Natural resistance to meglumine antimoniate is associated with treatment failure in cutaneous leishmaniasis caused by Leishmania (Viannia) panamensis.

The multifactorial basis of therapeutic response can obscure the relation between antimicrobial drug susceptibility and clinical outcome. To discern the relationship between parasite susceptibility to meglumine antimoniate (SbV) and therapeutic outcome of cutaneous leishmaniasis, risk factors for treatment failure were considered in evaluating this relationship in ninety-one cutaneous leishmaniasis patients and corresponding clinical strains of Leishmania (Viannia) panamensis. Parasite susceptibility to 32 µg SbV/mL (plasma Cmax) was evaluated in primary human macrophages, PBMCs, and U937 macrophages. Early parasitological response to treatment was determined in lesions of a subgroup of patients, and pathogenicity of Sb-resistant and sensitive clinical strains was compared in BALB/c mice. Parasite survival in cell models and patient lesions was determined by qRT-PCR of Leishmania 7SLRNA transcript. Parasite loads in BALB/c mice were quantified by limiting dilution analysis. The disparate Sb-susceptibility of parasite subpopulations distinguished by isoenzyme profiles (zymodemes) was manifest in all cell models. Notably, Sb-resistance defined by parasite survival, was most effectively discerned in U937 macrophages compared with primary human host cells, significantly higher among strains from patients who failed treatment than cured and, significantly associated with treatment failure. Each unit increase in transformed survival rate corresponded to a 10.6-fold rise in the odds of treatment failure. Furthermore, treatment failure was significantly associated with naturally Sb-resistant zymodeme 2.3 strains, which also produced larger lesions and parasite burdens in BALB/c mice than Sb-sensitive zymodeme 2.2 strains. The confounding effect of host risk factors for treatment failure in discerning this association was evidenced in comparing strains from patients with and without the defined risk factors for treatment failure. These results establish the association of natural resistance to meglumine antimoniate with treatment failure, the importance of host risk factors in evaluating drug susceptibility and treatment outcome, and the clinical and epidemiological relevance of natural Sb-resistance in L. (V.) panamensis subpopulations.

Topical application of ozonated sunflower oil accelerates the healing of lesions of cutaneous leishmaniasis in mice under meglumine antimoniate treatment.

Besides being scarce, the drugs available for treating cutaneous leishmaniasis have many adverse effects. Ozone is an option to enhance the standard treatment due to the wound-healing activity reported in the literature. In this study, we evaluated the efficiency of ozonated sunflower oil as an adjuvant in treating cutaneous lesions caused by Leishmania amazonensis. BALB/c mice were infected with L. amazonensis, and after the lesions appeared, they were treated in four different schedules using the drug treatment with meglumine antimoniate (Glucantime®), with or without ozonated oil. After thirty days of treatment, the lesions' thickness and their parasitic burden, blood leukocytes, production of NO and cytokines from peritoneal macrophages and lymph node cells were analyzed. The group treated with ozonated oil plus meglumine antimoniate showed the best performance, improving the lesion significantly. The parasitic burden showed that ozonated oil enhanced the leishmanicidal activity of the treatment, eliminating the parasites in the lesion. Besides, a decrease in the TNF levels from peritoneal macrophages and blood leukocytes demonstrated an immunomodulatory action of ozone in the ozonated oil-treated animals compared to the untreated group. Thus, ozonated sunflower oil therapy has been shown as an adjuvant in treating Leishmania lesions since this treatment enhanced the leishmanicidal and wound healing effects of meglumine antimoniate.

Effects of different cyclooxygenase inhibitors on prostaglandin E2 production, steroidogenesis and ovulation of bovine preovulatory follicles.

Ovulation is an inflammation-like process, and cyclooxygenase-2 (COX-2)-dependent production of prostaglandin E2 (PGE2) is its key mediator. Balanced regulation of inflammatory processes in high-yielding dairy cows may be essential for physiological ovulation and fertility. This study aimed to elucidate the mechanisms underlying ovulation failure and cyst development after disturbing intrafollicular inflammatory cascades. Therefore, nonselective (indomethacin and flunixin-meglumine), COX-2 selective (meloxicam), and highly COX-2 selective (NS-398) inhibitors were injected into preovulatory follicles 16 h after administration of GnRH, and ovulation was monitored via ultrasound examination. Additionally, follicular fluid was collected after injection of indomethacin, meloxicam, and NS-398. Moreover, primary granulosa cell cultures from preovulatory follicles were prepared and treated with indomethacin, meloxicam, and NS-398. The concentrations of 17ß-estradiol, progesterone, and prostaglandin E2 (PGE2) in the follicular fluid and cell supernatant were estimated. Indomethacin and flunixin-meglumine blocked ovulation, even at low doses, and led to ovarian cyst development. The selective and highly selective COX-2 inhibitors meloxicam and NS-398 were not effective in blocking ovulation. However, indomethacin, meloxicam, and NS-398 significantly and comparably reduced PGE2 concentration in vivo and in vitro (P < 0.05) but had no effect on estradiol or progesterone production. This may contradict the generally accepted hypothesis that PGE2 is a key mediator of ovulation and progesterone production. Our results suggest a connection between ovarian disorders and inflammatory actions in early postpartum cows.

