Multi-center study of inter-rater reproducibility, image quality, and diagnostic accuracy of CZT versus conventional SPECT myocardial perfusion imaging.

BACKGROUND: Cadmium-zinc-telluride (CZT)-based detectors exhibit higher diagnostic sensitivity in myocardial perfusion imaging (MPI) than conventional Anger-MPI for detection of coronary artery disease (CAD); however, reduced specificity and diagnostic accuracy of CZT-MPI were observed. This study aims to compare these different camera systems and to examine the degree of inter-rater reproducibility among readers with varying experience in MPI. METHODS: 83 patients who underwent double stress/rest examinations using both a CZT and conventional SPECT cameras within one visit were included. Anonymized and randomized MPI-images were distributed to 15 international readers using a standardized questionnaire. Subsequent coronary angiography findings of ten patients served as a reference for analysis of sensitivity and specificity. RESULTS: Image quality was significantly better in CZT-MPI with significantly lower breast attenuation (P < 0.05). CZT-MPI exhibited higher sensitivity than Anger-MPI (87.5% vs. 62.5%) and significantly reduced specificity (40% vs. 100%). Readers experienced with both camera systems had the highest inter-rater agreement indicating higher reproducibility (CZT 0.54 vs. conv. 0.49, P < 0.05). CONCLUSIONS: Higher diagnostic sensitivity of CZT-MPI offers advantages in detection of CAD yet potentially of at the cost of reduced specificity, therefore it requires special training and a differentiated evaluation approach, especially for non-experienced readers with such camera systems.

Phenylsulfonimide PPARα Antagonists Enhance Nrf2 Activation and Promote Oxidative Stress-Induced Apoptosis/Pyroptosis in MCF7 Breast Cancer Cells.

The NF-E2-related factor 2 transcription factor (Nrf2) orchestrates the basal and stress-inducible activation of a vast array of antioxidant genes. A high amount of reactive oxygen species (ROS) promotes carcinogenesis in cells with defective redox-sensitive signaling factors such as Nrf2. In breast cancer (BC), emerging evidence indicates that increased Nrf2 activity enhances cell metastatic potential. An interconnection between peroxisome proliferator-activated receptors (PPARs) and Nrf2 pathways in cancer has been shown. In this light, newly synthesized PPARα antagonists, namely IB42, IB44, and IB66, were tested in the BC cell line MCF7 in parallel with GW6471 as the reference compound. Our results show that the most promising compound of this phenylsulfonimide series (IB66) is able to decrease MCF7 proliferation by blocking cells at the G2/M checkpoint. The underlying mechanism has been investigated, disclosing a caspase 3/Akt-dependent apoptotic/pyroptotic pathway induced by the increased generation of oxidative stress. Moreover, the involvement of Nrf2 and COX2 in IB66-treated MCF7 cell response has been highlighted. The reported data lay the groundwork for the development of alternative targeted therapy involving the Nrf2/PPARα molecular axis, able to overcome BC cell chemoresistance and cause better clinical outcomes, promoting other forms of programmed cell death, such as pyroptosis.

Relation between high-sensitivity troponin I serum levels and myocardial ischemia in patients with suspected chronic coronary syndrome: The reset-MI study.

