Background-The mural thrombus of abdominal aortic aneurysms (AAA) is involved in aneurysm progression via several interdependent biological processes including platelet activation. 99m Tc-annexin V (ANX) is a scintigraphic tracer that binds to phosphatidylserine exposed on activated platelets and apoptotic cells. Here, we evaluated the potential of ANX imaging to assess mural thrombus biological activity in an experimental AAA model. The clinical applicability was further tested ex vivo on human samples of excised AAA thrombi. Methods and Results-Experimental AAA was created by infusing elastase into infrarenal abdominal aorta in 17 rats, and 6 sham-operated rats were used as controls. Abdominal ANX scintigraphy was performed 2 weeks later followed by quantitative autoradiography and histological studies. Among the 13 rats which developed AAA, 11 displayed intense ANX uptake within AAA by scintigraphy. ANX uptake in the aneurysms on planar and single-photon emission computed tomography (SPECT) imaging was higher than that observed in infrarenal aorta of sham-operated controls (target/background ratio: 5.7Ϯ0.9 versus 1.33Ϯ0.21; PϽ0.005 for SPECT). Aneurysm-to-background activity ratios obtained by scintigraphy correlated with ANX activity in corresponding autoradiograms (Rϭ0.69; PϽ0.02). This activity was located in the thrombus area where activated platelets and polymorphonuclear leukocytes accumulated. Similar patterns were also found in all of the 7 human AAA thrombi harvested during surgery. Conclusions-ANX imaging may assess mural thrombus renewal activity linked to permanent flowing blood interface.
BackgroundFibrosis, which is characterized by the pathological accumulation of collagen, is recognized as an important feature of many chronic diseases, and as such, constitutes an enormous health burden. We need non-invasive specific methods for the early diagnosis and follow-up of fibrosis in various disorders. Collagen targeting molecules are therefore of interest for potential in vivo imaging of fibrosis. In this study, we developed a collagen-specific probe using a new approach that takes advantage of the inherent specificity of Glycoprotein VI (GPVI), the main platelet receptor for collagens I and III.Methodology/Principal FindingsAn anti-GPVI antibody that neutralizes collagen-binding was used to screen a bacterial random peptide library. A cyclic motif was identified, and the corresponding peptide (designated collagelin) was synthesized. Solid-phase binding assays and histochemical analysis showed that collagelin specifically bound to collagen (Kd 10−7 M) in vitro, and labelled collagen fibers ex vivo on sections of rat aorta and rat tail. Collagelin is therefore a new specific probe for collagen. The suitability of collagelin as an in vivo probe was tested in a rat model of healed myocardial infarctions (MI). Injecting Tc-99m-labelled collagelin and scintigraphic imaging showed that uptake of the probe occurred in the cardiac area of rats with MI, but not in controls. Post mortem autoradiography and histological analysis of heart sections showed that the labeled areas coincided with fibrosis. Scintigraphic molecular imaging with collagelin provides high resolution, and good contrast between the fibrotic scars and healthy tissues. The capacity of collagelin to image fibrosis in vivo was confirmed in a mouse model of lung fibrosis.Conclusion/SignificanceCollagelin is a new collagen-targeting agent which may be useful for non-invasive detection of fibrosis in a broad spectrum of diseases.
Key Points• BCL-2 homology domain 3 mimetic inhibitor ABT-737 targets leukemia initiating cells and progenitors.• Dephosphorylates RAS signaling proteins and regulates proliferation and differentiation genes detected by gene expression profiling.Myelodysplastic syndrome (MDS) transforms into an acute myelogenous leukemia (AML) with associated increased bone marrow (BM) blast infiltration. Using a transgenic mouse model, MRP8[NRASD12/hBCL-2], in which the NRAS:BCL-2 complex at the mitochondria induces MDS progressing to AML with dysplastic features, we studied the therapeutic potential of a BCL-2 homology domain 3 mimetic inhibitor, ABT-737. Treatment significantly extended lifespan, increased survival of lethally irradiated secondary recipients transplanted with cells from treated mice compared with cells from untreated mice, with a reduction of BM blasts, Lin-/Sca-1 1 /c-Kit 1 , and progenitor populations by increased apoptosis of infiltrating blasts of diseased mice assessed in vivo by technicium-labeled annexin V single photon emission computed tomography and ex vivo by annexin V/7-amino actinomycin D flow cytometry, terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling, caspase 3 cleavage, and re-localization of the NRAS:BCL-2 complex from mitochondria to plasma membrane. Phosphoprotein analysis showed restoration of wild-type (WT) AKT or protein kinase B, extracellular signal-regulated kinase 1/2 and mitogen-activated protein kinase patterns in spleen cells after treatment, which showed reduced mitochondrial membrane potential. Exon specific gene expression profiling corroborates the reduction of leukemic cells, with an increase in expression of genes coding for stem cell development and maintenance, myeloid differentiation, and apoptosis. Myelodysplastic features persist underscoring targeting of BCL-2-mediated effects on MDS-AML transformation and survival of leukemic cells. (Blood. 2013; 122(16):2864-2876