Quantitative Knee Arthrography in a Large Animal Model of Osteoarthritis Using Photon-Counting Detector CT.

OBJECTIVE: The aim of this study was to grade cartilage damage in a swine model of osteoarthritis using a whole-body photon-counting detector (PCD) CT. MATERIALS AND METHODS: A multienergy phantom containing gadolinium (Gd) (2, 4, 8, and 16 mg/mL) and hydroxyapatite (200 and 400 mg/cc) was scanned using a PCD-CT system (48 × 0.25 mm collimation, 80 kV, 800 mAs, D50 reconstruction kernel) to serve as calibration for material decomposition and to assess quantification accuracy. Osteoarthritis was induced in Yucatan miniswine (n = 8) using 1.2 mg monoiodoacetate (MIA) injected into a randomized knee, whereas the contralateral control knee received saline. Twenty-one days later, a contrast bolus (gadoterate meglumine, 4 mL/knee) was intra-articularly administered into both knees. The knees were simultaneously scanned on the PCD-CT system (48 × 0.25 mm collimation, 80 kV, 800 mAs). Multienergy images were reconstructed with a sharp "V71" kernel and a quantitative "D50" kernel. Image denoising was applied to the V71 images before grading cartilage damage, and an iterative material decomposition technique was applied to D50 images to generate the Gd maps. Two radiologists blinded to the knee injection status graded the cartilage integrity based on a modified International Cartilage Repair Society scoring system. Histology was performed on excised cartilage using methylene blue/basic fuchsin. Statistical analysis of grade distribution was performed using an exact test of omnibus symmetry with P < 0.05 considered significant. RESULTS: Material decomposed images from the multienergy phantom scan showed delineation and quantification of Gd and hydroxyapatite with a root-mean-squared error of 0.3 mg/mL and 18.4 mg/cc, respectively. In the animal cohort, the radiologists reported chondromalacia in the MIA knees with International Cartilage Repair Society scores ranging from grade 1 (cartilage heterogeneity, n = 4 knees) to grade 3 (up to 100% cartilage loss, n = 4 knees). Grade 1 was characterized by cartilage heterogeneity and increased joint space in the patellofemoral compartment, whereas grade 3 was characterized by cartilage erosion and bone-on-bone articulation in the patellofemoral compartment. All control knees were scored as grade 0 (normal cartilage). Significant difference (P = 0.004) was observed in the grade distribution between the MIA and control knees. Gross examination of the excised knees showed cartilage lesions in the grade 3 MIA knees. The Gd maps from material decomposition showed lower contrast levels in the joint space of the MIA knee compared with the contralateral control knee due to joint effusion. Histology revealed chondrocyte loss in the MIA knee cartilage confirming the chondrotoxic effects of MIA on cartilage matrix. CONCLUSIONS: We demonstrated a high-resolution and quantitative PCD-CT arthrography technique for grading cartilage damage in a large animal model of osteoarthritis. Photon-counting detector CT offers simultaneous high-resolution and multienergy imaging capabilities that allowed morphological assessment of cartilage loss and quantification of contrast levels in the joint as a marker of joint disease. Cartilage damage in the MIA knees was graded using PCD-CT images, and the image-based findings were further confirmed using histology and gross examination of the excised knees.

Dynamic, Simultaneous Concentration Mapping of Multiple MRI Contrast Agents with Dual Contrast - Magnetic Resonance Fingerprinting.

Synchronous assessment of multiple MRI contrast agents in a single scanning session would provide a new "multi-color" imaging capability similar to fluorescence imaging but with high spatiotemporal resolution and unlimited imaging depth. This multi-agent MRI technology would enable a whole new class of basic science and clinical MRI experiments that simultaneously explore multiple physiologic/molecular events in vivo. Unfortunately, conventional MRI acquisition techniques are only capable of detecting and quantifying one paramagnetic MRI contrast agent at a time. Herein, the Dual Contrast - Magnetic Resonance Fingerprinting (DC-MRF) methodology was extended for in vivo application and evaluated by simultaneously and dynamically mapping the intra-tumoral concentration of two MRI contrast agents (Gd-BOPTA and Dy-DOTA-azide) in a mouse glioma model. Co-registered gadolinium and dysprosium concentration maps were generated with sub-millimeter spatial resolution and acquired dynamically with just over 2-minute temporal resolution. Mean tumor Gd and Dy concentration measurements from both single agent and dual agent DC-MRF studies demonstrated significant correlations with ex vivo mass spectrometry elemental analyses. This initial in vivo study demonstrates the potential for DC-MRF to provide a useful dual-agent MRI platform.

Safety and Diagnostic Efficacy of Gadobenate Dimeglumine in MRI of the Brain and Spine of Neonates and Infants.