BACKGROUND: Previous studies showed that exercise may increase cardiac troponin serum levels; whether the occurrence of myocardial ischemia influences the changes of exercise-induced troponin raise, however, remains debatable. METHODS: We prospectively enrolled consecutive patients undergoing for the first time an elective stress myocardial perfusion scintigraphy (MPS) because of clinical suspicion of obstructive coronary artery disease (CAD). Patients were divided into 3 groups based on the evidence and degree of stress-induced myocardial ischemia at MPS: 1) group 1, no myocardial ischemia (≤4 %); 2) group 2, mild myocardial ischemia (5-10 %); 3) group 3, moderate-to-severe myocardial ischemia (≥10 %). High-sensitivity cardiac troponin I (cTnI) was measured immediately before (T0) and 1 hour (T1) and 4 h (T2) after the stress test. RESULTS: One hundred-seven patients (71 males; age 65.6 ± 9.4 years) were enrolled in the study. Serum hs-cTnI concentrations (logarithmic values) significantly increased after MPS, compared to baseline, in the whole population, from 1.47±1.26 ng/L at T0, to 1.68±1.12 ng/L at T1 (p<0.001) and 2.15±1.02 ng/L at T2 (p<0.001 vs. both T0 and T1). The increase in hs-cTnI did not significantly differ between the 3 groups (p = 0.44). The heart rate achieved during the test was the strongest determinant of cTnI increase (p < 0.001) after the stress test. CONCLUSIONS: In patients with suspected CAD, stress MPS induces an increase of cTnI that is independent of the induction and extension/severity of myocardial ischemia and is mainly related to myocardial work, as indicated by the heart rate achieved during the test.

Dopaminergic dysfunction and psychiatric symptoms in movement disorders: a 123I-FP-CIT SPECT study.

PURPOSE: Psychiatric symptoms frequently occur in patients with movement disorders. They are not a mere reaction to chronic disability, but most likely due to a combination of psychosocial factors and biochemical dysfunction underlying the movement disorder. We assessed dopamine transporter (DAT) availability by means of (123)I-FP-CIT SPECT, and motor and psychiatric features in patients with Parkinson's disease, primary dystonia and essential tremor, exploring the association between SPECT findings and symptom severity. METHODS: Enrolled in the study were 21 patients with Parkinson's disease, 14 patients with primary dystonia and 15 patients with essential tremor. The severity of depression symptoms was assessed using the Hamilton depression rating scale, anxiety levels using the Hamilton anxiety rating scale and hedonic tone impairment using the Snaith-Hamilton pleasure scale. Specific (123)I-FP-CIT binding in the caudate and putamen was calculated based on ROI analysis. The control group included 17 healthy subjects. RESULTS: As expected, DAT availability was significantly decreased in patients with Parkinson's disease, whereas in essential tremor and dystonia patients it did not differ from that observed in the control group. In Parkinson's disease patients, an inverse correlation between severity of depression symptoms and DAT availability in the left caudate was found (r = -0.63, p = 0.002). In essential tremor patients, levels of anxiety symptoms were inversely correlated with DAT availability in the left caudate (r = -0.69, p = 0.004). In dystonia patients, the severities of both anxiety and depression symptoms were inversely associated with DAT availability in the left putamen (r = -0.71, p = 0.004, and r = -0.75, p = 0.002, respectively). There were no correlations between psychometric scores and (123)I-FP-CIT uptake ratios in healthy subjects. CONCLUSION: We found association between presynaptic dopaminergic function and affective symptoms in different movement disorders. Interestingly, the inverse correlation was present in each group of patients, supporting the fascinating perspective that common subcortical substrates may be involved in both anxiety and depression dimensions and movement disorders.

Myocardial perfusion single-photon emission tomography (SPET) and positron emission tomography-computed tomography (PET-CT) imaging for congenitally corrected transposition of great arteries.

Congenitally corrected transposition of great arteries (ccTGA) consists of both atrioventricular and ventriculo-arterial discordance. In patients with ccTGA, the pulmonary artery arises from the left ventricle, whereas the aorta arises from the right ventricle. The burden of the systemic blood pressure on the right ventricle involves an increased risk of coronary artery disease (CAD) and, as a long-term consequence, myocardial hypertrophy and gradual failure. This report describes the case of an adult patient affected by ccTGA who was referred for an episode of atypical chest pain while at rest. First-line diagnostic examinations were inconclusive. Myocardial perfusion single-photon emission tomography (SPET) was performed to exclude CAD, but the congenital abnormalities of the patient's heart made interpretation of the images particularly difficult. A perfusion positron emission tomography-computed tomography (PET-CT) scan with (13)N-ammonia then was suggested, which unmasked an unexpected artifact. The case report demonstrates that hybrid imaging techniques such as SPET-CT and PET-CT should be used systematically when CAD is suspected for patients with abnormal anatomy of the heart, including ccTGA.

