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ACS Omega Jun 2023Cesium-134 and -137 are prevalent, long-lived, radio-toxic contaminants released into the environment during nuclear accidents. Large quantities of insoluble, respirable...
Cesium-134 and -137 are prevalent, long-lived, radio-toxic contaminants released into the environment during nuclear accidents. Large quantities of insoluble, respirable Cs-bearing microparticles (CsMPs) were released into the environment during the Fukushima Daiichi nuclear accident. Monitoring for CsMPs in environmental samples is essential to understand the impact of nuclear accidents. The current detection method used to screen for CsMPs (phosphor screen autoradiography) is slow and inefficient. We propose an improved method: real-time autoradiography that uses parallel ionization multiplier gaseous detectors. This technique permits spatially resolved measurement of radioactivity while providing spectrometric data from spatially heterogeneous samples-a potential step-change technique for use after nuclear accidents for forensic analysis. With our detector configuration, the minimum detectable activities are sufficiently low for detecting CsMPs. Further, for environmental samples, sample thickness does not detrimentally affect detector signal quality. The detector can measure and resolve individual radioactive particles ≥465 μm apart. Real-time autoradiography is a promising tool for radioactive particle detection.
PubMed: 37396268
DOI: 10.1021/acsomega.3c00728 -
Journal of Nuclear Medicine : Official... Sep 2023Calcific aortic valve disease (CAVD) is a prevailing disease with increasing occurrence and no known medical therapy. mice have a high prevalence of bicuspid aortic...
Calcific aortic valve disease (CAVD) is a prevailing disease with increasing occurrence and no known medical therapy. mice have a high prevalence of bicuspid aortic valve (BAV), spontaneous aortic valve calcification, and aortic stenosis (AS). F-NaF PET/CT can detect the aortic valve calcification process in humans. However, its feasibility in preclinical models of CAVD remains to be determined. Here, we sought to validate F-NaF PET/CT for tracking murine aortic valve calcification and leveraged it to examine the development of calcification with aging and its interdependence with BAV and AS in mice. mice at 3-4 mo, 10-16 mo, and 18-24 mo underwent echocardiography, F-NaF PET/CT ( = 34, or autoradiography ( = 45)), and tissue analysis. A subset of mice underwent both PET/CT and autoradiography ( = 12). The aortic valve signal was quantified as SUV on PET/CT and as percentage injected dose per square centimeter on autoradiography. The valve tissue sections were analyzed by microscopy to identify tricuspid and bicuspid aortic valves. The aortic valve F-NaF signal on PET/CT was significantly higher at 18-24 mo ( < 0.0001) and 10-16 mo ( < 0.05) than at 3-4 mo. Additionally, at 18-24 mo BAV had a higher F-NaF signal than tricuspid aortic valves ( < 0.05). These findings were confirmed by autoradiography, with BAV having significantly higher F-NaF uptake in each age group. A significant correlation between PET and autoradiography data (Pearson = 0.79, < 0.01) established the accuracy of PET quantification. The rate of calcification with aging was significantly faster for BAV ( < 0.05). Transaortic valve flow velocity was significantly higher in animals with BAV at all ages. Finally, there was a significant correlation between transaortic valve flow velocity and aortic valve calcification by both PET/CT ( = 0.55, < 0.001) and autoradiography ( = 0.45, < 0.01). F-NaF PET/CT links valvular calcification to BAV and aging in mice and suggests that AS may promote calcification. In addition to addressing the pathobiology of valvular calcification, F-NaF PET/CT may be a valuable tool for evaluation of emerging therapeutic interventions in CAVD.
Topics: Humans; Mice; Animals; Aortic Valve; Bicuspid Aortic Valve Disease; Positron Emission Tomography Computed Tomography; Disease Models, Animal; Aortic Valve Stenosis
PubMed: 37321825
DOI: 10.2967/jnumed.123.265516 -
British Journal of Pharmacology May 2022Glucagon-like peptide-2 (GLP-2) is a pro-glucagon-derived hormone secreted from intestinal enteroendocrine L cells with actions on gut and bones. GLP-2(1-33) is cleaved...