BACKGROUND AND PURPOSE: Contrast-enhanced MR imaging provides essential information for pediatric imaging applications. We evaluated gadobenate dimeglumine for contrast-enhanced MR imaging of infants younger than 2 years of age. MATERIALS AND METHODS: Ninety children younger than 2 years of age (including 55 children younger than 1 year) who underwent enhanced MR imaging of the CNS with gadobenate dimeglumine at 0.1 mmol/kg body weight ± 25% by volume were retrospectively enrolled at 2 imaging centers. Safety data were assessed for adverse events and, when available, vital signs and electrocardiogram and clinical laboratory values obtained from 48 hours before until 48 hours after the MR imaging examination. The efficacy of gadobenate dimeglumine-enhanced MR imaging was evaluated prospectively by 3 blinded, unaffiliated readers in terms of the accuracy of combined pre- and postcontrast images relative to precontrast images alone for differentiation of tumor from non-neoplastic disease and the correct diagnosis of specific disease. Differences were tested using the McNemar test. A possible effect of dose on diagnostic accuracy was assessed using the Fisher exact test. RESULTS: Nine nonserious adverse events were reported for 8 (8.8%) patients. Five adverse events occurred in patients 12 months of age or older. All events occurred at least 24 hours after gadobenate dimeglumine administration, and in each case, the investigating radiologist considered that there was no reasonable possibility of a relationship to gadobenate dimeglumine. No clinically meaningful changes in vital signs, electrocardiogram results, or laboratory parameters were reported. Accurate differentiation of tumor from non-neoplastic disease and exact matching of each specific MR imaging-determined diagnosis with the on-site final diagnosis were achieved in significantly more patients by each reader following evaluation of combined pre- and postcontrast images relative to precontrast images alone (91.0%-94.4% versus 75.3%-87.6%, P < .04, and 66.3%-73.0% versus 52.8%-58.4%, P < .02, respectively). No significant differences (P > .133) in diagnostic accuracy were noted between patients receiving ≤0.08 mmol/kg of gadobenate dimeglumine and patients receiving >0.08 mmol/kg of gadobenate dimeglumine. CONCLUSIONS: Gadobenate dimeglumine is safe and effective for pediatric MR imaging.

Elevation of Intracellular Na+ Contributes to Expression of Early Response Genes Triggered by Endothelial Cell Shrinkage.

BACKGROUND/AIMS: Prolonged hyperosmotic shrinkage evokes expression of osmoprotective genes via nuclear factor NFAT5-mediated pathway and activates Na+ influx via hypertonicity-induced cation channels (HICC). In human umbilical vein endothelial cells (HUVEC) elevation of intracellular sodium concentration ([Na+]i) triggers transcription of dozens of early response genes (ERG). This study examined the role of monovalent cations in the expression of Na+i-sensitive ERGs in iso- and hyperosmotically shrunken HUVEC. METHODS: Cell volume was measured by 3D reconstruction of cell shape and as 14C-urea available space. Intracellular Na+ and K+ content was measured by flame atomic absorption spectrometry. ERG transcription was estimated by RT-PCR. RESULTS: Elevation of medium osmolality by 150 mM mannitol or cell transfer from hypo- to isosmotic medium decreased cell volume by 40-50%. Hyperosmotic medium increased [Na+]i by 2-fold whereas isosmotic shrinkage had no impact on this parameter. Hyperosmotic but not isosmotic shrinkage increased up-to 5-fold the content of EGR1, FOS, ATF3, ZFP36 and JUN mRNAs. Expression of these ERGs triggered by hyperosmotic shrinkage and Na+,K+-ATPase inhibition by 0.1 µM ouabain exhibited positive correlation (R2=0.9383, p=0.0005). Isosmotic substitution of NaCl by N-methyl-D-glucamine abolished an increment of [Na+]i and ERG expression triggered by mannitol addition. CONCLUSION: Augmented expression of ERGs in hyperosmotically shrunken HUVEC is mediated by elevation of [Na+]i.

Late Gadolinium Enhancement Magnetic Resonance Imaging Guided Treatment of Post-Atrial Fibrillation Ablation Recurrent Arrhythmia.

BACKGROUND: Macroreentrant atrial tachycardia (AT) accounts for 40% to 60% of recurrent atrial arrhythmias after atrial fibrillation (AF) ablation. To describe late gadolinium enhancement magnetic resonance imaging (LGE-MRI)-detected scar-based dechanneling as new ablation strategy to treat ATs after AF ablation. METHODS: Data from 102 patients who underwent initial AF ablation and repeat ablation for recurrent atrial arrhythmia within 1-year follow-up were analyzed. All patients underwent LGE-MRI before initial and repeat ablation. Depending on the recurrent rhythm, patients with AF and AT recurrence were assigned to group 1 or 2, respectively. Group 1 underwent fibrosis homogenization as second procedure. Group 2 underwent LGE-MRI-detected scar-based dechanneling. Both groups underwent reisolation of pulmonary veins if necessary. RESULTS: Forty-six patients (45%) presented with AF, and 56 patients (55%) presented with AT recurrence during follow-up after initial ablation. In the first 25 patients from group 2, the AT was electroanatomically mapped, and a critical isthmus was defined. It was found that those isthmi were located in the regions with nontransmural scarring detected by LGE-MRI. In the last 31 patients from group 2, an empirical LGE-MRI-based dechanneling was performed solely based on the LGE-MRI results. During 1-year follow-up after second ablation, 67% patients in group 1 and 64% patients in group 2 were free from recurrence (log-rank, P=1.000). In group 2, 64% in the electroanatomically guided and 65% in the LGE-MRI dechanneling group were free from recurrence (log-rank, P=0.900). CONCLUSIONS: Anatomic targeting of LGE-MRI-detected gaps and superficial atrial scar is feasible and effective to treat recurrent arrhythmias post-AF ablation. Homogenization of existing scar is the appropriate treatment for recurrent AF, whereas dechanneling of existing isthmi seems the right approach for patients recurring with AT.

