρ = - 0.70, p < 0.0001; ρ = 0.10, p = 0.35; and ρ = - 0.27, p = 0.010, respectively. When adjusting for fibrosis and steatosis, the correlation between f and inflammation (p < 0.0001) remained, and that between f and fibrosis was also significant to a lesser extent (p = 0.002). AUCs of f, D, and D* for distinguishing inflammation grades 0 vs. ≥ 1 were 0.84, 0.53, and 0.70; ≤ 1 vs. ≥ 2 were 0.88, 0.57, and 0.60; and ≤ 2 vs. 3 were 0.86, 0.54, and 0.65, respectively. CONCLUSION: Perfusion fraction f strongly correlated, D very weakly correlated, and D* weakly correlated with inflammation. Among all IVIM parameters, f accurately graded inflammation and showed promise as a biomarker of hepatic inflammation. KEY POINTS: • IVIM parameters derived from DWI series with 10 b-values are reproducible for liver tissue characterization. • This retrospective two-center study showed that perfusion fraction provided good diagnostic performance for distinguishing dichotomized grades of inflammation. • Fibrosis is a significant confounder on the association between inflammation and perfusion fraction.

The utility of arterial spin labeling in the presurgical evaluation of poorly defined focal epilepsy in children.

OBJECTIVE: The authors sought to assess the utility of arterial spin labeling (ASL) perfusion 3T-MRI for the presurgical evaluation of poorly defined focal epilepsy in pediatric patients. METHODS: Pseudocontinuous ASL perfusion 3T-MRI was performed in 25 consecutive children with poorly defined focal epilepsy. ASL perfusion abnormalities were detected qualitatively by visual inspection and quantitatively by calculating asymmetry index (AI) maps and significant z-score cluster maps based on successfully operated cases. ASL results were prospectively compared to scalp EEG, structural 3T-MRI, FDG-PET, ictal/interictal SPECT, magnetoencephalography (MEG), and intracranial recording results, as well as the final surgically proven epileptogenic zone (EZ) in operated patients who had at least 1 year of good (Engel class I/II) seizure outcome and positive histopathology results. RESULTS: Qualitative ASL perfusion abnormalities were found in 17/25 cases (68%), specifically in 17/20 MRI-positive cases (85.0%) and in none of the 5 MRI-negative cases. ASL was concordant with localizing scalp EEG findings in 66.7%, structural 3T-MRI in 90%, FDG-PET in 75%, ictal/interictal SPECT in 62.5%, and MEG in 75% of cases, and with intracranial recording results in 40% of cases. Eleven patients underwent surgery; in all 11 cases the EZ was surgically proven by positive histopathology results and the patient having at least 1 year of good seizure outcome. ASL results were concordant with this final surgically proven EZ in 10/11 cases (sensitivity 91%, specificity 50%). All 10 ASL-positive patients who underwent surgery had positive surgical pathology results and good long-term postsurgical seizure outcome at a mean follow-up of 39 months. Retrospective quantitative analysis based on significant z-score clusters found 1 true-positive result that was missed by qualitative analysis and 3 additional false-positive results (sensitivity 100%, specificity 23%). CONCLUSIONS: ASL supports the hypothesis regarding the EZ in poorly defined focal epilepsy cases in children. Due to its convenience and noninvasive nature, the authors recommend that ASL be added routinely to the presurgical MRI evaluation of epilepsy. Future optimized quantitative methods may improve the diagnostic yield of this technique.

Impact of temporal resolution and motion correction for dynamic contrast-enhanced MRI of the liver using an accelerated golden-angle radial sequence.

