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In this study, the total phenolic and flavonoid contents (TPC and TFC), secondary metabolite composition (LC-HRMS/MS analyses) and antioxidant potential (DPPH, ABTS, GOR, CUPRAC, and phenanthroline assays) of Linum trigynum L. (LT) extracts were determined. Our results showed for the first time that the extracts (PE, CHCl3, AcOEt, and n-BuOH) of LT exert antioxidant activity. The AcOEt and n-BuOH extracts were the most antioxidant compared to the standards, and had a higher amount of TPC (323.51 ± 0.62; 229.98 ± 6.80 µg GAE/mL) and TFC (183.75 ± 1.17 and 157.50 ± 1.77 µg QE/mL), resectively. The high antioxidant properties of these extracts may be due to their major compounds (phenolic compounds) detected by LC-HRMS/MS analyses including flavonoids (40 compounds) and phenolic acids and derivatives (18 and 19 compounds, respectively). AcOEt and n-BuOH extracts of LT can be used as an excellent source of antioxidant phytochemicals to prevent or treat various diseases.

Coronary microvascular dysfunction (CMVD) plays a major role in the occurrence of cardiovascular events (CVE). We recently suggested the clinical potential of myocardial perfusion entropy (MPE) quantification from SPECT myocardial perfusion images (MPI) for the prognosis of CVE occurrence. We hypothesized that the quantification of MPE from SPECT MPI would allow the assessment of CMVD-related MPE variations in a preclinical model of type 2 diabetes (T2D) including treatment with the anti-diabetic incretin liraglutide (LIR). Optimal conditions for the preclinical quantification of MPE using 201Tl SPECT MPI were determined in rats with a T2D-like condition induced by a high-fat diet and streptozotocin injection (feasibility study, n = 43). Using such conditions, echocardiography and post-mortem LV capillary density evaluation were then used in order to assess the effect of LIR and the ability of MPE to assess CMVD (therapeutic study, n = 39). The feasibility study identified dobutamine stress and acute NO synthase and cyclooxygenase inhibition as optimal conditions for the quantification of MPE, with significant increases in MPE being observed in T2D animals (P

Myocardial insulin resistance (IR) could be a predictive factor of cardiovascular events. This study aimed to introduce a new method using 123I-6-deoxy-6-iodo-d-glucose (6DIG), a pure tracer of glucose transport, for the assessment of IR using cardiac dynamic nuclear imaging. The protocol evaluated first in rat-models consisted in two 6DIG injections and one of insulin associated with planar imaging and blood sampling. Compartmental modeling was used to analyze 6DIG kinetics in basal and insulin conditions and to obtain an index of IR. As a part of a translational approach, a clinical study was then performed in 5 healthy and 6 diabetic volunteers. In rodent models, the method revealed reproducible when performed twice at 7 days apart in the same animal. Rosiglitazone, an insulin-sensitizing drug, induced a significant increase of myocardial IR index in obese Zucker rats from 0.96 ± 0.18 to 2.26 ± 0.44 (P

Risk stratification of patients with type 2 diabetes mellitus (T2D) remains suboptimal. We hypothesized that myocardial perfusion entropy (MPE) quantified from SPECT myocardial perfusion images may provide incremental prognostic value in T2D patients independently from myocardial ischemia. T2D patients with very high and high cardiovascular risk were prospectively included (n = 166, 65 ± 12 years). Stress perfusion defect was quantified by visual evaluation of SPECT MPI. SPECT MPI was also used for the quantification of rest and stress MPE. The primary end point was major adverse cardiac events (MACEs) defined as cardiac death, myocardial infarction (MI), and myocardial revascularization > 3 months after SPECT. Forty-four MACEs were observed during a 4.6-year median follow-up. Significant differences in stress MPE were observed between patients with and without MACEs (4.19 ± 0.46 vs. 3.93 ± 0.40; P ≤ .01). By Kaplan-Meier analysis, the risk of MACEs was significantly higher in patients with higher stress MPE (log-rank P ≤ 01). Stress MPE and stress perfusion defect (SSS ≥ 4) were significantly associated with the risk of MACEs (hazard ratio 2.77 and 2.06, respectively, P

Introduction: – The invasive quantification of coronary flow reserve (CFR), the index of microcirculatory resistance (IMR), and fractional flow reserve (FFR) allows to assess coronary physiology. Although semi-conductor (CZT) SPECT myocardial perfusion reserve (MPR) has been previously compared with FFR, there are no data documenting the relationships between CZT SPECT MPR on one hand and CFR and/or IMR on the other hand. We assessed the performances of noninvasive CZT SPECT MPR in comparison with invasively determined FFR, CFR, and IMR. Methods: – Rest and dipyridamole-induced stress myocardial blood flow and MPR were quantified using 99m Tc-SestaMIBI and a Discovery NM 530c camera in 26 patients with suspected or known coronary artery disease who underwent conventional invasive coronary angiography. Thermodilution-derived resting and adenosine-induced hyperemic mean transit times, distal intracoronary pressures, and mean aortic pressures were assessed for the quantification of FFR, CFR, and IMR values. Results: – Only 2/35 vessels presented with a pathological (P =.02). The sensitivity, specificity, positive and negative predictive value, and accuracy of regional CZT SPECT MPR vs CFR were 69% [44-86%], 94% [74-100%], 91% [65-100%], 77% [56-90%], and 82% [65-93%], respectively. In territories without underlying CAD (n=32), CZT SPECT MPR values were significantly higher in those with CFR≥2 and IMRvs 1.6 [1.2-1.8]), P Conclusions: – CZT SPECT MPR presented a moderate, significant correlation with thermodilution CFR and good diagnostic performances for the detection of patients at high risk of cardiovascular events (low CFR and high IMR) in the absence of obstructive CAD.