BACKGROUND
Glucagon-like peptide-2 (GLP-2) is a pro-glucagon-derived hormone secreted from intestinal enteroendocrine L cells with actions on gut and bones. GLP-2(1-33) is cleaved by DPP-4, forming GLP-2(3-33), having low intrinsic activity and competitive antagonism properties at GLP-2 receptors. We created radioligands based on these two molecules.
EXPERIMENTAL APPROACH
The methionine in position 10 of GLP-2(1-33) and GLP-2(3-33) was substituted with tyrosine (M10Y) enabling oxidative iodination, creating [ I]-hGLP-2(1-33,M10Y) and [ I]-hGLP-2(3-33,M10Y). Both were characterized by competition binding, on-and-off-rate determination and receptor activation. Receptor expression was determined by target-tissue autoradiography and immunohistochemistry.
KEY RESULTS
Both M10Y-substituted peptides induced cAMP production via the GLP-2 receptor comparable to the wildtype peptides. GLP-2(3-33,M10Y) maintained the antagonistic properties of GLP-2(3-33). However, hGLP-2(1-33,M10Y) had lower arrestin recruitment than hGLP-2(1-33). High affinities for the hGLP-2 receptor were observed using [ I]-hGLP-2(1-33,M10Y) and [ I]-hGLP-2(3-33,M10Y) with K values of 59.3 and 40.6 nM. The latter (with antagonistic properties) had higher B and faster on and off rates compared to the former (full agonist). Both bound the hGLP-1 receptor with low affinity (K of 130 and 330 nM, respectively). Autoradiography in wildtype mice revealed strong labelling of subepithelial myofibroblasts, confirmed by immunohistochemistry using a GLP-2 receptor specific antibody that in turn was confirmed in GLP-2 receptor knock-out mice.
CONCLUSION AND IMPLICATIONS
Two new radioligands with different binding kinetics, one a full agonist and the other a weak partial agonist with antagonistic properties were developed and subepithelial myofibroblasts identified as a major site for GLP-2 receptor expression.
Topics: Animals; Binding, Competitive; Glucagon-Like Peptide-2 Receptor; Humans; Mice; Peptide Fragments; Peptides
PubMed: 34855984
DOI: 10.1111/bph.15766 -
Arteriosclerosis, Thrombosis, and... Aug 2022Patients with thoracic aortopathy are at increased risk of catastrophic aortic dissection, carrying with it substantial mortality and morbidity. Although granular medial...
BACKGROUND
Patients with thoracic aortopathy are at increased risk of catastrophic aortic dissection, carrying with it substantial mortality and morbidity. Although granular medial calcinosis (medial microcalcification) has been associated with thoracic aortopathy, its relationship to disease severity has yet to be established.
METHODS
One hundred one thoracic aortic specimens were collected from 57 patients with thoracic aortopathy and 18 control subjects. Standardized histopathologic scores, immunohistochemistry, and nanoindentation (tissue elastic modulus) were compared with the extent of microcalcification on von Kossa histology and 18F-sodium fluoride autoradiography.
RESULTS
Microcalcification content was higher in thoracic aortopathy samples with mild (n=28; 6.17 [2.71-10.39]; ≤0.00010) or moderate histopathologic degeneration (n=30; 3.74 [0.87-11.80]; <0.042) compared with control samples (n=18; 0.79 [0.36-1.90]). Alkaline phosphatase (n=26; =0.0019) and OPN (osteopontin; n=26; =0.0045) staining were increased in tissue with early aortopathy. Increasingly severe histopathologic degeneration was related to reduced microcalcification (n=82; Spearman ρ, -0.51; <0.0001)-a process closely linked with elastin loss (n=82; Spearman ρ, -0.43; <0.0001) and lower tissue elastic modulus (n=28; Spearman ρ, 0.43; =0.026).F-sodium fluoride autoradiography demonstrated good correlation with histologically quantified microcalcification (n=66; r=0.76; <0.001) and identified areas of focal weakness in vivo.
