Immunosuppression use in primary antiphospholipid antibody-positive patients: Descriptive analysis of the AntiPhospholipid Syndrome Alliance for Clinical Trials and InternatiOnal Networking (APS ACTION) Clinical Database and Repository ("Registry").

BACKGROUND/PURPOSE: APS ACTION Registry was created to study the outcomes of patients with persistently positive antiphospholipid antibodies (aPL) with or without other systemic autoimmune disease (SAIDx). Given that immunosuppression (IS) is used for certain aPL manifestations, for example, thrombocytopenia (TP), our primary objective was to describe the indications for IS in aPL-positive patients without other SAIDx. Secondly, we report the type of IS used in patients with selected microvascular or non-thrombotic aPL manifestations. METHODS: An online database is used to collect clinical data. The inclusion criteria are positive aPL based on the laboratory section of the APS Classification Criteria, tested at least twice within one year prior to enrollment. Patients are followed every 12 ± 3 months. For this descriptive retrospective and prospective analysis, we included aPL-positive patients without other SAIDx and excluded those with new SAIDx classification during follow-up. For each patient, we retrieved clinical data at baseline and follow-up including selected aPL manifestations (diffuse alveolar hemorrhage [DAH], antiphospholipid-nephropathy [aPL-N], livedoid vasculopathy [LV]-related skin ulcers, TP, autoimmune hemolytic anemia [AIHA], cardiac valve disease [VD]), and IS medications. RESULTS: Of 899 patients enrolled, 537 were included in this analysis (mean age 45 ± 13 years, female 377 [70%], APS Classification in 438 [82%], and at least one selected microvascular or non-thrombotic aPL manifestation in 141 (26%)). Of 537 patients, 76 (14%) were reported to use IS (ever), and 41/76 (54%) received IS primarily for selected aPL manifestation. In six of 8 (75%) DAH patients, 6/19 (32%) aPL-N, 4/28 (14%) LV, 25/88 (28%) TP, 6/11 (55%) AIHA, and 1/43 (2%) VD, the IS (excluding corticosteroids/hydroxychloroquine) indication was specific for selected aPL manifestation. CONCLUSION: In our international cohort, 14% of aPL-positive patients without other SAIDx were reported to receive IS; the indication was at least one of the selected microvascular and/or non-thrombotic aPL-related manifestations in half. Thrombocytopenia was the most frequent among those selected aPL-related manifestations; however, approximately one-third received IS specifically for that indication. Diffuse alveolar hemorrhage was frequently treated with IS followed by AIHA and aPL-N. Systematic controlled studies are urgently needed to better define the role of IS in APS.

Quantification of heavy metals and health risk assessment in Sichuan pickle.

Sichuan pickle is one of popular traditional fermented foods in China. However, the contamination of heavy metals in Sichuan pickle, particularly home-made Sichuan pickle and aged pickle brine, is little known. Therefore, the content of trace (Cr, Cu, and Zn) and toxic elements (As, Pb, and Cd) in Sichuan industrial pickle (SIP), Sichuan home-made pickle (SHP), and aged pickle brine collected from local markets and families in Sichuan province, respectively, was detected by inductively coupled plasma-tandem mass spectrometry (ICP-MS/MS) and the health risk was assessed by target hazard quotients including target hazard quotient (THQ) and total target hazard quotient (TTHQ). Consequently, the mean concentrations of Cr, Cu, Zn, As, Pb, and Cd were 0.122, 0.540, 2.516, 0.023, 0.015, and 0.106 mg/kg in SIP and 0.071, 0.364, 2.698, 0.014, 0.015, and 0.289 mg/kg in SHP, respectively, lower than the maximum allowable concentrations set by Chinese regulations, except for Cr and Cd in few samples. Principal component analysis of the heavy metal content could obviously distinguish between SIP and SHP. The content of As, Pb, and Cd in leaf pickles was significantly higher than that in pickles fermented with other types of vegetables. A significant enrichment of heavy metals in aged pickle brine over 10 years was observed, but pickle jars had no significant effect on heavy metal content in aged pickle brine. The intake of heavy metals through daily consumption of SIP and SHP was at a safe level, whereas the TTHQ of leaf pickle was 1.006, indicating a potential health risk. In conclusion, this study provided fundamental data for food safety assurance of Sichuan pickle. PRACTICAL APPLICATION: Sichuan pickle is one of popular traditional fermented foods in China. In the present study, we investigated the contamination of heavy metals in Sichuan pickles by detecting the content of Cr, Cu, Zn, As, Cd, and Pb in Sichuan industrial pickle, Sichuan home-made pickle, and aged pickle brine, and estimated the health risk to local residents. This study can provide a reference for the safety risk of Sichuan industrial and home-made pickle in terms of heavy metal contamination, and enhance the food safety in the processing, production, and consumption of Sichuan pickle in local families and pickle industry.