International audience; PURPOSE:Insulin resistance is a key feature of the metabolic syndrome and type 2 diabetes, in which noninvasive assessment is not currently allowed by any methodology. We previously validated an iodinated tracer of glucose transport (6DIG) and a new methodology for the in vivo quantification of cardiac insulin resistance in rodents. The aim of this study was to investigate the safety, biodistribution, and radiation dosimetry of this method using I-6DIG in 5 healthy and 6 diabetic volunteers.METHODS:The collection of adverse effects (AEs) and medical supervision of vital parameters and biological variables allowed the safety evaluation. Biodistribution was studied by sequentially acquiring whole-body images at 1, 2, 4, 8, and 24 hours postinjection. The total number of disintegrations in each organ normalized to the injected activity was calculated as the area under the time-activity curves. Dosimetry calculations were performed using OLINDA/EXM.RESULTS:No major adverse events were observed. The average dose corresponding to the 2 injections of I-6DIG used in the protocol was 182.1 ± 7.5 MBq. A fast blood clearance of I-6DIG was observed. The main route of elimination was urinary, with greater than 50% of urine activity over 24 hours. No blood or urine metabolite was detected. I-6DIG accumulation mostly occurred in elimination organs such as kidneys and liver. Mean radiation dosimetry calculations indicated an effective whole-body absorbed dose of 3.35 ± 0.57 mSv for the whole procedure.CONCLUSIONS:I-6DIG was well tolerated in human with a dosimetry profile comparable to that of other commonly used iodinated tracers, thereby allowing further clinical development of the tracer.

Coronary microvascular dysfunction (CMVD) plays a major role in the occurrence of cardiovascular events (CVE). We recently suggested the clinical potential of myocardial perfusion entropy (MPE) quantification from SPECT myocardial perfusion images (MPI) for the prognosis of CVE occurrence. We hypothesized that the quantification of MPE from SPECT MPI would allow the assessment of CMVD-related MPE variations in a preclinical model of type 2 diabetes (T2D) including treatment with the anti-diabetic incretin liraglutide (LIR).Optimal conditions for the preclinical quantification of MPE usingThe feasibility study identified dobutamine stress and acute NO synthase and cyclooxygenase inhibition as optimal conditions for the quantification of MPE, with significant increases in MPE being observed in T2D animals (P 0.01 vs controls). In the therapeutic study, T2D rats were hyperglycemic (5.5 ± 0.5 vs 1.1 ± 0.3 g/L for controls, P 0.001) and had a significantly lower left ventricular ejection fraction (LVEF) (65 ± 4% vs 74 ± 9%, P 0.01) and LV capillary density (2400 ± 300 vs 2800 ± 600 mmMPE quantification allowed the preclinical noninvasive assessment of CMVD. Both MPE and capillary density quantification suggested that LIR did not improve T2D-induced CMVD. The relevance of MPE for CMVD assessment warrants further clinical investigation.

NeoB is a radiotracer targeting the gastrin-releasing peptide receptor (GRPR), a G-protein–coupled receptor expressed in various cancers. The aim of the present study was to evaluate the biodistribution and efficacy of this new therapeutic agent in Gastrointestinal Stromal Tumors (GIST). Eighty-two SCID mice bearing GIST-882 tumors were employed. [177Lu]Lu-NeoB biodistribution was evaluated up to seven days by organ sampling (200 pmol/0.8 MBq, i.v.). For efficacy evaluation, mice received either saline, 400 pmol or 800 pmol of [177Lu]Lu-NeoB (37MBq, 1/w, 3 w, i.v.). SPECT/CT imaging was performed at 24 h, and tumor volume was determined up to 100 days. Elevated and specific [177Lu]Lu-NeoB uptake was found in the GIST tumor, as demonstrated by in vivo competition (19.1 ± 3.9 %ID/g vs. 0.3 ± 0.1 %ID/g at 4h). [177Lu]Lu-NeoB tumor retention (half-life of 40.2 h) resulted in elevated tumor-to-background ratios. Tumor volumes were significantly reduced in both treated groups (p &lt, 0.01), even leading to complete tumor regression at the 400 pmol dose. [177Lu]Lu-NeoB exhibited excellent pharmacokinetics with elevated and prolonged tumor uptake and low uptake in non-target organs such as pancreas. The potential of this new theragnostic agent in different indications, including GIST, is under evaluation in the FIH [177Lu]Lu-NeoB clinical trial.

International audience; Coronary microvascular dysfunction has recently emerged as a major independent prognostic factor and can be invasively assessed by coronary flow reserve (CFR) and the index of microvascular resistance (IMR). The incremental prognostic value of myocardial ischemia from SPECT myocardial perfusion imaging (MPI) over clinical characteristics, cardiac risk factors, and stress test data for the prediction of hard cardiac events (myocardial infarction and cardiac death) has been well demonstrated over the last two decades regardless of the absence or presence of epicardial CAD. Recently developed semi-conductor, cardiac-dedicated cameras allow for decreased acquisition times and systematic procubitus and decubitus acquisitions thereby limiting the occurrence of false positives historically attributable to artefactual motion, attenuation, and digestive artifacts. It is therefore likely that pathophysiological causes rather than acquisition artifacts might underlie SPECT perfusion abnormalities. Here, we report four representative examples of patients presenting with ischemia in the setting of no obstructive CAD and normal fractional flow reserve together with elevated IMR and low CFR. The results indicate that ischemia from SPECT MPI could result from microvascular dysfunction in patients without obstructive CAD and should be considered as a prognostic factor for hard cardiac events.