This paper presents a prospective study evaluating the impact on image quality and quantitative dynamic contrast-enhanced (DCE)-MRI perfusion parameters when varying the number of respiratory motion states when using an eXtra-Dimensional Golden-Angle Radial Sparse Parallel (XD-GRASP) MRI sequence. DCE acquisition was performed using a 3D stack-of-stars gradient-echo golden-angle radial acquisition in free-breathing with 100 spokes per motion state and temporal resolution of 6 s/volume, and using a non-rigid motion compensation to align different motion states. Parametric analysis was conducted using a dual-input single-compartment model. Nonparametric analysis was performed on the time-intensity curves. A total of 22 hepatocellular carcinomas (size: 11-52 mm) were evaluated. XD-GRASP reconstructed with increasing number of spokes for each motion state increased the signal-to-noise ratio (SNR) (p < 0.05) but decreased temporal resolution (0.04 volume/s vs 0.17 volume/s for one motion state) (p < 0.05). A visual scoring by an experienced radiologist show no change between increasing number of motion states with same number of spokes using the Likert score. The normalized maximum intensity time ratio, peak enhancement ratio and tumor arterial fraction increased with decreasing number of motion states (p < 0.05) while the transfer constant from the portal venous plasma to the surrounding tissue significantly decreased (p < 0.05). These same perfusion parameters show a significant difference in case of tumor displacement more than 1 cm (p < 0.05) whereas in the opposite case there was no significant variation. While a higher number of motion states and higher number of spokes improves SNR, the resulting lower temporal resolution can influence quantitative parameters that capture rapid signal changes. Finally, fewer displacement compensation is advantageous with lower number of motion state due to the higher temporal resolution. XD-GRASP can be used to perform quantitative perfusion measures in the liver, but the number of motion states may significantly alter some quantitative parameters.

MRI cine-tagging of cardiac-induced motion for noninvasive staging of liver fibrosis.

BACKGROUND: MR elastography is a noninvasive technique that provides high diagnostic accuracy for the staging of liver fibrosis; however, it requires external hardware and mainly assesses the right lobe. PURPOSE: To evaluate the diagnostic performance of MRI cine-tagging for staging fibrosis in the left liver lobe, using biopsy as the reference standard. STUDY TYPE: Institutional Review Board (IRB)-approved two-center prospective study. POPULATION: Seventy-six patients with chronic liver disease who underwent an MRI cine-tagging examination and a liver biopsy within a 6-week interval. FIELD STRENGTH/SEQUENCE: 2D-GRE multislice sequence at 3.0T with spatial modulation of the magnetization preparation sequence and peripheral pulse-wave triggering on two coronal slices chosen underneath the heart apex to capture maximal deformation with consecutive breath-holds adapted to patient cardiac frequency. ASSESSMENT: A region of interest was selected in the liver close to the heart apex. Maximal strain was evaluated with the harmonic phase (HARP) technique. STATISTICAL TESTS: Spearman's correlation, Kruskal-Wallis test, Mann-Whitney U-test, and receiver operating characteristic (ROC) analysis were performed. RESULTS: Liver strain measured on tagged images decreased with higher histological fibrosis stage (ρ = -0.68, P < 0.0001). Strain values were significantly different between all fibrosis stages (P < 0.0001), and between groups of fibrosis stages ≤F3 vs. F4 (P < 0.05). Areas under the ROC curves were 0.95 (95% confidence interval: 0.89-1.00) to distinguish fibrosis stages F0 vs. F4, 0.81 (0.70-0.92) for stages F0 vs. ≥F1, 0.84 (0.76-0.93) for stages ≤F1 vs. ≥F2, 0.86 (0.78-0.94) for stages ≤F2 vs. ≥F3, and 0.87 (0.77-0.96) for stages ≤F3 vs. F4. DATA CONCLUSION: MRI cine-tagging is a promising technique for measuring liver strain without additional elastography hardware. It could be used to assess the left liver lobe as a complement to current techniques assessing the right lobe. LEVEL OF EVIDENCE: 1 Technical Efficacy: 3 J. Magn. Reson. Imaging 2020;51:1570-1580.

Prospective comparison of transient, point shear wave, and magnetic resonance elastography for staging liver fibrosis.