Dynamic contrast-enhanced MR imaging of the prostate: intraindividual comparison of gadoterate meglumine and gadobutrol.

OBJECTIVES: To intraindividually compare the signal-enhancing effect of 0.5 M gadoterate meglumine and 1.0 M gadobutrol in dynamic contrast-enhanced magnetic resonance (DCE-MR) imaging of the prostate. METHODS: Fifty patients who underwent two 3-T MR examinations of the prostate were included in this IRB-approved retrospective uncontrolled, unrandomized study. All received two scans (mean time interval, 20.5 months) including T1-weighted DCE-MR imaging, one with 0.5 M gadoterate meglumine and one with 1.0 M gadobutrol. Equimolar doses of gadolinium (0.1 mmol/kg body weight) were administered with identical injection speed (2 mL/s), resulting in differing gadolinium delivery rate. An identical region of interest (ROItz) within a BPH-node was identified on both scans. The area under the time-enhancement curve of each ROItz from 0 to 180 s post contrast arrival and pharmacokinetic parameters were calculated. Relative enhancement and signal-to-noise (SNR) and contrast-to-noise (CNR) ratios in the delayed phase at about 180 s were compared between both agents. RESULTS: There was a significantly larger area under the time-enhancement curve (5.53 vs 4.97 p = 0.0007) and higher relative enhancement of BPH nodules (2.23 vs 1.96 p < 0.0001) with gadobutrol compared with gadoterate meglumine. There were no significant differences in SNR (44.55 vs 37.63 p = 0.12), CNR (31.22 vs 26.39 p = 0.18), and pharmacokinetic parameters Ktrans (0.31 vs 0.32 p = 0.86), Ve (1.36 vs 0.98 p = 0.13), and Kep (0.34 vs 0.36 p = 0.12). CONCLUSIONS: At equimolar doses, increased gadolinium delivery over time using gadobutrol provides higher relative enhancement parameters in BPH nodules compared with gadoterate meglumine, but does not translate into improved SNR or CNR. KEY POINTS: • At equal injection rate and equimolar total dose, gadobutrol compared with gadoterate meglumine provides a significantly greater relative enhancement in DCE-MR imaging of BPH over the first 180 s. • There are no significant differences in SNRs, CNRs, and pharmacokinetic parameters between the two GBCAs.

Age, But Not Repeated Exposure to Gadoterate Meglumine, Is Associated With T1- and T2-Weighted Signal Intensity Changes in the Deep Brain Nuclei of Pediatric Patients.

OBJECTIVES: Current findings on gadolinium deposition in the pediatric brain due to repeated exposure to macrocyclic contrast agents are inconclusive and possibly confounded by brain maturation processes. We evaluated the longitudinal effects of repeated gadoterate meglumine exposure (Dotarem; Guerbet, Villepinte, France) on the T1- and T2-weighted signal intensity (SI) in pediatric patients, and assessed the magnitude of age-related increase in T1-weighted (and decrease in T2-weighted) SI in a control cohort without prior gadolinium exposure. MATERIALS AND METHODS: In this retrospective, double-cohort study, magnetic resonance imaging (MRI) data of 24 patients (0.7-16.4 years, M = 5.74, SD = 4.15) who received at least 10 doses of exclusively gadoterate meglumine were included in the longitudinal study. The MRI data of 190 controls (age range, 1-20 years; 10 patients/bin; bin width, 1 year) without any prior gadolinium-based contrast exposure were included in the control, cross-sectional study to assess the age-dependent SI changes in the regions of interest (ROIs). We measured SI (native), T1-weighted gradient echo, and T2-weighted fast spin-echo of 12 deep brain nuclei. The ROIs were measured at each of the first 11 MRI examinations of the contrast-exposed patients and in the control subject's MRI. Regions of interest's SIs, normalized by the pons, were analyzed with mixed effects models, accounting for the potential confounding factors, such as radiotherapy and chemotherapy. RESULTS: The number of gadoterate meglumine administrations had no effect on the SI increase in any of the ROIs (all P > 0.05), but age significantly correlated with increased SI in T1-weighted globus pallidus (GP; P < 0.01) and caudate (P < 0.05), and with decreased SI in T2-weighted GP (P < 0.001) and dentate nucleus (P < 0.005) in the contrast-exposed group. The cross-sectional analyses of the control cohort showed a significant age-dependent T1-weighted SI increase in multiple ROIs, including the GP and caudate, and decrease in the T2-weighted GP and dentate nucleus (P < 0.05). CONCLUSIONS: Repeated exposure to gadoterate meglumine was not associated with brain hyperintensity in the pediatric patients, whereas age importantly contributed to the SI changes in several deep brain nuclei.