The objective of this study was to determine the accuracy of right ventricular function (RVF) assessed by Cadmium Zinc Telluride ECG-gated SPECT equilibrium radionuclide angiocardiography (CZT-ERNA). Twenty-one consecutive patients with cardiomyopathy (aged 54 ± 19 years; 62% male) were included. RV ejection fraction (EF) and volumes were analyzed by CZT-ERNA and compared with values obtained by cardiac magnetic resonance imaging (CMR). Mean values were not different between CZT-ERNA and MRI for RVEF (48.1 ± 10.4% vs 50.8 ± 10.0%; P = .23). Significant correlations (P

Introduction Myocardial perfusion reserve (MPR) is a validated diagnostic and prognostic value by Positron Emission Tomography (PET) scans. However, PET availability stays limited in certain countries as France. Gamma cameras with cadmium-zinc telluride detector (CZT-SPECT) are more available and allow the evaluation of this MPR. However, there is no comparison of its results with the interventional diagnostic procedure. Method Twenty-seven patients with suspected of epicardial or microcirculatory coronary involvement were prospectively included. All patients benefited from an evaluation of the MPR by CZT SPECT as well as an interventional diagnostic procedure with measure of the Fractionnal Flow Reserve (FFR), coronary flow reserve (CRF) and index of microcirculation resistance (IMR). Correlation between MPR and CFR was measured and sensitivity and specificity to detect severe coronary microcirculation disease (CMVD) defined by FFR > 0.8, CFR 25. Results Coronary angiography was performed in 27 patients, with a complete functional evaluation (FFR, CFR, IMR) on 33 vessels. Two patients had significant stenosis (50-90% stenosis and FFR Conclusion MPR was correlated with CRF and presented satisfactory diagnostic performance to discriminate, in the absence of significant stenosis, patients free from patients with severe CMVD.

International audience; no abstract

Objective In Genetic Absence Epilepsy Rats From Strasbourg (GAERSs), epileptogenesis takes place during brain maturation and correlates with increased mRNA expression of D3 dopamine receptors (D3R). Whether these alterations are the consequence of seizure repetition or contribute to the development of epilepsy remains to be clarified. Here, we addressed the involvement of the dopaminergic system in epilepsy onset in GAERSs. Methods Experiments were performed using rats at different stages of brain maturation from three strains according to their increasing propensity to develop absence seizures: nonepileptic control rats (NECs), Wistar Hannover rats, and GAERSs. Changes in dopaminergic neurotransmission were investigated using different behavioral and neurochemical approaches: autoradiography of D3R and dopamine transporter, single photon emission computed tomographic imaging, acute and chronic drug effects on seizure recordings (dopaminergic agonists and antagonists), quinpirole-induced yawns and dopamine synaptosomal uptake, microdialysis, brain tissue monoamines, and brain-derived neurotrophic factor quantification. Results Autoradiography revealed an increased expression of D3R in 14-day-old GAERSs, before absence seizure onset, that persists in adulthood, as compared to age-matched NECs. This was confirmed by increased yawns, a marker of D3R activity, and increased seizures when animals were injected with quinpirole at low doses to activate D3R. We also observed a concomitant increase in the expression and activity of the dopamine transporter in GAERSs before seizure onset, consistent with both lowered dopamine basal level and increased phasic responses. Significance Our data show that the dopaminergic system is persistently altered in GAERSs, which may contribute not only to behavioral comorbidities but also as an etiopathogenic factor in the development of epilepsy. The data suggest that an imbalanced dopaminergic tone may contribute to absence epilepsy development and seizure onset, as its reversion by a chronic treatment with a dopamine stabilizer significantly suppressed epileptogenesis. Our data suggest a potential new target for antiepileptic therapies and/or improvement of quality of life of epileptic patients.

Recent progress in breast cancer research has led to the identification of Vascular Cell Adhesion Molecule-1 (VCAM-1) as a key actor of metastatic colonization. VCAM-1 promotes lung-metastases and is associated with clinical early recurrence and poor outcome in triple negative breast cancer (TNBC). Our objective was to perform the in vivo imaging of VCAM-1 in mice models of TNBC. The Cancer Genomic Atlas (TCGA) database was analyzed to evaluate the prognostic role of VCAM-1 in TNBC. MDA-MB-231 (VCAM-1+) and control HCC70 (VCAM-1-) TNBC cells were subcutaneously xenografted in mice and VCAM-1 expression was assessed in vivo by single-photon emission computed tomography (SPECT) imaging using 99mTc-cAbVCAM1-5. Then, MDA-MB-231 cells were intravenously injected in mice and VCAM-1 expression in lung metastasis was assessed by SPECT imaging after 8 weeks. TCGA analysis showed that VCAM-1 is associated with a poor prognosis in TNBC patients. In subcutaneous tumor models, 99mTc-cAbVCAM1-5 uptake was 2-fold higher in MDA-MB-231 than in HCC70 (p < 0.01), and 4-fold higher than that of the irrelevant control (p < 0.01). Moreover, 99mTc-cAbVCAM1-5 uptake in MDA-MB-231 lung metastases was also higher than that of 99mTc-Ctl (p < 0.05). 99mTc-cAbVCAM1-5 is therefore a suitable tool to evaluate the role of VCAM-1 as a marker of tumor aggressiveness of TNBC.