OBJECTIVES: To perform head-to-head comparisons of the feasibility and diagnostic performance of transient elastography (TE), point shear-wave elastography (pSWE), and magnetic resonance elastography (MRE). METHODS: This prospective, cross-sectional, dual-center imaging study included 100 patients with known or suspected chronic liver disease caused by hepatitis B or C virus, nonalcoholic fatty liver disease, or autoimmune hepatitis identified between 2014 and 2018. Liver stiffness measured with the three elastographic techniques was obtained within 6 weeks of a liver biopsy. Confounding effects of inflammation and steatosis on association between fibrosis and liver stiffness were assessed. Obuchowski scores and AUCs for staging fibrosis were evaluated and the latter were compared using the DeLong method. RESULTS: TE, pSWE, and MRE were technically feasible and reliable in 92%, 79%, and 91% subjects, respectively. At univariate analysis, liver stiffness measured by all techniques increased with fibrosis stages and inflammation and decreased with steatosis. For classification of dichotomized fibrosis stages, the AUCs were significantly higher for distinguishing stages F0 vs. ≥ F1 with MRE than with TE (0.88 vs. 0.71; p < 0.05) or pSWE (0.88 vs. 0.73; p < 0.05), and for distinguishing stages ≤ F1 vs. ≥ F2 with MRE than with TE (0.85 vs. 0.75; p < 0.05). TE, pSWE, and MRE Obuchowski scores for staging fibrosis stages were respectively 0.89 (95% CI 0.85-0.93), 0.90 (95% CI 0.85-0.94), and 0.94 (95% CI 0.91-0.96). CONCLUSION: MRE provided a higher diagnostic performance than TE and pSWE for staging early stages of liver fibrosis. TRIAL REGISTRATION: NCT02044523 KEY POINTS: • The technical failure rate was similar between MRE and US-based elastography techniques. • Liver stiffness measured by MRE and US-based elastography techniques increased with fibrosis stages and inflammation and decreased with steatosis. • MRE provided a diagnostic accuracy higher than US-based elastography techniques for staging of early stages of histology-determined liver fibrosis.

Dynamic contrast-enhanced MRI to assess hepatocellular carcinoma response to Transarterial chemoembolization using LI-RADS criteria: A pilot study.

PURPOSE: To identify quantitative dynamic contrast-enhanced (DCE)-MRI perfusion parameters indicating tumor response of hepatocellular carcinoma (HCC) to transarterial chemoembolization (TACE). MATERIALS AND METHODS: This prospective pilot study was approved by our institutional review board; written and informed consent was obtained for each participant. Patients underwent DCE-MRI examinations before and after TACE. A variable flip-angle unenhanced 3D mDixon sequence was performed for T1 mapping. A dynamic 4D mDixon sequence was performed after contrast injection for assessing dynamic signal enhancement. Nonparametric analysis was conducted on the time-intensity curves. Parametric analysis was performed on the time-concentration curves using a dual-input single-compartment model. Treatment response according to Liver Reporting and Data System (LI-RADS) v2018 was used as the reference standard. The comparisons within groups (before vs. after treatment) and between groups (nonviable vs. equivocal or viable tumor) were performed using nonparametric bootstrap taking into account the clustering effect of lesions in patients. RESULTS: Twenty-eight patients with 52 HCCs (size: 10-104 mm) were evaluated. For nonviable tumors (n = 27), time to peak increased from 62.5 ±â€¯18.2 s before to 83.3 ±â€¯12.8 s after treatment (P< 0.01). For equivocal or viable tumors (n = 25), time to peak and mean transit time significantly increased (from 54.4 ±â€¯24.1 s to 69.5 ±â€¯18.9 s, P < 0.01 and from 14.2 ±â€¯11.8 s to 33.9 ±â€¯36.8 s, P= 0.01, respectively) and the transfer constant from the extracellular and extravascular space to the central vein significantly decreased from 14.8 ±â€¯14.1 to 8.1 ±â€¯9.1 s-1 after treatment (P= 0.01). CONCLUSION: This prospective pilot DCE-MRI study showed that time to peak significantly changed after TACE treatment for both groups (nonviable tumors and equivocal or viable tumors). In our cohort, several perfusion parameters may provide an objective marker for differentiation of treatment response after TACE in HCC patients.

Hyperactive ryanodine receptors in human heart failure and ischaemic cardiomyopathy reside outside of couplons.