Cardiac MRI Myocardial Functional and Tissue Characterization Detects Early Cardiac Dysfunction in a Mouse Model of Chemotherapy-Induced Cardiotoxicity.

BACKGROUND: Doxorubicin and doxorubicin-trastuzumab combination chemotherapy have been associated with cardiotoxicity that eventually leads to heart failure and may limit dose-effective cancer treatment. Current diagnostic strategies rely on decreased ejection fraction (EF) to diagnose cardiotoxicity. PURPOSE: The aim of this study is to explore the potential of cardiac MR (CMR) imaging to identify imaging biomarkers in a mouse model of chemotherapy-induced cardiotoxicity. METHODS: A cumulative dose of 25 mg/kg doxorubicin was administered over three weeks using subcutaneous pellets (n = 9, Dox). Another group (n = 9) received same dose of Dox and a total of 10 mg/kg trastuzumab (DT). Mice were imaged at baseline, 5/6 weeks and 10 weeks post-treatment on a 7T MRI system. The protocol included short-axis cine MRI covering the left ventricle (LV) and mid-ventricular short-axis tissue phase mapping (TPM), pre- and post-contrast T1 mapping, T2 mapping and Displacement Encoding with Stimulated Echoes (DENSE) strain encoded MRI. EF, peak myocardial velocities, native T1, T2, extracellular volume (ECV), and myocardial strain were quantified. N = 7 mice were sacrificed for histopathologic assessment of apoptosis at 5/6 weeks. RESULTS: Global peak systolic longitudinal velocity was reduced at 5/6 weeks in Dox (0.6 ± 0.3 vs 0.9 ± 0.3, p = 0.02). In the Dox group, native T1 was reduced at 5/6 weeks (1.3 ± 0.2 ms vs 1.6 ± 0.2 ms, p = 0.02), and relatively normalized at week 10 (1.4 ± 0.1 ms vs 1.6 ± 0.2 ms, p > 0.99). There was no change in EF and other MRI parameters and histopathologic results demonstrated minimal apoptosis in all mice (~1-2 apoptotic cell/high power field), suggesting early-stage cardiotoxicity. CONCLUSIONS: In a mouse model of chemotherapy-induced cardiotoxicity using doxorubicin and trastuzumab, advanced CMR shows promise in identifying treatment-related decrease in myocardial velocity and native T1 prior to the onset of cardiomyocyte apoptosis and reduction of EF.

Early Immunologic Response of Irreversible Electroporation versus Cryoablation in a Rodent Model of Pancreatic Cancer.

PURPOSE: To investigate the differences in immune responses between cryoablation and irreversible electroporation (IRE) in a preclinical mouse model. MATERIAL AND METHODS: A mouse pancreatic cancer cell line (PANC-2) was implanted in the bilateral flanks of mice, and tumor-bearing mice were divided into 6 groups. One of the tumors was ablated either with contact cryoablation using an argon-cooled cryoablation probe for 1 minute at 5% power or by IRE for a total of 64 100-µs-duration, 1250-V/cm2 pulses with 100-ms spacing. The contralateral tumors in the same animal served as controls. At immediate, 6, 12, and 24 hours after ablation, the tumors were processed for immunostaining with F480 (macrophages), CD3 (T cells), and CD-56 (natural killer cells) antibodies. RESULTS: CD3 staining demonstrated significantly more T cells in the IRE group than in the cryoablation group at 6 hours (45 vs 16; P = .027), 12 hours (67 vs 33; P = .020), and 24 hours (161 vs 94; p = .003), with almost a 2-fold increase at every time point. Although the mean number of natural killer cells in the treated tumors was higher, no significant differences were observed between the 2 groups at any of the time points. A significant difference was observed in F480 positivity between the cryoablation group and the IRE group at 12 hours (210 vs 356; P = .0004) and 24 hours (220 vs 328; P = .04), respectively. CONCLUSIONS: In a mouse model of pancreatic cancer, IRE evokes a more robust infiltration of macrophages and T cells than cryoablation within 24 hours.