International audience; PURPOSE:To determine whether the assessment of regional wall thickening (WT) in addition to myocardial perfusion from stress supine acquisitions could compensate for the lack of prone acquisition and the corresponding decrease in the diagnostic performance of SPECT myocardial perfusion imaging (MPI) in patients with known or suspected coronary artery disease (CAD).METHODS:The study group comprised 41 patients (123 vessels) with known or suspected CAD prospectively recruited for systematic prone and supine 201Tl stress SPECT MPI. The diagnostic performance of SPECT MPI was determined for various image sets including nongated supine images (supine NG), nongated combined prone and supine images (prone and supine NG) and gated supine images, allowing WT evaluation from NG images in addition to perfusion (supine NG + WT) using invasive coronary angiography and fractional flow reserve as the gold standards.RESULTS:The rate of false positives was significantly higher among the supine NG images (20.8%) than among either the prone and supine NG or the supine NG + WT images (3.3% and 2.7%, respectively, P

International audience; OBJECTIVE:The two related tumor necrosis factor members a proliferation-inducing ligand (APRIL) and B-cell activation factor (BAFF) are currently targeted in autoimmune diseases as B-cell regulators. In multiple sclerosis (MS), combined APRIL/BAFF blockade led to unexpected exacerbated inflammation in the central nervous system (CNS) of patients. Here, we investigate the role of the APRIL/BAFF axis in the CNS.METHODS:APRIL expression was analyzed in MS lesions by immunohistochemistry. The in vivo role of APRIL was assessed in the murine MS model, experimental autoimmune encephalitis (EAE). Functional in vitro studies were performed with human and mouse astrocytes.RESULTS:APRIL was expressed in lesions from EAE. In its absence, the disease was worst. Lesions from MS patients also showed APRIL expression upon infiltration of macrophages. Notably, all the APRIL secreted by these macrophages specifically targeted astrocytes. The upregulation of chondroitin sulfate proteoglycan, sometimes bearing chondroitin sulfate of type E sugar moieties, binding APRIL, in reactive astrocytes explained the latter selectivity. Astrocytes responded to APRIL by producing a sufficient amount of IL-10 to dampen antigen-specific T-cell proliferation and pathogenic cytokine secretion. Finally, an intraspinal delivery of recombinant APRIL before disease onset, shortly reduced EAE symptoms. Repeated intravenous injections of recombinant APRIL before and even at disease onset also had an effect.INTERPRETATION:Our data show that APRIL mediates an anti-inflammatory response from astrocytes in MS lesions. This protective activity is not shared with BAFF. ANN NEUROL 2019;85:406-420.© 2019 American Neurological Association.

Introduction Atherosclerosis is associated with a worse prognosis in many diseases, but its impact in non-ischemic dilated cardiomyopathy (NIDCM) is not known. Purpose This study investigated the prognostic value of coronary atherosclerotic burden, as measured by Gensini score, in a cohort of NIDCM patients. Methods In total, 139 patients with left ventricular (LV) dysfunction due to NIDCM were classified according to both invasive coronary angiography (ICA) and cardiovascular magnetic resonance (CMR) imaging data in 3 subtypes of NIDCM: true NIDCM, NIDCM with bystander coronary artery disease (CAD) and NIDCM with bystander myocardial infarction (MI). Percentage, extent, location of fibrosis was assessed with CMR and coronary atherosclerotic burden by calculating Gensini score. Primary endpoint was a composite of cardiovascular mortality, non-fatal MI and revascularisation by percutaneous coronary intervention (PCI). Results Out of 139 patients (mean age 59.4 ± 14.7 years old, 74% male), there were 101 patients (73%) with true NIDCM, 30 patients (22%) with NIDCM and bystander MI and 8 patients (5%) with NIDCM and bystander MI. 6 patients (4.3%) died and 6 (4.3%) underwent PCI during a median follow-up of 34.2 ± 18 months ( Table 1 ). Gensini score predicted primary composite endpoint, in univariate and multivariate analysis, hazard ratio = 1.08, confidence interval 95% (1.034–1.13) P = 0.001, as well as a history of CAD, LV ejection fraction (LVEF) and age (P Conclusion Coronary atherosclerotic burden, as measured by Gensini score, is a new prognostic factor in NIDCM. Assessing this parameter improves risk stratification and could be used to help personalise treatment in this population ( Fig. 1 ).

Background Single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) provides valuable prognostic value. However, the risk stratification of patients with type 2 diabetes mellitus (T2D) remains suboptimal. Objectives We hypothesised that myocardial perfusion entropy (MPE) quantified from SPECT myocardial perfusion images may provide an incremental prognostic value in T2D patients independently from the routinely performed assessment of myocardial ischemia. Methods T2D patients with very high and high cardiovascular risk were studied (n = 166, 65 ± 12 years). Ischemia (> 10% of left ventricular area) was assessed by SPECT MPI. In addition, SPECT MPI was used for the quantification of rest and stress MPE. The primary endpoint was major adverse cardiac events (MACEs) defined as cardiac death, Q-wave myocardial infarction (MI) and myocardial revascularisation > 3 months after SPECT. Results Forty-six patients underwent MACEs over a median follow-up of 4.6 years. Significant differences in stress MPE were observed between patients with and without MACEs (4.19 ± 0.46 vs. 3.93 ± 0.39; P ≤ .01). By Kaplan–Meier analysis, the risk of MACEs was significantly higher in patients with higher stress MPE (log-rank P ≤ .01). Stress MPE and ischemia were significantly associated with the risk of MACEs (hazard ratio: 2.30 and 1.12, respectively, P ≤ .01 for both) after adjustment for clinical and imaging risk factors as identified from preliminary, univariate analysis and including age, hypertension, stress test and ischemia. The incremental prognostic value of MPE over clinical risk factors was quantified using nested models showing improved AIC, reclassification (global continuous Net Reclassification Improvement [NRI]: 54, global Integrated Discrimination Improvement [IDI]: 4.6%), discrimination (change in c-statistic: 0.69 vs. 0.74). Conclusions Stress MPE provided independent and incremental prognostic information for the prediction of MACEs in diabetic patients.