Aims: In ventricular myocytes from humans and large mammals, the transverse and axial tubular system (TATS) network is less extensive than in rodents with consequently a greater proportion of ryanodine receptors (RyRs) not coupled to this membrane system. TATS remodelling in heart failure (HF) and after myocardial infarction (MI) increases the fraction of non-coupled RyRs. Here we investigate whether this remodelling alters the activity of coupled and non-coupled RyR sub-populations through changes in local signalling. We study myocytes from patients with end-stage HF, compared with non-failing (non-HF), and myocytes from pigs with MI and reduced left ventricular (LV) function, compared with sham intervention (SHAM). Methods and results: Single LV myocytes for functional studies were isolated according to standard protocols. Immunofluorescent staining visualized organization of TATS and RyRs. Ca2+ was measured by confocal imaging (fluo-4 as indicator) and using whole-cell patch-clamp (37°C). Spontaneous Ca2+ release events, Ca2+ sparks, as a readout for RyR activity were recorded during a 15 s period following conditioning stimulation at 2 Hz. Sparks were assigned to cell regions categorized as coupled or non-coupled sites according to a previously developed method. Human HF myocytes had more non-coupled sites and these had more spontaneous activity than in non-HF. Hyperactivity of these non-coupled RyRs was reduced by Ca2+/calmodulin-dependent kinase II (CaMKII) inhibition. Myocytes from MI pigs had similar changes compared with SHAM controls as seen in human HF myocytes. As well as by CaMKII inhibition, in MI, the increased activity of non-coupled sites was inhibited by mitochondrial reactive oxygen species (mito-ROS) scavenging. Under adrenergic stimulation, Ca2+ waves were more frequent and originated at non-coupled sites, generating larger Na+/Ca2+ exchange currents in MI than in SHAM. Inhibition of CaMKII or mito-ROS scavenging reduced spontaneous Ca2+ waves, and improved excitation-contraction coupling. Conclusions: In HF and after MI, RyR microdomain re-organization enhances spontaneous Ca2+ release at non-coupled sites in a manner dependent on CaMKII activation and mito-ROS production. This specific modulation generates a substrate for arrhythmia that appears to be responsive to selective pharmacologic modulation.

Liver Iron Quantification with MR Imaging: A Primer for Radiologists.

Iron overload is a systemic disorder and is either primary (genetic) or secondary (exogenous iron administration). Primary iron overload is most commonly associated with hereditary hemochromatosis and secondary iron overload with ineffective erythropoiesis (predominantly caused by ß-thalassemia major and sickle cell disease) that requires long-term transfusion therapy, leading to transfusional hemosiderosis. Iron overload may lead to liver cirrhosis and hepatocellular carcinoma, in addition to cardiac and endocrine complications. The liver is one of the main iron storage organs and the first to show iron overload. Therefore, detection and quantification of liver iron overload are critical to initiate treatment and prevent complications. Liver biopsy was the historical reference standard for detection and quantification of liver iron content. Magnetic resonance (MR) imaging is now commonly used for liver iron quantification, including assessment of distribution, detection, grading, and monitoring of treatment response in iron overload. Several MR imaging techniques have been developed for iron quantification, each with advantages and limitations. The liver-to-muscle signal intensity ratio technique is simple and widely available; however, it assumes that the reference tissue is normal. Transverse magnetization (also known as R2) relaxometry is validated but is prone to respiratory motion artifacts due to a long acquisition time, is presently available only for 1.5-T imaging, and requires additional cost and delay for off-line analysis. The R2* technique has fast acquisition time, demonstrates a wide range of liver iron content, and is available for 1.5-T and 3.0-T imaging but requires additional postprocessing software. Quantitative susceptibility mapping has the highest sensitivity for detecting iron deposition; however, it is still investigational, and the correlation with liver iron content is not yet established. ©RSNA, 2018.

Liver Fibrosis Quantification by Magnetic Resonance Imaging.