Volumetric Apparent Diffusion Coefficient Histogram Analysis in Differentiating Intrahepatic Mass-Forming Cholangiocarcinoma From Hepatocellular Carcinoma.

BACKGROUND: Accurate differentiation between intrahepatic mass-forming cholangiocarcinoma (IMCC) and hepatocellular carcinoma (HCC) is needed because treatment and prognosis differ significantly. PURPOSE: To explore whether volumetric apparent diffusion coefficient (ADC) histogram analysis can provide additional value to dynamic enhanced MRI in differentiating IMCC from HCC. STUDY TYPE: Retrospective. POPULATION: In all, 131 patients with pathologically proven IMCC (n = 33) or HCC (n = 98). FIELD STRENGTH/SEQUENCE: 3.0T MRI/conventional T1 -weighted imaging (T1 WI), T2 WI, and diffusion-weighted imaging (DWI) with b value of 800 sec/mm2 , dynamic enhanced MRI with gadobenate dimeglumine. ASSESSMENT: Dynamic enhanced MR images were analyzed by two independent reviewers using a five-point scale to determine the diagnosis. Volumetric ADC assessments were performed independently by two radiologists to obtain different histogram parameters for each lesion. Quantitative histogram parameters were compared between the IMCC group and HCC group. Diagnostic performance of dynamic enhanced MRI, volumetric ADC histogram analysis, and the combination of both were analyzed. STATISTICAL TESTS: Intraclass correlation coefficient (ICC) analysis, independent Student's t-test, or Mann-Whitney U-test, receiver operator characteristic (ROC) curves analysis, and McNemar test. RESULTS: The sensitivity and specificity for dynamic enhanced MRI to differentiate IMCC from HCC were 82.1% and 82.6%, respectively. For all volumetric ADC histogram parameters, the 75th percentile ADC (ADC75% ) had the highest AUC (0.791) in differentiating IMCC from HCC, with sensitivity and specificity of 69.7% and 77.6%, respectively. When combining dynamic enhanced MRI with ADC75% , the sensitivity and specificity were 82.1% and 91.9%, respectively. Compared to dynamic enhanced MRI alone, the specificity for combined dynamic enhanced MRI and ADC75% was significantly increased (P = 0.008). DATA CONCLUSION: Volumetric ADC histogram analysis provides additional value to dynamic enhanced MRI in differentiating IMCC from HCC. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;49:975-983.

Breast lesion detection and characterization with contrast-enhanced magnetic resonance imaging: Prospective randomized intraindividual comparison of gadoterate meglumine (0.15 mmol/kg) and gadobenate dimeglumine (0.075 mmol/kg) at 3T.

BACKGROUND: Contrast-enhanced magnetic resonance imaging (CE-MRI) of the breast is highly sensitive for breast cancer detection. Multichannel coils and 3T scanners can increase signal, spatial, and temporal resolution. In addition, the T1 -reduction effect of a gadolinium-based contrast agent (GBCA) is higher at 3T. Thus, it might be possible to reduce the dose of GBCA at 3T without losing diagnostic information. PURPOSE: To compare a three-quarter (0.075 mmol/kg) dose of the high-relaxivity GBCA gadobenate dimeglumine, with a 1.5-fold higher than on-label dose (0.15 mmol/kg) of gadoterate meglumine for breast lesion detection and characterization at 3T CE-MRI. STUDY TYPE: Prospective, randomized, intraindividual comparative study. POPULATION: Eligible were patients with imaging abnormalities (BI-RADS 0, 4, 5) on conventional imaging. Each patient underwent two examinations, 24-72 hours apart, one with 0.075 mmol/kg gadobenate and the other with 0.15 mmol/kg gadoterate administered in a randomized order. In all, 109 patients were prospectively recruited. FIELD STRENGTH/SEQUENCE: 3T MRI with a standard breast protocol (dynamic-CE, T2 w-TSE, STIR-T2 w, DWI). ASSESSMENT: Histopathology was the standard of reference. Three blinded, off-site breast radiologists evaluated the examinations using the BI-RADS lexicon. STATISTICAL TESTS: Lesion detection, sensitivity, specificity, and diagnostic accuracy were calculated per-lesion and per-region, and compared by univariate and multivariate analysis (Generalized Estimating Equations, GEE). RESULTS: Five patients were excluded, leaving 104 women with 142 histologically verified breast lesions (109 malignant, 33 benign) available for evaluation. Lesion detection with gadobenate (84.5-88.7%) was not inferior to gadoterate (84.5-90.8%) (P ≥ 0.165). At per-region analysis, gadobenate demonstrated higher specificity (96.4-98.7% vs. 92.6-97.3%, P ≤ 0.007) and accuracy (96.3-97.8% vs. 93.6-96.1%, P ≤ 0.001) compared with gadoterate. Multivariate analysis demonstrated superior, reader-independent diagnostic accuracy with gadobenate (odds ratio = 1.7, P < 0.001 using GEE). DATA CONCLUSION: A 0.075 mmol/kg dose of the high-relaxivity contrast agent gadobenate was not inferior to a 0.15 mmol/kg dose of gadoterate for breast lesion detection. Gadobenate allowed increased specificity and accuracy. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;49:1157-1165.