Background The risk assessment for ventricular arrhythmia in patients with ischemic cardiomyopathy is, at the present time, unspecific. Left ventricular (LV) entropy is a measure of myocardial heterogeneity derived from single photon emission computed tomography (SPECT). Purpose This study assesses the utility of LV entropy for predicting cardiovascular events in patients with ischemic cardiomyopathy. Methods Patients with ischemic cardiomyopathy referred for implantable cardioverter-defibrillator (ICD) implantation were included retrospectively. Their LV entropy was measured on SPECT. Patients were followed from implantable cardioverter-defibrillator placement to detect arrhythmic events (appropriate implantable cardioverter-defibrillator therapy and sustained ventricular arrhythmia), end-stage heart failure events (congestive heart failure, transplantation, or ventricular assist device placement), and cardiac death. Results Forty patients (mean age 68.1 ± 9.4 years, 75% men, LV ejection fraction 29.7 ± 4.6%) were followed for 22.8 ± 12.9 months. Of the forty patients, three (7.5%) experienced arrhythmic events, one died of advanced heart failure after receiving the appropriate shock, and three others (7.5%) experienced end-stage heart failure events. On univariate analysis, age (HR: 1.02 [0.99; 1.04]; P = 0.176); diabetes (HR: 0.30 [0.05; 1.68]; P = 0.17), CRT-D (HR: 0.06 [0.007; 0.53]; P = 0.01), NYHA class (HR: 7.6 [2.00; 29.5]; P = 0.003) and ischemia (HR: 1.07 [0.96; 1.18]; P = 0.19) were significant predictors of cardiac events. On multivariate analysis, CRT-D (HR: 0.06 [0.04; 0.89]; P = 0.04) remained a significant predictor of cardiac events. LV entropy was not a predictor of cardiac events. Conclusion In patients with ischemic cardiomyopathy, LV entropy measurement is not a predictor of life-threatening ventricular arrhythmia. However, CRT-D is a strong protector of ventricular arrhythmia in ischemic cardiomyopathy.

New strategies allowing the transfer of molecules, especially peptides, through the blood-brain barriers are a major pharmacological challenge for the treatment of brain diseases. The present study aims at evaluating in vivo the cerebral bioavailability of carrier systems, based on small and functionalizable 2,5-diketopiperazine (DKP) motifs. We studied 2 different cyclo(Lys-Lys) DKP scaffolds alone and a cyclo(Lys-Gly) DKP carrier bearing as peptide model, the tau protein hexapeptide VQIVYK sequence. The different carrier systems were synthesized and radiolabeled using one of the free domains. The stability, biodistribution, and ability to cross blood-brain barrier were investigated in vivo in mice for 99mTc-DKP scaffolds, 99mTc-HVQIVYK peptide alone, and 99mTc-DKP-VQIVYK. 125I-labelled bovine serum albumin was used as negative control for brain uptake. Both radiolabeled DKPs scaffolds and 99mTc-DKP-VQIVYK showed a high stability, while peptide 99mTc-HVQIVYK alone was quickly degraded in vivo. The presence of 99mTc-DKPs scaffolds and 99mTc-DKP-VQIVYK was observed in the ventricular and subarachnoid spaces and to a lower extent in the brain parenchyma up to 45 minutes post-injection in mice. This work highlights the potentiality of DKP scaffolds as vectors to transport peptides into the brain by limiting proteolysis and favoring cerebral bioavailability.

a Department of Cardiology, General Hospital Center, Chambery, France b Department of Radiology, University Hospital, Grenoble, France c Department of Nuclear Medicine, General Hospital Center, Chambery, France d INSERM U1039, Bioclinic Radiopharmaceutics Laboratory, Joseph Fourier University, Grenoble, France e Department of Nuclear Medicine, University Hospital, Grenoble, France f Department of Cardiology, University Hospital, Grenoble, France

Introduction Coronary microvascular dysfunction (CMD) is associated with a higher rate of major adverse cardiovascular events (MACEs) in diabetic patients. Liraglutide, a glucagon-like peptide-1 analog, decreases MACEs and all-cause mortality in this population. Purpose The present paper aims to study the effects of liraglutide on heart function and myocardial perfusion entropy (MPE) as a surrogate marker of coronary microvascular dysfunction (CMVD) in a rat model of type-2 diabetes. Methods Thirty-nine rats were divided into three groups, control (CTL), diabetic (T2D) and liraglutide (DT2-LIR). T2D and T2D-LIR rats were fed a high-fat diet and injected with 35 mg/kg streptozotocin intra-peritoneally (IP) to induce diabetes. T2D-LIR rats were injected with a subcutaneous liraglutide solution for four weeks. Heart structure and function were assessed with trans-thoracic-doppler echocardiography and CMVD was assessed with a novel 201 Thallium SPECT-technique, measuring MPE, under stress conditions. Histological analysis was later performed. Results T2D rats had a significantly lower left ventricular (LV) ejection fraction (LVEF) versus CTL (64.5 ± 4.3% vs. 74.4 ± 9.2% P Conclusion Liraglutide is associated with an improvement in heart systolic function and reduced LV hypertrophy in type 2 diabetic rats but only has a small specific effect on CMVD.