Background-The pathophysiology of infective endocarditis involves a pathogen/host tissue interaction, leading to formation of infected thrombotic vegetations. Annexin V is a ligand of phosphatidylserines exposed by activated platelets and apoptotic cells. Because vegetations are platelet-fibrin clots in which platelet proaggregant activity is enhanced by bacterial colonization, we investigated the ability of annexin V labeled with technetium Tc 99m ( 99m Tc-ANX) to provide functional imaging of these vegetations in experimental models of infective endocarditis. This ability was assessed in rabbits and rats because of the different interest of these 2 species in preclinical analysis. Methods and Results-Nonbacterial thrombotic endocarditis was induced with the use of a catheter left indwelling through the aortic or tricuspid valve, and animals were injected with either a bacterial inoculum or saline. Scintigraphic investigations were performed 5 days later and showed a higher 99m Tc-ANX uptake by vegetations in infected versus noninfected animals (ratio, 1.3 for in vivo acquisitions and 2 for autoradiography; PϽ0.0001 for all), whereas no significant uptake was present in controls. Right-sided endocarditis was associated with pulmonary uptake foci corresponding to emboli. Histological analysis of vegetations showed a specific uptake of 99m Tc-ANX at the interface between circulating blood and vegetation. In parallel, underlying myocardial tissue showed myocyte apoptosis and mucoid degeneration, without extracellular matrix degradation at this stage. Conclusions-99m Tc-ANX is suitable for functional imaging of platelet-fibrin vegetations in endocarditis, as well as embolic events.99m Tc-ANX uptake reflects mainly platelet activation in the luminal layer of vegetations. This uptake is enhanced by bacterial colonization. (Circulation. 2008;117:781-789.) Key Words: endocarditis Ⅲ imaging Ⅲ nuclear medicine Ⅲ thrombus Ⅲ valves I nfective endocarditis remains a diagnostic and therapeutic challenge, as evidenced by the stability of its incidence over time and its morbidity and mortality rates. 1,2 In addition to the direct valvular damage due to endocardial vegetations, embolic events are frequent and life-threatening complications of infective endocarditis. 3 In this context, morphological imaging such as echocardiography is useful for the diagnosis and may have a prognostic value in predicting embolic events. 4 Clinical Perspective p 789The endocardial thrombotic vegetation represents a specific model of pathogen/host tissue interaction, involving the formation of a septic thrombus leading to injury of both underlying valvular and cardiac tissue and to possible peripheral septic dissemination. 5 Pathogen-platelet molecular interactions are probably one of the main determinants of vegetation formation 6 and growth that are linked to septic thrombus formation, including platelet activation and aggregation 7 and fibrin-fibronectin deposition. 8,9 The pathological consequences of vegetation formation, including degradatio...
In this experimental study, (99m)Tc-UBI 29-41 scintigraphy permitted the early detection of acute prosthetic joint infection, and exclusion of infection in chronic sterile prosthetic joint inflammation.
These data suggest that ANX and AM allow temporal and regional evaluations of PS exposure and membrane disruption, respectively, during myocytes death after 20-min myocardial ischemia followed by reperfusion. Also, (i) apoptosis starts very early in injured myocardium, (ii) myocyte necrosis occurs later (3-4 h post-reperfusion), and (iii) most dead cells are removed from mid-myocardium between 6 h and 24 h after reperfusion.
Gastric H+-K+-ATPase activity was examined in subcellular fractions (P1, 1,000 g; P2, 20,000 g; P3, 100,000 g) obtained from fundic mucosae of fetal, newborn, and adult rats. Depending on the tissue secretory state the distribution of this enzyme activity predominates in P3, i.e., resting adult, or in P2, i.e., stimulated adult, while total enzyme activity (P2 + P3) remains constant. Enzyme activity was detected as soon as day 19 of gestation and P2 + P3 reached 2.2 +/- 0.2 mumol Pi X mg prot-1 X h-1 at parturition. H+-K+-ATPase activity steadily decreased from 4.0 +/- 0.7 mumol Pi X mg prot-1 X h-1 on day 6 after birth to approximately 0 on day 12. This activity recovered as soon as day 13 (3.5 +/- 0.6 mumol Pi X mg prot-1 X h-1) and continued to rise slowly until adulthood. Incubation of subcellular fractions with 0.1 mM omeprazole resulted in a total loss of H+-K+-ATPase activity at all the stages of development examined. These studies of functional relationship during the development between gastric acid secretion and distribution of gastric H+-K+-ATPase activity among P2 and P3 fractions indicate that this last could be considered as an index of the secretory state of the parietal cell. This enzyme's pattern of development in P2 + P3, correlated with the one previously observed for stimulated H+ secretion in intact tissue, suggest that the H+-K+-ATPase is the limiting step in response to secretagogues during postnatal period.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.