90Y-DOTA-Nimotuzumab: Synthesis of a Promising ß- Radiopharmaceutical.

BACKGROUND: Nimotuzumab is a humanized anti-epidermal growth factor receptor (EGFR) monoclonal antibody, nowadays used for tumour immunochemotherapy. This study aimed to label the conjugate DOTA-nimotuzumab with yttrium-90, in order to provide a ß- emitting radioimmunoconjugate (90Y-DOTA-nimotuzumab) potentially useful to assess the feasibility of a new radio-guided surgery approach. METHODS: The synthesis of 90Y-DOTA-nimotuzumab was performed in two days. Nimotuzumab was conjugated with a 50-fold excess of DOTA and then labelled with 90Y3+. The 90Y-DOTA-nimotuzumab preparation was optimized considering several parameters such as pH, temperature and reaction volume. Moreover, the 90Y-DOTA-nimotuzumab stability was evaluated in human plasma. RESULTS: The radioimmunoconjugate 90Y-DOTA-nimotuzumab was obtained with a radiochemical purity greater than 96%, and showed a good stability at 20°C as well as at 37°C in human plasma. CONCLUSIONS: The optimized conditions for a mild and easy preparation of 90Y-DOTA-nimotuzumab joined to a promising stability under physiological conditions suggest to propose this radioimmunoconjugate as a potential diagnostic radiopharmaceutical for ß- radio-guided surgery.

Sulfonimide and Amide Derivatives as Novel PPARα Antagonists: Synthesis, Antiproliferative Activity, and Docking Studies.

An agonist-antagonist switching strategy was performed to discover novel PPARα antagonists. Phenyldiazenyl derivatives of fibrates were developed, bearing sulfonimide or amide functional groups. A second series of compounds was synthesized, replacing the phenyldiazenyl moiety with amide or urea portions. Final compounds were screened by transactivation assay, showing good PPARα antagonism and selectivity at submicromolar concentrations. When tested in cancer cell models expressing PPARα, selected derivatives induced marked effects on cell viability. Notably, 3c, 3d, and 10e displayed remarkable antiproliferative effects in two paraganglioma cell lines, with CC50 lower than commercial PPARα antagonist GW6471 and a negligible toxicity on normal fibroblast cells. Docking studies were also performed to elucidate the binding mode of these compounds and to help interpretation of SAR data.

Novel Phenyldiazenyl Fibrate Analogues as PPAR α/γ/δ Pan-Agonists for the Amelioration of Metabolic Syndrome.

The development of PPARα/γ dual or PPARα/γ/δ pan-agonists could represent an efficacious approach for a simultaneous pharmacological intervention on carbohydrate and lipid metabolism. Two series of new phenyldiazenyl fibrate derivatives of GL479, a previously reported PPARα/γ dual agonist, were synthesized and tested. Compound 12a was identified as a PPAR pan-agonist with moderate and balanced activity on the three PPAR isoforms (α, γ, δ). Moreover, docking experiments showed that 12a adopts a different binding mode in PPARγ compared to PPARα or PPARδ, providing a structural basis for further structure-guided design of PPAR pan-agonists. The beneficial effects of 12a were evaluated both in vitro, on the expression of PPAR target key metabolic genes, and ex vivo in two rat tissue inflammatory models. The obtained results allow considering this compound as an interesting lead for the development of a new class of PPAR pan-agonists endowed with an activation profile exploitable for therapy of metabolic syndrome.

Effect of spinal cord stimulation on cardiac adrenergic nerve function in patients with cardiac syndrome X.