Background The routine acquisition of combined prone and supine SPECT myocardial perfusion images remains limited despite the associated improvement in diagnostic and prognostic accuracies. Our aim was to determine whether the assessment of regional wall thickening (WT) in addition to myocardial perfusion from stress supine acquisitions could overcome the lack of prone acquisition and the corresponding decrease in the diagnostic performances of SPECT myocardial perfusion imaging (MPI) in patients with known or suspected coronary artery disease (CAD). Methods Forty-one (41) patients (123 vessels) with known or suspected CAD were prospectively recruited for systematic prone and supine thallium-201 stress SPECT myocardial perfusion imaging using a semi-conductor, cardiac dedicated SPECT camera. The diagnostic performances of SPECT MPI were determined for various image sets including non-gated, supine images (supine NG), non-gated, combined prone and supine acquisitions (prone & supine NG), and gated supine acquisition allowing the evaluation of WT in addition to that of perfusion from NG images (supine NG + WT) using invasive coronary angiography (ICA) and fractional flow reserve (FFR) as the gold standard. Myocardial perfusion was scored using a 5-point scale (0 = normal, 1 = equivocal, 2 = moderate, 3 = severely reduced radiotracer uptake, 4 = no detectable uptake) and a 17-segment model of the left ventricle leading to summed stress score values (SSS), with patients being classified as positive for the presence of ischemia if SSS ≥ 2. Additional WT analysis was used to classify myocardial perfusion as pathological when a myocardial segment with a SSS ≥ 2 also presented with a WT abnormality. Significant CAD was defined by the presence of ≥ 90% stenosis/occlusion or fractional flow reserve ≤ 0.80 in the presence of a ≥ 50% coronary stenosis. Results Upon per patient analysis, the occurrence of false positives was significantly higher in supine NG images (36.6%) than in both prone & supine NG and supine NG + WT image sets (9.8% and 7.8%, respectively, P Conclusions The diagnostic performances of supine stress SPECT MPI are restored compared with combined prone & supine acquisitions when WT assessment in the ischemic segments is used as an additional diagnostic criterion.

Background Single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) for the assessment of myocardial ischemia provides valuable prognostic value. However, the risk stratification of patients with type 2 diabetes mellitus (T2D) remains suboptimal. Recent studies have highlighted the role of coronary microvascular disease in the occurrence of coronary symptoms in this population. Objectives We hypothesized that enhanced signal analysis from SPECT myocardial perfusion images may allow insights into the status of the coronary microvasculature. More specifically, we hypothesized that myocardial perfusion entropy (MPE) as a surrogate marker of microvascular disease quantified from SPECT myocardial perfusion images may provide an incremental prognostic value in T2D patients independently from the routinely performed assessment of myocardial ischemia. Methods T2D patients with very high cardiovascular risk were studied (n = 166, 65 ± 12 years). Ischemia was assessed by SPECT myocardial perfusion imaging (MPI). In addition, SPECT MPI was used for the quantification of rest and stress MPE using an original algorithm providing a global value of MPE from reconstructed rest and stress SPECT images. The primary end point was major adverse cardiac events (MACEs) defined as cardiac death, Q-wave myocardial infarction (MI) and myocardial revascularization > 3 months after SPECT. Results Forty-six patients underwent MACEs over a median follow-up of 4.6 years. Significant differences in stress MPE were observed between patients with and without MACEs (4.19 ± 0.46 vs. 3.93 ± 0.39; P ≤ 0.01). By Kaplan-Meier analysis, the risk of MACEs was significantly higher in patients with higher stress MPE (log-rank P ≤ 0.01). Stress MPE was significantly associated with the risk of MACEs (hazard ratio: 2.80, P ≤ 0.01) after adjustment for clinical and imaging risk factors as identified from preliminary, univariate analysis and including age, hypertension and ischemia. The risk of overfitting was controlled by internal validation procedures such as LASSO, stepwise and random forests selections on time-to-MACEs Cox models. A competing risk event (“other deaths”) slightly overestimated Cox estimates. However, the impact of informative censorship was assessed by Fine-Gray subdistribution hazard estimates and proved to be marginal. The incremental prognostic value of MPE over clinical risk factors was quantified using nested models showing improved AIC, reclassification (global continuous Net Reclassification Improvement [NRI]: 70.1, global Integrated Discrimination Improvement [IDI]: 6.6%), discrimination (change in c-statistic: 0.69 vs. 0.74), and time-dependent AUC (0.71 vs. 0.77 at 4 years of follow-up). Conclusions Stress MPE provided independent and incremental prognostic information for the prediction of MACEs in diabetic patients.