Assessment and optimization of electroporation-assisted tumoral nanoparticle uptake in a nude mouse model of pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a particularly lethal form of cancer. In 2012, the incidence of PDAC was 43,920. Five-year survival for patients with PDAC is around 6%, regardless of staging, making PDAC one of the deadliest forms of cancer. One reason for this dismal prognosis is chemoresistance to the current first-line therapy, gemcitabine. There are multiple factors that contribute to the chemoresistance observed in pancreatic cancer. Among them, desmoplasia has been increasingly seen as a significant contributor to chemoresistance. To overcome desmoplastic chemoresistance, several novel methods of treatment have been developed. Electroporation is one such novel treatment. High electrical fields are applied to cells to create pores that increase cell permeability. It has been previously demonstrated that electroporation enhances the therapeutic efficacy of anticancer drugs in pancreatic tumor models. Nanoparticle-based drug delivery systems constitute a second novel method to overcome desmoplastic chemoresistance. Due to their intrinsic design advantages, nanoparticles have been shown to increase the effectiveness of chemotherapeutic agents, while further reducing or even eliminating side effects. To date, there have been no studies evaluating the cumulative effect of combining both nanoparticle and electroporation strategies to overcome chemoresistance in PDAC. Our preliminary studies assessed the in vitro and in vivo uptake of doxorubicin-loaded iron oxide nanoparticles as a function of electroporation voltage and timing of administration in pancreatic adenocarcinoma cells. Our studies demonstrated that addition of electroporation to administration of nanoparticles significantly increased the amount of intracellular iron oxide nanoparticle uptake by a PANC-1 cell line in an athymic nude mouse model of PDAC. Further, electroporation-assisted nanoparticle uptake could be significantly altered by changing the timing of application of electroporation.

Dual-contrast cellular magnetic resonance imaging.

Negative contrast magnetic resonance imaging (MRI) methods using magnetic susceptibility shifting agents have become one of the most important approaches in cellular imaging research. However, visualizing and tracking labeled cells on the basis of negative contrast is often met with limited specificity and sensitivity. Here we report on a MRI method for cellular imaging that generates a new contrast with a distinct topology for identifying labeled cells that has the potential to significantly improve both the sensitivity and the specificity. Specifically, we show that low flip-angle steady-state free precession MRI can be used to generate fast three-dimensional images of tissue that can be rapidly processed to generate quantitative metrics enabling color overlays indicative of regions containing labeled cells. The technique substantially improves the ability of MRI for detecting labeled cells by overcoming the fundamental limits that currently plague negative contrast methods.

Assessment of regional myocardial oxygenation changes in the presence of coronary artery stenosis with balanced SSFP imaging at 3.0 T: theory and experimental evaluation in canines.

PURPOSE: To examine the dependence of steady-state free-precession (SSFP) -based myocardial blood-oxygen-level-dependent (BOLD) contrast on field strength using theoretical and experimental models. MATERIALS AND METHODS: Numerical simulations using a two-pool exchange model and a surgically prepared dog model were used to assess the SSFP-based myocardial BOLD signal changes at 1.5T and 3.0T. Experimental studies were performed in eight canines with pharmacological vasodilation under various levels of left circumflex coronary artery stenosis. Experimentally obtained BOLD signal changes were correlated against microsphere-based true flow changes. RESULTS: Theoretical results showed that, at 3.0T, relative to 1.5T, a threefold increase in oxygen sensitivity can be expected. Experimental studies in canines showed near similar results-a 2.5 +/- 0.2-fold increase in BOLD sensitivity at 3.0T relative to 1.5T (P < 0.05). Based on the scatter gram of BOLD data and microsphere data, it was found that the minimum regional flow difference that can be detected with SSFP-based myocardial BOLD imaging at 1.5T and 3.0T were 2.9 and 1.6, respectively (P < 0.05). CONCLUSION: This study demonstrated that SSFP-based myocardial BOLD sensitivity is substantially greater at 3.0T compared with 1.5T. The findings here suggest that SSFP-based myocardial BOLD imaging at 3.0T may have the necessary sensitivity to detect the clinically required minimum flow difference of 2.0.