BACKGROUND: In patients with cardiac syndrome X (CSX) who present with refractory angina episodes, spinal cord stimulation (SCS) has beneficial effects. The mechanisms of SCS, however, remain speculative. We assessed the effects of SCS on cardiac sympathetic function in these patients. METHODS AND RESULTS: We studied 11 CSX patients treated by SCS for refractory angina (mean age, 60 +/- 9 years; 5 men and 6 women), both during SCS therapy (SCS-ON) and after withdrawal of SCS therapy (SCS-OFF), using a randomized crossover design. Planar and single photon emission computed tomography iodine 123 metaiodobenzylguanidine (MIBG) myocardial scintigraphy and technetium 99m sestamibi (MIBI) bicycle exercise stress testing were performed at the end of each period. Compared with 10 healthy control subjects, CSX patients showed a lower heart-mediastinum ratio for MIBG uptake (2.19 +/- 0.3 vs 1.69 +/- 0.3, P = .001) and a higher cardiac MIBG uptake score (4.0 +/- 2.5 vs 19.7 +/- 27, P = .08). There were no differences in CSX patients during the SCS-ON and SCS-OFF phases of the study in heart-mediastinum ratio (1.74 +/- 0.3 vs 1.69 +/- 0.3, P = .13), cardiac washout rate of MIBG (42.9% +/- 14% vs 43.3% +/- 14%, P = .08), or MIBG defect score (18.7 +/- 25 vs 19.7 +/- 27, P = .22). Reversible perfusion defects during the SCS-OFF phase were detected in 8 patients; an improvement in perfusion defects was observed in 2 patients (25%) during the SCS-ON phase. CONCLUSIONS: Our data confirm the presence of abnormal cardiac adrenergic nerve function in CSX patients. SCS was unable to result in significant improvement of cardiac MIBG uptake abnormalities, suggesting that its therapeutic effects are unlikely to be mediated by modulation of cardiac adrenergic nerve activity.

Cytotoxic effect of a family of peroxisome proliferator-activated receptor antagonists in colorectal and pancreatic cancer cell lines.

Recent studies report an interesting role of peroxisome proliferator-activated receptor (PPAR) antagonists in different tumor models, being these compounds able to perturb metabolism and viability in cancer cells. In this work, the identification of a novel PPAR antagonist, showing inhibitory activity on PPARα and a weaker antagonism on PPARγ, is described. The activity of this compound and of a series of chemical analogues was investigated in selected tumor cell lines, expressing both PPARα and PPARγ. Data obtained show a dose-dependent cytotoxic effect of the novel PPAR antagonist in colorectal and pancreatic cancer models.

Synthesis of Naphthyl-, Quinolin- and Anthracenyl Analogues of Clofibric Acid as PPARα Agonists.

PPARα is a ligand activated transcription factor belonging to the nuclear receptor subfamily, involved in fatty acid metabolism in tissues with high oxidative rates such as muscle, heart and liver. PPARα activation is important in steatosis, inflammation and fibrosis in preclinical models of non-alcoholic fatty liver disease identifying a new potential therapeutic area. In this work, three series of clofibric acid analogues conjugated with naphthyl, quinolin, chloroquinolin and anthracenyl scaffolds were synthesized. In an effort to obtain new compounds active as PPARα agonists, these molecules were evaluated for PPARα transactivation activity. Naphthyl and quinolin derivatives showed a good activation of PPARα; noteworthy, optically active naphthyl derivatives activated PPARα better than corresponding parent compound.

Screening of NOS activity and selectivity of newly synthesized acetamidines using RP-HPLC.

Nitric Oxide Synthase (NOS) inhibitors could play a powerful role in inflammatory and neurodegenerative diseases. In this work, novel acetamidine derivatives of NOS were synthesized and the inhibitor activity was evalued. To screen the activity and selectivity, the l-citrulline residue, after the enzymatic NOS assay, was derivatized with o-phthaldialdehyde/N-acetyl cysteine (OPA/NAC) and then evaluated by RP-HPLC method with fluorescence detection. All compounds did not affect the activity of endothelial and neuronal isoforms, while nine of them possessed a percentage of iNOS activity at 10µM lower than 50%, and were selected for IC50 evaluation. Among them, a compound emerged as a very potent (IC50 of 53nM) and selective iNOS inhibitor.

The value of imaging in subclinical coronary artery disease.