International audience; Mesothelin is a cell-surface glycoprotein restricted to mesothelial cells overexpressed in several types of cancer, including triple-negative breast cancer not responding to trastuzumab or hormone-based therapies. Mesothelin-targeting therapies are currently being developed. However, the identification of patients potentially eligible for such a therapeutic strategy remains challenging. The objective of this study was to perform the radiolabeling and preclinical evaluation of 99mTc-A1 and 99mTc-C6, two antimesothelin single-domain antibody (sdAb)-derived imaging agents. Methods: A1 and C6 were radiolabeled with 99mTc and evaluated in vitro on recombinant protein and cells, as well as in vivo in xenograft mouse models of the triple-negative breast cancer cell lines HCC70 (mesothelin-positive) and MDA-MB-231 (mesothelin-negative). Results: Both 99mTc-A1 and 99mTc-C6 bound mesothelin with high affinity in vitro, with 99mTc-A1 affinity being 2.4-fold higher than that of 99mTc-C6 (dissociation constant, 43.9 ± 4.0 vs. 107 ± 16 nM, P < 0.05). 99mTc-A1 and 99mTc-C6 remained stable in vivo in murine blood (>80% at 2 h) and ex vivo in human blood (>90% at 6 h). In vivo 99mTc-A1 uptake (percentage injected dose) in HCC70 tumors was 5-fold higher than in MDA-MB-231 tumors and 1.5-fold higher than that of 99mTc-C6 (2.34% ± 0.36% vs. 0.48% ± 0.18% and 1.56% ± 0.43%, respectively, P < 0.01) and resulted in elevated tumor-to-background ratios. In vivo competition experiments demonstrated the specificity of 99mTc-A1 uptake in HCC70 tumors. Conclusion: Mesothelin-positive tumors were successfully identified by SPECT using 99mTc-A1 and 99mTc-C6. Considering its superior characteristics, 99mTc-A1 was selected as the most suitable tool for further clinical translation.

Background The modification of β-cyclodextrins (βCDs) by grafting alkyl chains on the primary and/or secondary face yields derivatives (βCD-C10) able to self-organize under nanoprecipitating conditions into nanoparticles (βCD-C10-NP) potentially useful for drug delivery. The co-nanoprecipitation of βCD-C10 with polyethylene glycol (PEG) chains yields PEGylated NPs (βCD-C10-PEG-NP) with potentially improved stealthiness. The objectives of the present study were to characterize the in vivo biodistribution of βCD-C10-PEG-NP with PEG chain length of 2000 and 5000 Da using nuclear imaging, and to preliminarily evaluate the in vivo acute and extended acute toxicity of the most suitable system. Research design and methods The in vivo and ex vivo biodistribution features of naked and decorated nanoparticles were investigated over time following intravenous injection of 125I-radiolabeled nanoparticles to mice. The potential toxicity of PEGylated βCD-C10 nanosuspensions was evaluated in a preliminary in vivo toxicity study involving blood assays and tissue histology following repeated intraperitoneal injections of nanoparticles to healthy mice. Results The results indicated that βCD-C10-PEG5000-NP presented increased stealthiness with decreased in vivo elimination and increased blood kinetics without inducing blood, kidney, spleen, and liver acute and extended acute toxicity. Conclusions βCD-C10-PEG5000-NPs are stealth and safe systems with potential for drug delivery.

Comment inRole of I-123 MIBG in sepsis-induced cardiomyopathy. [J Nucl Cardiol. 2018]; International audience; BACKGROUND:Sympathetic system abnormalities have been reported in sepsis-related cardiac dysfunction. The present study aimed at evaluating the potential of the norepinephrine radiolabeled analogue [123I]-meta-iodobenzylguanidine (123I-MIBG) for the noninvasive assessment of modifications in cardiac sympathetic activity occurring in lipopolysaccharide (LPS)-induced experimental acute sepsis by single-photon emission computed tomographic imaging (SPECT).METHODS AND RESULTS:Sepsis was induced in male Wistar rats by intraperitoneal injection of 10 mg·kg-1 lipopolysaccharide (n = 16), whereas control animals (n = 7) were injected with vehicle (NaCl 0.9%). Echocardiography in LPS-injected animals (n = 8) demonstrated systolic and diastolic cardiac dysfunction. 123I-MIBG was injected 1 hour after LPS or vehicle administration (n = 8 and 7, respectively), and in vivo SPECT imaging was performed early and late (20 and 180 minutes) after tracer injection prior to animal euthanasia and ex vivo assessment of 123I-MIBG biodistribution. Global and 17-segment SPECT image analysis indicated that early 123I-MIBG activity was not affected by LPS treatment, whereas late cardiac tracer activity was significantly decreased in LPS-treated animals. Consequently, the cardiac washout of 123I-MIBG was significantly higher in LPS-treated (63.3% ± 4.0%) than that in control animals (56.7% ± 5.8%) (P < .05).CONCLUSION:Sepsis-induced modifications in cardiac sympathetic nervous system activity were evidenced by noninvasive in vivo 123I-MIBG SPECT imaging.

International audience; Cardiac computed tomography (CT) provides additional information with ultrasound in the transcatheter heart valve (THV) size selection. However, the influence of these incremental data on outcomes has not been evaluated in a randomized study. A single-center prospective, randomized, and open study was performed. Patients referred for transfemoral transcatheter aortic valve implantation with a balloon-expandable endoprothesis were included. THV size selection was performed using either transthoracic and transesophageal echocardiography data (control group) or ultrasound and CT results (CT group). The primary composite end point included the occurrence of stroke, major vascular complications, and moderate or severe paravalvular aortic regurgitation (PAR) at 1 year. Fifty patients (n = 25 in the control and CT groups) were enrolled. The primary composite end point occurred in 40% and 8% of patients from the control and CT groups, respectively (p = 0.008). The Kaplan-Meier analysis revealed a pejorative association with not performing the CT (p = 0.007). A decrease in the occurrence of PAR was observed in the CT group compared with the control group (PAR 28% vs 4%, p = 0.04; major vascular complications 12% vs 4%, p = 0.6; all-cause death 16% vs. 4%, p = 0.34; no stroke). In conclusion, the use of cardiac CT in addition to ultrasound data in THV size selection reduced the long-term occurrence of cardiovascular events.