CONCLUSIONS
Medial microcalcification is a marker of aortopathy, although progression to severe aortopathy is associated with loss of both elastin fibers and microcalcification.F-sodium fluoride positron emission tomography quantifies medial microcalcification and is a feasible noninvasive imaging modality for identifying aortic wall disruption with major translational promise.
Topics: Aorta; Calcinosis; Elastin; Humans; Severity of Illness Index; Sodium Fluoride
PubMed: 35770666
DOI: 10.1161/ATVBAHA.122.317111 -
Chimia Dec 2020Radiopharmacy at ETH has worked on the development of novel PET tracers for neuro-, cardiac- and tumor imaging for many years. In this paper, our efforts on targeting...
Radiopharmacy at ETH has worked on the development of novel PET tracers for neuro-, cardiac- and tumor imaging for many years. In this paper, our efforts on targeting the glutamatergic system of the metabotropic glutamate receptor subtype 5 (mGluR5) and the ionotropic -methyl-D-aspartate (NMDA) receptor are summarized. We briefly described the principles of positron emission tomography (PET) tracer development for the central nervous system (CNS) and the radiolabeling methods used in our laboratory. To assess the radioligands, results of autoradiography, biodistribution, and metabolite studies as well as PET imaging data are discussed. Furthermore, key PET parameters for kinetic modeling and quantification methods are provided. Two mGluR5 PET tracers, [C]ABP688 and [F]PSS232, were translated in our GMP labs and evaluated in human subjects. The newly developed GluN2B PET tracer [C]Me-NB1 is currently being investigated in a first-in-human PET study and several F-18 labeled tracers are being evaluated in non-human primates in which the first-in-class will be translated for human studies.
Topics: Brain; Neuroimaging; Positron-Emission Tomography; Radiopharmaceuticals; Tissue Distribution
PubMed: 33357289
DOI: 10.2533/chimia.2020.960 -
Environment International Dec 2022A variety of isothiazolinone-containing small molecules have been registered and used as chemical additives in many household products. However, their biodistribution...
A variety of isothiazolinone-containing small molecules have been registered and used as chemical additives in many household products. However, their biodistribution and potential harmful effects on human health, especially respiratory effects, were not yet identified in sufficient detail. The purpose of this study was to investigate whether a biocide comprising a mixture of chloromethylisothiazolinone (CMIT) and methylisothiazolinone (MIT) could reach the lungs and induce lung injury when exposure occurs by two administration routes involving the respiratory tract: intratracheal and intranasal instillation. To investigate the biodistribution of CMIT/MIT, we quantified the uptake of C-labeled CMIT/MIT in experimental animals for up to seven days after intratracheal and intranasal instillation. In the toxicity study, lung injury was assessed in mice using total inflammatory cell count in bronchoalveolar lavage fluid (BALF) and lung histopathology. The results of the biodistribution study indicated that CMIT/MIT were rapidly distributed throughout the respiratory tract. Using quantitative whole-body autoradiogram analysis, we confirmed that following intranasal exposure, CMIT/MIT reached the lungs via the respiratory tract (nose-trachea-lung). After 5 min post intratracheal and intranasal instillation, the amount of radiotracer ([C]CMIT/MIT) in the lungs was 2720 ng g and 752 ng g tissue, respectively, and lung damage was observed. A higher amount of the radiotracer resulted in higher toxicity. Both intratracheal and intranasal instillation of CMIT/MIT increased inflammatory cell counts in the BALF and induced injuries in the alveoli. The frequency and the severity scores of injuries caused by intratracheal instillation were approximately-four to five times higher than those induced by intranasal instillation. Therefore, we concluded that CMIT/MIT could reach the lungs following nasal and intratracheal exposure and cause lung injuries, and the extent of injury was dependent on the exposure dose.