Although the treatment of acute coronary syndromes (ACS) has advanced considerably, the ability to detect, predict, and prevent complications of atherosclerotic plaques, considered the main cause of ACS, remains elusive. Several imaging tools have therefore been developed to characterize morphological determinants of plaque vulnerability, defined as the propensity or probability of plaques to complicate with coronary thrombosis, able to predict patients at risk. By utilizing both intravascular and noninvasive imaging tools, indeed prospective longitudinal studies have recently provided considerable knowledge, increasing our understanding of determinants of plaque formation, progression, and instabilization. In the present review we aim at 1) critically analyzing the incremental utility of imaging tools over currently available "traditional" methods of risk stratification; 2) documenting the capacity of such modalities to monitor atherosclerosis progression and regression according to lifestyle modifications and targeted therapy; and 3) evaluating the potential clinical relevance of advanced imaging, testing whether detection of such lesions may guide therapeutic decisions and changes in treatment strategy. The current understanding of modes of progression of atherosclerotic vascular disease and the appropriate use of available diagnostic tools may already now gauge the selection of patients to be enrolled in primary and secondary prevention studies. Appropriate trials should now, however, evaluate the cost-effectiveness of an aggressive search of vulnerable plaques, favoring implementation of such diagnostic tools in daily practice.

Synthesis, in vitro evaluation, and molecular modeling investigation of benzenesulfonimide peroxisome proliferator-activated receptors α antagonists.

Recent evidences suggest a moderate activation of Peroxisome Proliferator-Activated Receptors (PPARs) could be favorable in metabolic diseases, reducing side effects given from full agonists. PPAR partial agonists and antagonists represent, to date, interesting tools to better elucidate biological processes modulated by these receptors. In this work are reported new benzenesulfonimide compounds able to block PPARα, synthesized and tested by transactivation assays and gene expression analysis. Some of these compounds showed a dose-dependent antagonistic behavior on PPARα, submicromolar potency, different profiles of selectivity versus PPARγ, and a repressive effect on CPT1A expression. Dockings and molecular dynamics on properly selected benzenesulfonimide derivatives furnished fresh insights into the molecular determinant most likely responsible for PPARα antagonism.

Role of myocardial gated SPECT scintigraphy in the clinical suspicion of ischemic cardiomyopathy: discussion of an unusual case.

The case of a 72-year-old patient affected by myasthenia gravis under pyridostigmine therapy, admitted to the hospital for the onset of oppressive thoracic pain associated with mild enzyme increase, electrocardiographic and echocardiographic disorders, is discussed. Dypiridamole/gated SPECT perfusion scintigraphy at rest evidenced reduced coronary reserve at the level of the lateral wall with apical akinesia and normokinesia of mediobasal left ventricle. On coronarography, coronary arteries were free of significant stenoses and left ventricular apical akinesia. The diagnostic approach to ischemic cardiomyopathy with the correct sequence of performed diagnostic imaging led to the presumptive identification of a rare syndrome.

Combined diagnostic imaging in a patient with Forestier disease and dysphagia.

The case of a patient with dysphonia and ingravescent dysphagia, associated with crises of lipothymia "ab ingestis" is discussed. ENT examination with videolaryngoscopy evidenced a swelling of the posterior hypopharyngeal wall. X-ray study of the upper digestive tract was discontinued for inhalation. The scintigraphic study of swalling documented marked alteration of the oropharyngeal phase with phenomena of post-deglutitory aspiration. CT of the cervical vertebral column documented anterior diffuse vertebral hyperostosis of C3-C6: this finding was suggestive of Forestier disease.

Combined diagnostic imaging in a patient with suspected biliary atresia.

The case of a newborn infant of 40 days of age with persistent jaundice and blood chemistry values suggestive of cholestasis is discussed. Liver and bile duct US documented missed visualization of the gallbladder. In the suspicion of biliary atresia, hepatobiliary scintigraphy was performed; it showed preserved hepatocyte function, missed visualization of the gallbladder and absence of intestinal bile flow which confirmed the diagnostic hypothesis. Based on possible diagnostic alternatives, signs perceived and interpreted, are analyzed.