Diterpene ginkgolides meglumine injection protects against paraquat-induced lung injury and pulmonary fibrosis in rats.

In this study, we aimed to investigate the effects of diterpene ginkgolides meglumine injection (DGMI) on paraquat (PQ)-induced lung injury and pulmonary fibrosis in rats. Male SD rats were challenged by PQ (20?mg/kg, i.p.) with or without either DGMI (1.25, 2.5, 5?mg/kg, i.p.) or Edaravone (EDA, 6?mg/kg, i.p.) posttreatment 2?h after PQ administration. Lung tissues were removed for biochemical analyses and pathological examinations on day 1, day 3, day 7, day 14 and day 21. Results showed that the administration of DGMI significantly increased the survival of PQ-challenged rats. At the same time, DGMI reversed the increase of Malondialdehyde (MDA) level and the decrease of Super Oxide Dismutase (SOD) level in lung tissues. Moreover, lung to body weight ratio, Interleukin-1beta (IL-1?), Interleukin-6 (IL-6) and Tumor necrosis factor-alpha (TNF-?) levels in lung tissues were reduced compared with the model group. H&E and Masson staining revealed that DGMI (5?mg/kg) alleviated histological injury and pulmonary fibrosis, and EDA (6?mg/kg) exerted approximate effects. Immunohistochemistry staining presented that the benefit effects of DGMI were associated with its ability to activate Akt-Nrf-2 pathway. In conclusion, these results suggest that DGMI possesses potential role in future therapies for PQ-induced lung injury and pulmonary fibrosis.

Antileishmanial Activity of 2-Methoxy-4H-spiro-[naphthalene-1,2'-oxiran]-4-one (Epoxymethoxy-lawsone): A Promising New Drug Candidate for Leishmaniasis Treatment.

Epoxymethoxylawsone is a naphthoquinone derivative promising as drug candidate for the treatment of leishmaniases. In the present work the effectiveness of epoxymethoxylawsone, and meglumine antimoniate on Leishmania (Leishmania) amazonensis parasites and on mice paw lesions of infected BALB/c mice was assessed. In an intracellular amastigotes assay, the half-maximal inhibitory concentration (IC50) value for epoxymethoxylawsone was slightly higher (1.7-fold) than that found for meglumine antimoniate. The efficacy of both drugs became more evident after 48 h of exposure when either the oxirane compound and reference drug reached 18-fold and 7.4-fold lower IC50 values (0.40 ± 0.001 µM and 0.60 ± 0.02 µM), respectively. Promastigotes were also affected by epoxymethoxylawsone after 24 h of incubation (IC50 = 45.45 ± 5.0 µM), but with IC50 6-fold higher than those found for intracellular amastigotes. Cytotoxicity analysis revealed that epoxymethoxylawsone (CC50 = 40.05 ± µM) has 1.7-fold higher effects than meglumine antimoniate (CC50 = 24.14 ± 2.6 µM). Treatment of the paw lesion in infected BALB/c mice with epoxymethoxy-lawsone led to a significant 27% reduction (p < 0.05) of the lesion size, for all administrated doses, compared to the control group. Lesion reduction was also detected after mice treatment with meglumine antimoniate, reaching 31.0% (0.23 mg of Sb(V)/Kg/day and 2.27 mg of Sb(V)/Kg/day) and 64.0% (22.7 mg of Sb(V)/Kg/day). In addition, mice lesion ultrastructural changes were evidenced in amastigotes. The set of data gathered here indicate that epoxymethoxylawsone has pronounced effects on parasites and merits furthering to the preclinical stage.

Effects of gadolinium-based contrast agents on submandibular gland tissue in rats.

AIM: The aim of this prospective animal study is to investigate the influence of multiple administrations of macrocyclic ionic (gadoteric acid) and linear nonionic (gadodiamide) gadolinium-based contrast agents (GBCA) on submandibular gland tissue (SGT) of the rats. MATERIAL AND METHOD: Twenty-four Sprague Dawley female rats were included the study. Group 1 was determined as a control group (n = 6). Group 2 was determined as saline group (n = 6). Group 3 was determined as Omniscan group (n = 6) and received only intraperitoneal (IP) 0.1 mmol (0.2 mL/kg)/kg gadodiamide for 8 days. Group 4 was determined as Dotarem group (n = 6) and received only IP 0.1 mmol (0.2 mL/kg)/mg/kg gadoteric acid daily for 8 days. On the 9th day of the administration, the rats were sedated with ketamine and xylazine through IP injection. The right SGT was removed after sedation. Histopathological and immunohistochemical changes in SGT were evaluated. RESULTS: The SGT of the Omniscan and Dotarem groups decreased SGT acini surface area, and serous acinar cells number were observed. On the other hand, no pathology was observed. Mucous acinar cells' caspase-3 positivity for the same markers in Omniscan and Dotarem sections was similar to the control group. However, Omniscan and Dotarem groups serous acinar cells were caspase-3 (+) staining. The intensity of serous acinar cells' caspase-3 (+) for the same markers in Dotarem sections was similar to the Omniscan group. The results also revealed in the analysis of the mean area of the acinus area of the SGT; there were significantly decreased Dotarem group rats when compared to control rats (p < 0.05). CONCLUSION: We consider that numerical increased apoptosis results arise from repeated doses of GBCAs. Being aware of this effect of the contrast agent may have significance for the chronic sialo-adenitis patients group when used for recurrent contrasted MRI for diagnosis of diseases like MS which requires in follow-up. We should be aware about the frequently contrasted MRI in routine investigations.