International audience; BACKGROUND:The aim of this study was to determine the diagnostic accuracy of stress thallium-201/rest technetium-99m-sestamibi sequential dual-isotope high-speed myocardial perfusion imaging (DI-HS-MPI) against invasively determined fractional flow reserve (FFR).METHODS:Fifty-four consecutive patients prospectively underwent DI-HS-MPI before invasive coronary angiography. Perfusion was scored visually by summed stress score on a patient and coronary territory basis. Significant coronary artery disease (CAD) was defined by the presence of ≥ 90% stenosis/occlusion or fractional flow reserve ≤ 0.80 for coronary stenosis ≥ 50%.RESULTS:FFR was measured in 69 of 162 coronary vessels, with 1.28 ± 0.56 vessels assessed/patient. Sensitivity, specificity, and diagnostic accuracy of MPI for the detection of significant CAD were 92.8%, 69.2%, and 81.4%, on a patient basis, and 83.7%, 90.4%, and 88.8% by coronary territory.CONCLUSIONS:DI-HS-MPI accurately detects functionally significant CAD as defined by using FFR.

International audience; The addition of ezetimibe, an intestinal cholesterol absorption inhibitor, to statin therapy has recently shown clinical benefits in the Improved Reduction of Outcomes: Vytorin Efficacy International Trial by reducing low-density-lipoprotein (LDL) cholesterol levels more than statin therapy alone. Here, we investigated the mechanisms by which inhibition of intestinal cholesterol absorption might contribute to the clinically observed reduction in cardiovascular events by evaluating its effect on inflammatory plaque development in apolipoprotein E-/- mice. Methods: Apolipoprotein E-/- mice were fed the Paigen diet (1.25% cholesterol, 0.5% cholic acid, and 15% fat) without or with ezetimibe (7 mg/kg/d) for 6 wk. In a first set of mice (n = 15), we intravenously injected 3H-cholesteryl oleate-labeled human LDL to test whether ezetimibe promotes LDL-derived cholesterol fecal excretion. In a second set (n = 20), we used the imaging agent 99mTc-cAbVCAM1-5 to evaluate expression of an inflammatory marker, vascular cell adhesion molecule 1 (VCAM-1), in atherosclerotic plaques. In a third set (n = 21), we compared VCAM-1 expression with 99mTc-cAbVCAM1-5 uptake in various tissues. Results: Mice treated with ezetimibe showed a 173% higher LDL-cholesteryl ester plasma disappearance rate (P < 0.001 vs. control) after 3H-cholesteryl oleate-labeled LDL injection. At 96 h after injection, the hepatic fraction of 3H-tracer was 61% lower in mice treated with ezetimibe (P < 0.001). Meanwhile, LDL-derived 3H-cholesterol excretion in the feces was 107% higher (P < 0.001). The antiatherogenic effect of ezetimibe monitored by 99mTc-cAbVCAM1-5 SPECT showed a 49% reduction in aortic tracer uptake (percentage injected dose per cubic centimeter, 0.95 ± 0.04 vs. 1.87 ± 0.11; P < 0.01). In addition to hypercholesterolemia, the proinflammatory Paigen diet significantly increased VCAM-1 expression with respect to the control group in various tissues, including the aorta, and this expression correlated strongly with 99mTc-cAbVCAM1-5 uptake (r = 0.75; P < 0.05). Conclusion: Inhibition of intestinal cholesterol absorption with ezetimibe promotes antiatherosclerotic effects through increased LDL cholesterol catabolism and LDL-derived cholesterol fecal excretion and reduces inflamed atherosclerotic plaques. These mechanisms may contribute to the benefits of adding ezetimibe to a statin therapy.

Mono-and poly- iodinated peptides form frequently during radioiodination procedures. However, the formation of a single species in its mono-iodinated form is essential for quantitative studies such as determination of tissue concentration or image quantification. Therefore, the aim of the present study was to define the optimal experimental conditions in order to exclusively obtain the mono-iodinated form of L-maurocalcine (L-MCa). L-MCa is an animal venom toxin which was shown to act as a cell-penetrating peptide. In order to apply the current direct radioiodination technique using oxidative agents including chloramine T, Iodo-Gen® or lactoperoxidase, an analogue of this peptide containing a tyrosine residue (Tyr-L-MCa) was synthesized and was shown to fold/oxidize properly. The enzymatic approach using lactoperoxidase/H2O2 was found to be the best method for radioiodination of Tyr-L-MCa. MALDI-TOF mass spectrometry analyses were then used for identification of the chromatographic eluting components of the reaction mixtures. We observed that the production of different radioiodinated species depended upon the reaction conditions. Our results successfully described the experimental conditions of peptide radioiodination allowing the exclusive production of the mono-iodinated form with high radiochemical purity and without the need for a purification step. Mono-radioiodination of L-Tyr-MCa will be crucial for future quantitative studies, investigating the mechanism of cell penetration and in vivo biodistribution.