Liver fibrosis is a hallmark of chronic liver disease characterized by the excessive accumulation of extracellular matrix proteins. Although liver biopsy is the reference standard for diagnosis and staging of liver fibrosis, it has some limitations, including potential pain, sampling variability, and low patient acceptance. Hence, there has been an effort to develop noninvasive imaging techniques for diagnosis, staging, and monitoring of liver fibrosis. Many quantitative techniques have been implemented on magnetic resonance imaging (MRI) for this indication. The most widely validated technique is magnetic resonance elastography, which aims to measure viscoelastic properties of the liver and relate them to fibrosis stage. Several additional MRI methods have been developed or adapted to liver fibrosis quantification. Diffusion-weighted imaging measures the Brownian motion of water molecules which is restricted by collagen fibers. Texture analysis assesses the changes in the texture of liver parenchyma associated with fibrosis. Perfusion imaging relies on signal intensity and pharmacokinetic models to extract quantitative perfusion parameters. Hepatocellular function, which decreases with increasing fibrosis stage, can be estimated by the uptake of hepatobiliary contrast agents. Strain imaging measures liver deformation in response to physiological motion such as cardiac contraction. T1ρ quantification is an investigational technique, which measures the spin-lattice relaxation time in the rotating frame. This article will review the MRI techniques used in liver fibrosis staging, their advantages and limitations, and diagnostic performance. We will briefly discuss future directions, such as longitudinal monitoring of disease, prediction of portal hypertension, and risk stratification of hepatocellular carcinoma.

Proton MR Spectroscopy in Patients with Nonlesional Insular Cortex Epilepsy Confirmed by Invasive EEG Recordings.

BACKGROUND AND PURPOSE: Recent studies suggest that a nonnegligible proportion of drug-resistant epilepsy surgery candidates have an epileptogenic zone that involves the insula. We aimed to examine the value of proton magnetic resonance spectroscopy (1 H-MRS) in identifying patients with insular cortex epilepsy. METHODS: Patients with possible nonlesional drug-refractory insular epilepsy underwent a voxel-based 1 H-MRS study prior to an intracranial electroencephalographic (EEG) study. Patients were then divided into two groups based on invasive EEG findings: the insular group with evidence of insular seizures and the noninsular group with no evidence of insular seizures. Sixteen age-matched healthy controls were also scanned for normative data. RESULTS: Twenty-two epileptic patients were recruited, 12 with insular seizures and 10 with extra-insular seizures. Ipsilateral and contralateral insular N-acetyl-aspartate concentrations ([NAA]) and NAA/Cr ratios were found to be similar in both patient groups. No significant differences in [NAA] or NAA/Cr ratios were found between the insular group, noninsular group, and healthy controls. [NAA] and NAA/Cr asymmetry indices correctly lateralized the seizure focus in only 16.7% and 0% of patients, respectively. CONCLUSIONS: Our preliminary findings suggest that 1 H-MRS fares poorly in identifying patients with nonlesional insular epilepsy.

Liver fibrosis: Review of current imaging and MRI quantification techniques.

Liver fibrosis is characterized by the accumulation of extracellular matrix proteins such as collagen in the liver interstitial space. All causes of chronic liver disease may lead to fibrosis and cirrhosis. The severity of liver fibrosis influences the decision to treat or the need to monitor hepatic or extrahepatic complications. The traditional reference standard for diagnosis of liver fibrosis is liver biopsy. However, this technique is invasive, associated with a risk of sampling error, and has low patient acceptance. Imaging techniques offer the potential for noninvasive diagnosis, staging, and monitoring of liver fibrosis. Recently, several of these have been implemented on ultrasound (US), computed tomography, or magnetic resonance imaging (MRI). Techniques that assess changes in liver morphology, texture, or perfusion that accompany liver fibrosis have been implemented on all three imaging modalities. Elastography, which measures changes in mechanical properties associated with liver fibrosis-such as strain, stiffness, or viscoelasticity-is available on US and MRI. Some techniques assessing liver shear stiffness have been adopted clinically, whereas others assessing strain or viscoelasticity remain investigational. Further, some techniques are only available on MRI-such as spin-lattice relaxation time in the rotating frame (T1 ρ), diffusion of water molecules, and hepatocellular function based on the uptake of a liver-specific contrast agent-remain investigational in the setting of liver fibrosis staging. In this review, we summarize the key concepts, advantages and limitations, and diagnostic performance of each technique. The use of multiparametric MRI techniques offers the potential for comprehensive assessment of chronic liver disease severity. LEVEL OF EVIDENCE: 5 J. MAGN. RESON. IMAGING 2017;45:1276-1295.