Diterpene ginkgolides protect against cerebral ischemia/reperfusion damage in rats by activating Nrf2 and CREB through PI3K/Akt signaling.

Diterpene ginkgolides meglumine injection (DGMI) is a therapeutic extract of Ginkgo biloba L, which has been used for the treatment of cerebral ischemic stroke in China. Ginkgolides A, B and C are the main components of DGMI. This study was designed to investigate the neuroprotective effects of DGMI components against ischemic stroke in vivo and in vitro. Acute cerebral ischemic injury was induced in rats by occlusion of the middle cerebral artery (MCA) for 1.5 h followed by 24 h reperfusion. The rats were treated with DGMI (1, 3 and 10 mg/kg, iv) at the onset of reperfusion and 12 h after reperfusion. Administration of DGMI significantly decreased rat neurological deficit scores, reduced brain infarct volume, and induced protein kinase B (Akt) phosphorylation, which prompted the nuclear translocation of nuclear factor-erythroid 2-related factor 2 (Nrf2) and phosphorylation of the survival regulatory protein cyclic AMP-responsive element binding protein (CREB). Nrf2 activation led to expression of the downstream protein heme oxygenase-1 (HO-1). In addition, PC12 cells were subjected to oxygen-glucose deprivation/reperfusion (OGD/R) in vitro, treatment with DGMI (1, 10 and 20 µg/mL) or ginkgolides A, B or C (10 µmol/L for each) significantly reduced PC12 cell death and increased phosphorylation of Akt, nuclear translocation of Nrf2 and activation of CREB. Activation of Nrf2 and CREB could be reversed by co-treatment with a phosphoinositide-3-kinase (PI3K) inhibitor LY294002. These observations suggest that ginkgolides act as novel extrinsic regulators activating both Akt/Nrf2 and Akt/CREB signaling pathways, protecting against cerebral ischemia/reperfusion (I/R) damage in vivo and in vitro.

High Signal Intensity in the Dentate Nucleus and Globus Pallidus on Unenhanced T1-Weighted MR Images: Comparison between Gadobutrol and Linear Gadolinium-Based Contrast Agents.

BACKGROUND AND PURPOSE: In view of the recent observations that gadolinium deposits in brain tissue after intravenous injection, our aim of this study was to compare signal changes in the globus pallidus and dentate nucleus on unenhanced T1-weighted MR images in patients receiving serial doses of gadobutrol, a macrocyclic gadolinium-based contrast agent, with those seen in patients receiving linear gadolinium-based contrast agents. MATERIALS AND METHODS: This was a retrospective analysis of on-site patients with brain tumors. Fifty-nine patients received only gadobutrol, and 60 patients received only linear gadolinium-based contrast agents. Linear gadolinium-based contrast agents included gadoversetamide, gadobenate dimeglumine, and gadodiamide. T1 signal intensity in the globus pallidus, dentate nucleus, and pons was measured on the precontrast portions of patients' first and seventh brain MRIs. Ratios of signal intensity comparing the globus pallidus with the pons (globus pallidus/pons) and dentate nucleus with the pons (dentate nucleus/pons) were calculated. Changes in the above signal intensity ratios were compared within the gadobutrol and linear agent groups, as well as between groups. RESULTS: The dentate nucleus/pons signal ratio increased in the linear gadolinium-based contrast agent group (t = 4.215, P < .001), while no significant increase was seen in the gadobutrol group (t = -1.422, P = .08). The globus pallidus/pons ratios followed similarly, with an increase in the linear gadolinium-based contrast agent group (t = 2.931, P < .0001) and no significant change in those receiving gadobutrol (t = 0.684, P = .25). CONCLUSIONS: Successive doses of gadobutrol do not result in T1 shortening compared with changes seen in linear gadolinium-based contrast agents.

Development of High Signal Intensity within the Globus Pallidus and Dentate Nucleus following Multiple Administrations of Gadobenate Dimeglumine.