Topics: Humans; Animals; Mice; Lung Injury; Tissue Distribution
PubMed: 36403329
DOI: 10.1016/j.envint.2022.107643 -
Biology Mar 2022Non-invasive imaging of atherosclerosis can help in the identification of vulnerable plaque lesions. CD40 is a co-stimulatory molecule present on various immune and...
Non-invasive imaging of atherosclerosis can help in the identification of vulnerable plaque lesions. CD40 is a co-stimulatory molecule present on various immune and non-immune cells in the plaques and is linked to inflammation and plaque instability. We hypothesize that a Zr-labeled anti-CD40 monoclonal antibody (mAb) tracer has the potential to bind to cells present in atherosclerotic lesions and that CD40 Positron Emission Tomography (PET) can contribute to the detection of vulnerable atherosclerotic plaque lesions. To study this, wild-type (WT) and ApoE mice were fed a high cholesterol diet for 14 weeks to develop atherosclerosis. Mice were injected with [Zr]Zr-anti-CD40 mAb and the aortic uptake was evaluated and quantified using PET/Computed Tomography (CT) imaging. Ex vivo biodistribution was performed post-PET imaging and the uptake in the aorta was assessed with autoradiography and compared with Oil red O staining to determine the tracer potential to detect atherosclerotic plaques. On day 3 and 7 post injection, analysis of [Zr]Zr-anti-CD40 mAb PET/CT scans showed a more pronounced aortic signal in ApoE compared to WT mice with an increased aorta-to-blood uptake ratio. Autoradiography revealed [Zr]Zr-anti-CD40 mAb uptake in atherosclerotic plaque areas in ApoE mice, while no signal was found in WT mice. Clear overlap was observed between plaque areas as identified by Oil red O staining and autoradiography signal of [Zr]Zr-anti-CD40 mAb in ApoE mice. In this proof of concept study, we showed that PET/CT with [Zr]Zr-anti-CD40 mAb can detect atherosclerotic plaques. As CD40 is associated with plaque vulnerability, [Zr]Zr-anti-CD40 mAb has the potential to become a tracer to detect vulnerable atherosclerotic plaques.
PubMed: 35336782
DOI: 10.3390/biology11030408 -
JAMA Neurology Nov 2020Progressive supranuclear palsy (PSP) is a 4-repeat tauopathy. Region-specific tau aggregates establish the neuropathologic diagnosis of definite PSP post mortem. Future...
IMPORTANCE
Progressive supranuclear palsy (PSP) is a 4-repeat tauopathy. Region-specific tau aggregates establish the neuropathologic diagnosis of definite PSP post mortem. Future interventional trials against tau in PSP would strongly benefit from biomarkers that support diagnosis.
OBJECTIVE
To investigate the potential of the novel tau radiotracer 18F-PI-2620 as a biomarker in patients with clinically diagnosed PSP.
DESIGN, SETTING, AND PARTICIPANTS
In this cross-sectional study, participants underwent dynamic 18F-PI-2620 positron emission tomography (PET) from 0 to 60 minutes after injection at 5 different centers (3 in Germany, 1 in the US, and 1 in Australia). Patients with PSP (including those with Richardson syndrome [RS]) according to Movement Disorder Society PSP criteria were examined together with healthy controls and controls with disease. Four additionally referred individuals with PSP-RS and 2 with PSP-non-RS were excluded from final data analysis owing to incomplete dynamic PET scans. Data were collected from December 2016 to October 2019 and were analyzed from December 2018 to December 2019.