BACKGROUND AND PURPOSE: Previous studies have evaluated various gadolinium based contrast agents and their association with gadolinium retention, however, there is a discrepancy in the literature concerning the linear agent gadobenate dimeglumine. Our aim was to determine whether an association exists between the administration of gadobenate dimeglumine and the development of intrinsic T1-weighted signal in the dentate nucleus and globus pallidus. MATERIALS AND METHODS: In this single-center, retrospective study, the signal intensity of the globus pallidus, dentate nucleus, thalamus, and middle cerebellar peduncle was measured on unenhanced T1-weighted images in 29 adult patients who had undergone multiple contrast MRIs using exclusively gadobenate dimeglumine (mean, 10.1 ± 3.23 doses; range, 6-18 doses). Two neuroradiologists, blinded to the number of prior gadolinium-based contrast agent administrations, separately placed ROIs within the globi pallidi, thalami, dentate nuclei, and middle cerebellar peduncles on the last MR imaging examinations. The correlations between the globus pallidus:thalamus and the dentate nucleus:middle cerebellar peduncle signal intensity ratios with the number of gadolinium-based contrast agent administrations and cumulative dose were tested with either 1-tailed Pearson or Spearman correlations. A priori, P < .05 was considered statistically significant. RESULTS: Both the globus pallidus:thalamus and dentate nucleus:middle cerebellar peduncle ratios showed significant correlation with the number of gadolinium-based contrast agent administrations (r = 0.39, P = .017, and r = 0.58, P = .001, respectively). Additionally, the globus pallidus:thalamus and dentate nucleus:middle cerebellar peduncle ratios showed significant correlation with the cumulative dose of gadobenate dimeglumine (r = 0.48, P = .004, and r = 0.43, P = .009, respectively). Dentate nucleus hyperintensity was qualitatively present on the last MR imaging in 79.3%-86.2% of patients and in all patients who had received >10 doses. CONCLUSIONS: At high cumulative doses (commonly experienced by patients, for example, with neoplastic disease), gadobenate dimeglumine is associated with an increase in the globus pallidus:thalamus and dentate nucleus:middle cerebellar peduncles signal intensity ratios.

Hepatic fibropoiesis in dogs naturally infected with Leishmania (Leishmania) infantum treated with liposome-encapsulated meglumine antimoniate and allopurinol.

Hepatic fibropoiesis in canine visceral leishmaniasis (CVL) were evaluated by histological (morphometrical collagen deposition) and immunohistochemical assays characterizing alpha-actin (α-SMA), vimentin, calprotectin (L1 antigen), and TGF-ß in 46 naturally infected dogs with Leishmania infantum treated with liposome-encapsulated meglumine antimoniate and allopurinol separately and in combination. Six treatment groups were defined: meglumine antimoniate encapsulated in nanometric liposomes (LMA), allopurinol (ALLOP); liposome-encapsulated meglumine antomoniate combined with allopurinol (LMA+ALLOP); empty liposomes (LEMP); empty liposomes combined with allopurinol (LEMP+ALLOP) and saline. Relative liver weight was lower in LMA, LMA+ALLOP, and ALLOP groups compared to the LEMP control. Significantly lower granulomatous chronic inflammatory reaction was seen in the ALLOP group compared to a control group. Calprotectin was lowest in liver of those dogs showing lower numbers of intralobular hepatic granulomas. Collagen deposits were significantly higher in LMA compared to ALLOP, LEMP+ALLOP, and Saline groups. LMA+ALLOP group collagen deposition was higher than dogs treated only with allopurinol. Immunohistochemical analysis showed significant higher α-SMA in hepatic stellate cells (HSCs), hepatic perisinusoidal cells, in control groups than LMA+ALLOP and LEMP+ALLOP. Alpha-actin and Vimentin positive cells were diffusely distributed throughout the liver parenchyma in the hepatic lobule, mainly in HSCs. Vimentin expression was significantly higher in the saline group than in the ALLOP group. Our data suggest that allopurinol inhibits HSC and results in lower collagen deposits in liver during CVL progression, as supported by the significantly lower expression of TGF-ß in the ALLOP group compared to other groups. Results demonstrated that treatment with allopurinol inhibited chronic granulomatous inflammatory reaction and hepatic fibrosis in CVL.

Leishmania infantum exerts immunomodulation in canine Kupffer cells reverted by meglumine antimoniate.

Kupffer cells (KC) are the liver macrophage population that resides in the hepatic sinusoids and efficiently phagocyte pathogens by establishing an intimate contact with circulating blood. KC constitute the liver host cells in Leishmania infection, nevertheless little is described about their role, apart from their notable contribution in granulomatous inflammation. The present study aims to investigate how canine KC sense and react to the presence of Leishmania infantum promastigotes and amastigotes by evaluating the gene expression of specific innate immune cell receptors and cytokines, as well as the induction of nitric oxide and urea production. Complementarily, the impact of a leishmanicidal drug - meglumine antimoniate (MgA) - in infected KC was also explored. KC revealed to be susceptible to both parasite forms and no major differences were found in the immune response generated. L. infantum parasites seem to interact with KC innate immune receptors and induce an anergic state, promoting immune tolerance and parasite survival. The addition of MgA to infected KC breaks the parasite imposed silence and increased gene expression of Toll-like receptors (TLR) 2 and TLR4, possibly activating downstream pathways. Understanding how KC sense and react to parasite presence could bring new insights into the control or even elimination of canine leishmaniasis.