MAIN OUTCOMES AND MEASURES
Postmortem autoradiography was performed in independent PSP-RS and healthy control samples. By in vivo PET imaging, 18F-PI-2620 distribution volume ratios were obtained in globus pallidus internus and externus, putamen, subthalamic nucleus, substantia nigra, dorsal midbrain, dentate nucleus, dorsolateral, and medial prefrontal cortex. PET data were compared between patients with PSP and control groups and were corrected for center, age, and sex.
RESULTS
Of 60 patients with PSP, 40 (66.7%) had RS (22 men [55.0%]; mean [SD] age, 71 [6] years; mean [SD] PSP rating scale score, 38 [15]; score range, 13-71) and 20 (33.3%) had PSP-non-RS (11 men [55.0%]; mean [SD] age, 71 [9] years; mean [SD] PSP rating scale score, 24 [11]; score range, 11-41). Ten healthy controls (2 men; mean [SD] age, 67 [7] years) and 20 controls with disease (of 10 [50.0%] with Parkinson disease and multiple system atrophy, 7 were men; mean [SD] age, 61 [8] years; of 10 [50.0%] with Alzheimer disease, 5 were men; mean [SD] age, 69 [10] years). Postmortem autoradiography showed blockable 18F-PI-2620 binding in patients with PSP and no binding in healthy controls. The in vivo findings from the first large-scale observational study in PSP with 18F-PI-2620 indicated significant elevation of tracer binding in PSP target regions with strongest differences in PSP vs control groups in the globus pallidus internus (mean [SD] distribution volume ratios: PSP-RS, 1.21 [0.10]; PSP-non-RS, 1.12 [0.11]; healthy controls, 1.00 [0.08]; Parkinson disease/multiple system atrophy, 1.03 [0.05]; Alzheimer disease, 1.08 [0.06]). Sensitivity and specificity for detection of PSP-RS vs any control group were 85% and 77%, respectively, when using classification by at least 1 positive target region.
CONCLUSIONS AND RELEVANCE
This multicenter evaluation indicates a value of 18F-PI-2620 to differentiate suspected patients with PSP, potentially facilitating more reliable diagnosis of PSP.
Topics: Aged; Biomarkers; Cross-Sectional Studies; Diagnosis; Female; Fluorine Radioisotopes; Gray Matter; Humans; Male; Middle Aged; Multiple System Atrophy; Parkinson Disease; Positron-Emission Tomography; Pyridines; Sensitivity and Specificity; Severity of Illness Index; Supranuclear Palsy, Progressive; tau Proteins
PubMed: 33165511
DOI: 10.1001/jamaneurol.2020.2526 -
Brain Communications 2023A cerebral gyrus is made up of an external layer of folded cortex and an inner core of white matter. The architecture of the core has specific features that make it... (Review)
Review
A cerebral gyrus is made up of an external layer of folded cortex and an inner core of white matter. The architecture of the core has specific features that make it distinct from the white matter of the deep brain regions. Limited externally by the grey matter that covers the top of the gyrus and the neighbouring sulci, this gyral white matter is made up of a mix of fibre populations with multiple directions and destinations. The presence of densely packed fibres with multiple crossings, the proximity to the cortex and the existence of inter-regional and inter-individual variations make the task of depicting this microanatomy extremely challenging. The topic is, however, of paramount relevance for both fundamental and applied neurosciences. This fibre colocalization is crucial for the functional role of each cerebral region and is key to clinical manifestations in cases of parenchymal damage. As track tracing, imaging and dissection are based on different biological or physical principles, it is natural for their results to sometimes be different, but they are often complementary. As the amount of available information increases, it becomes fragmented due to the multiplicity of methods, target phenomena and studied species. In this scoping review, we present the key concepts and map the primary sources of evidence regarding identifying the fibre pathways that compose the gyral white matter, enabling the discussion of avenues for future research. The general pattern in which these pathways are distributed in the gyral white matter was detailed, and the main variations as a function of brain topography were explained and illustrated with typical examples.
PubMed: 38074075
DOI: 10.1093/braincomms/fcad265